#sen2geneID pmid senID geneID hgncID approvedSymbol matchString actualString startPos score flankingText matchCodeID tag SciMinerVersion SciMinerMethod inExClude inExCludeCond phenotypeOnly conflictCode hgncIDbyNR NRText editTag editUser oldGeneID oldHgncID oldApprovedSymbol oldInExClude oldInExCludeCond 299736 7841373 429641 18723 10261 ROS1 ROS ROS 26 0.3 in neurones through reduced generation of reactive oxygen species (ROS) ROS 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 299737 7841373 429645 18723 10261 ROS1 ROS ROS-mediated 17 0.3 lipofuscinogenesis accumulation of bcl-2 may reflect a mechanism for counterbalancing ROS-mediated damage or it might represent the impairment of bcl-2-dependent protection 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 299738 7841373 429645 18723 10261 ROS1 ROS ROS 29 0.3 or it might represent the impairment of bcl-2-dependent protection from ROS 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 298742 8586987 427611 20996 11179 SOD1 ALS ALS 33 0.0 cord from 5 patients with sporadic amyotrophic lateral sclerosis (ALS) ALS and 5 age-matched controls using laser microprobe mass spectrometry (LMMS) 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000727349961528597<>ScoreDetail__5468|IGFALS|0.000285127737226277__11179|SOD1|0.000727349961528597__ 0 0 0 0 0 298743 8586987 427612 20996 11179 SOD1 ALS ALS 12 0.0 of Al was not altered in any area in the ALS samples 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000727349961528597<>ScoreDetail__5468|IGFALS|0.000285127737226277__11179|SOD1|0.000727349961528597__ 0 0 0 0 0 298744 8586987 427613 20996 11179 SOD1 ALS ALS 14 0.0 Ca were increased 1.5-2-fold in the nucleus and cytoplasm of ALS neurons but not in capillaries and neuropil 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000727349961528597<>ScoreDetail__5468|IGFALS|0.000285127737226277__11179|SOD1|0.000727349961528597__ 0 0 0 0 0 298745 8586987 427614 20996 11179 SOD1 ALS ALS 16 0.0 hypothesis that Al is enriched in spinal cord of sporadic ALS as has been reported for Guamanian ALS/Parkinson's ALS Parkinson's dementia 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000727349961528597<>ScoreDetail__5468|IGFALS|0.000285127737226277__11179|SOD1|0.000727349961528597__ 0 0 0 0 0 298746 8586987 427614 20996 11179 SOD1 ALS ALS 23 0.0 of sporadic ALS as has been reported for Guamanian ALS/Parkinson's ALS Parkinson's dementia 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000727349961528597<>ScoreDetail__5468|IGFALS|0.000285127737226277__11179|SOD1|0.000727349961528597__ 0 0 0 0 0 298747 8586987 427615 20996 11179 SOD1 ALS ALS 18 0.0 consistent with reports of increased Fe in bulk samples of ALS spinal cord 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000727349961528597<>ScoreDetail__5468|IGFALS|0.000285127737226277__11179|SOD1|0.000727349961528597__ 0 0 0 0 0 297950 8588576 425841 20996 11179 SOD1 ALS ALS 4 2.9 Reduced fecundity in male ALS gene-carriers 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000851657011290818<>ScoreDetail__5468|IGFALS|0.000668635426533683__11179|SOD1|0.000851657011290818__ 0 0 0 0 0 297951 8588576 425842 20996 11179 SOD1 ALS ALS 13 2.9 genetic aspects in multicase families 89 amyotrophic lateral sclerosis (ALS) ALS and 214 Parkinson disease (PD) PD kindreds were analyzed in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000851657011290818<>ScoreDetail__5468|IGFALS|0.000668635426533683__11179|SOD1|0.000851657011290818__ 0 0 0 0 0 297952 8588576 425844 20996 11179 SOD1 ALS ALS 19 2.9 gene-carrier female (3.25, 3.25 Student's t-test P _lt_ .0003 for ALS but not for other diseases 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000851657011290818<>ScoreDetail__5468|IGFALS|0.000668635426533683__11179|SOD1|0.000851657011290818__ 0 0 0 0 0 297953 8588576 425845 20996 11179 SOD1 ALS ALS 8 2.9 The data taken together suggest that fecundity in ALS gene-carriers was reduced in males possibly as a result of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000851657011290818<>ScoreDetail__5468|IGFALS|0.000668635426533683__11179|SOD1|0.000851657011290818__ 0 0 0 0 0 297954 8588576 425846 20996 11179 SOD1 ALS ALS 13 2.9 usually accomplished well before the onset of neurological symptoms in ALS and since reduced fecundity was found in male ALS gene-carriers 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000851657011290818<>ScoreDetail__5468|IGFALS|0.000668635426533683__11179|SOD1|0.000851657011290818__ 0 0 0 0 0 297955 8588576 425846 20996 11179 SOD1 ALS ALS 22 2.9 in ALS and since reduced fecundity was found in male ALS gene-carriers these findings raise the possibility that an ALS gene 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000851657011290818<>ScoreDetail__5468|IGFALS|0.000668635426533683__11179|SOD1|0.000851657011290818__ 0 0 0 0 0 297956 8588576 425846 20996 11179 SOD1 ALS ALS 31 2.9 male ALS gene-carriers these findings raise the possibility that an ALS gene might have a pleiotrophic effect on fertility in males 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000851657011290818<>ScoreDetail__5468|IGFALS|0.000668635426533683__11179|SOD1|0.000851657011290818__ 0 0 0 0 0 297131 8841988 424206 20996 11179 SOD1 ALS ALS 21 1.4 of the spinal cord associated with amyotrophic lateral sclerosis (ALS) ALS has still not been elucidated 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00144115096667033<>ScoreDetail__5468|IGFALS|0.00119171756293758__11179|SOD1|0.00144115096667033__ 0 0 0 0 0 297132 8841988 424208 20996 11179 SOD1 SOD SOD 8 1.4 We measured the antioxidant actions of superoxide dismutase (SOD), SOD glutathione peroxidase (GSH-Px), GSH-Px and cytochrome c oxidase (CO) CO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 297133 8841988 424208 20996 11179 SOD1 ALS ALS 25 1.4 (CO) CO of the human spinal cord in patients with ALS in comparison with those in control patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00144115096667033<>ScoreDetail__5468|IGFALS|0.00119171756293758__11179|SOD1|0.00144115096667033__ 0 0 0 0 0 297134 8841988 424209 20996 11179 SOD1 SOD SOD 1 1.4 Total SOD activity in spinal cord transections from patients with sporadic ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 297135 8841988 424209 20996 11179 SOD1 ALS ALS 11 1.4 SOD activity in spinal cord transections from patients with sporadic ALS was not significantly different from the controls in ventral lateral 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00144115096667033<>ScoreDetail__5468|IGFALS|0.00119171756293758__11179|SOD1|0.00144115096667033__ 0 0 0 0 0 297136 8841988 424210 20996 11179 SOD1 ALS ALS 7 1.4 GSH-Px activity in the spinal cord of ALS patients was not very different from that in the control 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00144115096667033<>ScoreDetail__5468|IGFALS|0.00119171756293758__11179|SOD1|0.00144115096667033__ 0 0 0 0 0 297137 8841988 424211 20996 11179 SOD1 ALS ALS 18 1.4 all three regions of the spinal cord in patients with ALS although the reduction was more marked in the ventral region 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00144115096667033<>ScoreDetail__5468|IGFALS|0.00119171756293758__11179|SOD1|0.00144115096667033__ 0 0 0 0 0 297266 8899665 424393 20996 11179 SOD1 SOD1 SOD1 32 1.2 the same patients was examined for superoxide dismutase 1 (SOD1) SOD1 mutations 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 297267 8899665 424397 20996 11179 SOD1 SOD1 SOD1 3 1.2 The search for SOD1 mutations by linkage study and cycle sequencing proved negative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 297268 8899665 424398 20996 11179 SOD1 SOD1 SOD1 6 1.2 We did not find evidence for SOD1 mutations by either method of study 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 296646 8910880 423319 926 620 APP amyloid amyloid 29 1.3 damage aberrant calcium homeostasis metabolic compromise and under certain circumstances amyloid precursor protein mismetabolism 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 295070 8922414 420713 9947 5468 IGFALS ALS ALS 20 0.3 some of the clinical features of amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000941536966293652<>ScoreDetail__5468|IGFALS|0.000832372903060571__11179|SOD1|0.000941536966293652__ 0 0 0 0 0 295071 8922414 420714 9947 5468 IGFALS ALS ALS 20 0.3 play a role in the pathogenesis of disorders such as ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000941536966293652<>ScoreDetail__5468|IGFALS|0.000832372903060571__11179|SOD1|0.000941536966293652__ 0 0 0 0 0 295072 8922414 420714 18723 10261 ROS1 ROS ROS 8 0.0 It has been suggested that reactive oxygen species (ROS) ROS may play a role in the pathogenesis of disorders such 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295073 8922414 420715 14452 14374 NLRP1 NAC NAC 22 0.3 the effects of agents such as N -acetyl-L -cysteine (NAC), NAC which reduce free radical damage 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295074 8922414 420715 18723 10261 ROS1 ROS ROS 5 0.0 To examine the relationship between ROS and neural degeneration we have studied the effects of agents 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295075 8922414 420716 14452 14374 NLRP1 NAC NAC 13 0.3 mice were given a 1% solution of the glutathione precursor NAC in their drinking water for a period of 9 weeks 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295076 8922414 420717 14452 14374 NLRP1 NAC NAC 13 0.3 examination of these animals revealed that wobbler mice treated with NAC exhibited (1) 1 a significant reduction in motor neuron loss 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295077 8922414 420718 14452 14374 NLRP1 NAC NAC 25 0.3 neurons in wobbler mice and demonstrate that oral administration of NAC effectively reduces the degree of motor degeneration in wobbler mice 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295078 8922414 420722 18723 10261 ROS1 ROS ROS 15 0.0 shown to elevate intracellular levels of reactive oxygen species (ROS), ROS which in turn enhance the rate of programmed cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295079 8922414 420724 18723 10261 ROS1 ROS ROS 3 0.0 The importance of ROS in programmed cell death also has been suggested from the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295080 8922414 420724 18723 10261 ROS1 ROS ROS-induced 26 0.0 of bcl-2 family proteins which seem to act by inhibiting ROS-induced cell damage (Kane Kane et al. 1993 Zhong et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295081 8922414 420725 9947 5468 IGFALS ALS ALS 27 0.3 disease infantile spinal muscular atrophy and amyotrophic lateral sclerosis (ALS; ALS Olanow and Arendash 1994 Beal 1995 Eisen 1995 Mattson and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000941536966293652<>ScoreDetail__5468|IGFALS|0.000832372903060571__11179|SOD1|0.000941536966293652__ 0 0 0 0 0 295082 8922414 420725 18723 10261 ROS1 ROS ROS 3 0.0 In humans elevated ROS levels also have been linked to neuropathies such as Parkinson's 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295083 8922414 420726 14452 14374 NLRP1 NAC NAC 6 0.3 The compound N -acetyl-L -cysteine (NAC) NAC has been shown to inhibit ROS thus increasing the viability 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295084 8922414 420726 18723 10261 ROS1 ROS ROS 12 0.0 N -acetyl-L -cysteine (NAC) NAC has been shown to inhibit ROS thus increasing the viability of cells in culture including spinal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295085 8922414 420727 14452 14374 NLRP1 NAC NAC 3 0.3 In vivo NAC also has been shown to reduce the toxicity of compounds 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295086 8922414 420728 14452 14374 NLRP1 NAC NAC 6 0.3 In humans extensive clinical experience with NAC suggests that it is a compound of low toxicity most 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295087 8922414 420729 14452 14374 NLRP1 NAC NAC 0 0.3 NAC seems to exert these effects by acting directly as an 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295088 8922414 420730 18723 10261 ROS1 ROS ROS 24 0.0 examined the possibility that agents that inhibit the formation of ROS may be useful as therapeutic agents in vivo for certain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295089 8922414 420737 14452 14374 NLRP1 NAC NAC 5 0.3 To examine the effects of NAC on motor neuron degeneration in vivo we treated wobbler mice 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295090 8922414 420737 14452 14374 NLRP1 NAC NAC 20 0.3 degeneration in vivo we treated wobbler mice per os with NAC over a period of 9 weeks 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295091 8922414 420738 14452 14374 NLRP1 NAC NAC 4 0.3 The results demonstrate that NAC treatment reduces the decline in several important morphological and functional 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295092 8922414 420792 1617 1027 BDH1 BDH BDH 21 0.0 water supplemented with either 1% N -acetyl-L -cysteine (B24001-30, B24001-30 BDH Chemicals Poole UK L -alanine (A5824, A5824 Sigma St Louis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295093 8922414 420793 14452 14374 NLRP1 NAC NAC-treated 13 0.3 solutions were adjusted to the same pH and molarity as NAC-treated animals (61.2 61.2 m M and served as control agents 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295094 8922414 420796 14452 14374 NLRP1 NAC NAC-treated 1 0.3 Four-week-old NAC-treated mice drank an average of 3.4 _amp_#177 0.6 ml per 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295095 8922414 420797 14452 14374 NLRP1 NAC NAC 4 0.3 The mean quantity of NAC ingested was ~2.3 mg/gm mg gm body weight 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295096 8922414 420799 14452 14374 NLRP1 NAC NAC 4 0.3 The mean quantity of NAC received was 2.1 mg/gm mg gm body weight 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295097 8922414 420802 14452 14374 NLRP1 NAC NAC-treated 3 0.3 Even within the NAC-treated group the distinction between wr/wr wr wr and NW mice 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295098 8922414 420816 14452 14374 NLRP1 NAC NAC-treated 18 0.3 of the facial nerve for wr/wr wr wr NW and NAC-treated wr/wr wr wr and NW mice is shown in Figure 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295099 8922414 420818 14452 14374 NLRP1 NAC NAC-treated 1 0.3 In NAC-treated wr/wr wr wr mice [wr/wr(N)] wr wr N this reduction 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295100 8922414 420820 14452 14374 NLRP1 NAC NAC 35 0.3 nerve as compared with NW controls wobbler animals treated with NAC do not show this loss of motor axons instead giving 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295101 8922414 420832 14452 14374 NLRP1 NAC NAC-treated 12 0.3 the distribution of axon areas in wr/wr wr wr and NAC-treated wr/wr wr wr mice respectively 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295102 8922414 420835 14452 14374 NLRP1 NAC NAC-treated 2 0.3 In contrast NAC-treated wobbler mice do not show a marked reduction in axon 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295103 8922414 420837 14452 14374 NLRP1 NAC NAC 13 0.3 the wobbler controls are significantly different from both the wr NAC treatment and NW groups pair-wise comparisons wr/wr wr wr vs 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295104 8922414 420839 14452 14374 NLRP1 NAC NAC 12 0.3 given above demonstrate that oral treatment of wobbler mice with NAC can reduce significantly the degree of axonal atrophy and loss 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295105 8922414 420842 14452 14374 NLRP1 NAC NAC 5 0.3 To examine the effects of NAC on neuromuscular aspects of the forelimb we took 10 micro 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295106 8922414 420845 14452 14374 NLRP1 NAC NAC 28 0.3 neurons by 9 weeks of age wobbler mice treated with NAC exhibited significantly greater numbers of ChAT-positive neurons than wr/wr wr 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295107 8922414 420846 14452 14374 NLRP1 NAC NAC-wobbler 1 0.3 However NAC-wobbler mice still exhibited a substantial loss of ChAT-positive neurons as 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295108 8922414 420848 14452 14374 NLRP1 NAC NAC 5 0.3 To determine the effects of NAC treatment on the innervation targets of these spinal motor neurons 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295109 8922414 420849 14452 14374 NLRP1 NAC NAC 10 0.3 As shown in Figure 4 A B animals treated with NAC show a significant increase in the overall mass of the 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295110 8922414 420850 14452 14374 NLRP1 NAC NAC 3 0.3 Thus treatment with NAC reduces the degree of overt muscular atrophy that is induced 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295111 8922414 420851 14452 14374 NLRP1 NAC NAC 7 0.3 To delineate more clearly the effects of NAC on muscle morphology within the distal forelimb we determined cross-sectional 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295112 8922414 420852 14452 14374 NLRP1 NAC NAC 13 0.3 shown in Figure 4 C indicate that animals treated with NAC show a marked increase in mean fiber area (~603 ~603 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295113 8922414 420854 14452 14374 NLRP1 NAC NAC 7 0.3 These data demonstrate that oral administration of NAC can reduce significantly motor neuron loss and axonal atrophy in 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295114 8922414 420858 14452 14374 NLRP1 NAC NAC 8 0.3 These results demonstrate that although wobbler mice receiving NAC do exhibit a significant reduction in forelimb function they perform 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295115 8922414 420859 14452 14374 NLRP1 NAC NAC 6 0.3 These data suggest that treatment with NAC does result in some reduction in the functional losses that 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295116 8922414 420861 14452 14374 NLRP1 NAC NAC 5 0.3 Previous work has suggested that NAC acts in part by increasing intracellular supplies of cysteine the 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295117 8922414 420864 14452 14374 NLRP1 NAC NAC 5 0.3 To determine the ability of NAC to enhance the free-radical scavenging ability of the GPx system 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295118 8922414 420866 14452 14374 NLRP1 NAC NAC 9 0.3 As shown in Figure 6 animals that received NAC in their drinking water exhibited a substantial increase in GPx 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295119 8922414 420867 14452 14374 NLRP1 NAC NAC 16 0.3 similar to that of NW mice that did not receive NAC supplementation 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295120 8922414 420868 14452 14374 NLRP1 NAC NAC 6 0.3 To further assess the ability of NAC to effect GPx activity levels in non-wobbler mice we injected 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295121 8922414 420868 14452 14374 NLRP1 NAC NAC 28 0.3 (glucose glucose treatment group daily with 1 mg/gm mg gm NAC for 3 d before the analysis 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295122 8922414 420870 14452 14374 NLRP1 NAC NAC 6 0.3 These results demonstrate the ability of NAC to enhance antioxidant activity in tissues affected by the wobbler 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295123 8922414 420873 14452 14374 NLRP1 NAC NAC 8 0.3 The results demonstrate that daily oral administration of NAC significantly reduces the degeneration of lower motor neurons in wobbler 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295124 8922414 420874 14452 14374 NLRP1 NAC NAC 9 0.3 For motor axons of the facial nerve application of NAC resulted in a generalized increase in axon number and caliber 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295125 8922414 420875 14452 14374 NLRP1 NAC NAC 5 0.3 Within the cervical spinal cord NAC reduced losses of choline acetyltransferase-positive neurons 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295126 8922414 420879 9947 5468 IGFALS ALS ALS 16 0.3 play an important role in several human neurodegenerative diseases including ALS a disorder that shares some of the features of the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000941536966293652<>ScoreDetail__5468|IGFALS|0.000832372903060571__11179|SOD1|0.000941536966293652__ 0 0 0 0 0 295127 8922414 420879 18723 10261 ROS1 ROS ROS 1 0.0 However ROS have been suggested to play an important role in several 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295128 8922414 420880 18723 10261 ROS1 ROS ROS 6 0.0 Consistent with this agents that inhibit ROS have been shown to be neuroprotective both in vitro and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295129 8922414 420881 14452 14374 NLRP1 NAC NAC 0 0.3 NAC has been shown previously in several of these paradigms to 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295130 8922414 420882 14452 14374 NLRP1 NAC NAC 3 0.3 The ability of NAC to reduce the loss of these lower motor neurons in 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295131 8922414 420882 14452 14374 NLRP1 NAC NAC 39 0.3 in the cervical spinal cord suggests a means by which NAC may act to reduce local ROS levels 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295132 8922414 420882 18723 10261 ROS1 ROS ROS 45 0.0 a means by which NAC may act to reduce local ROS levels 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295133 8922414 420883 14452 14374 NLRP1 NAC NAC 5 0.3 Previous work also demonstrates that NAC directly supports glutathione synthesis in neural cells thus reducing intracellular 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295134 8922414 420883 18723 10261 ROS1 ROS ROS 16 0.0 directly supports glutathione synthesis in neural cells thus reducing intracellular ROS levels (Mayer Mayer and Noble 1994 kappa b (Brennan Brennan 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295135 8922414 420884 14452 14374 NLRP1 NAC NAC 4 0.3 These data suggest that NAC may exert survival-promoting effects in a manner independent of its 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295136 8922414 420885 14452 14374 NLRP1 NAC NAC 0 0.3 NAC has been used previously in a limited trial over a 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295137 8922414 420886 14452 14374 NLRP1 NAC NAC 11 0.3 no net clinical improvement was observed in patients treated with NAC segregation of ALS cases into bulbar and limb onset groups 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295138 8922414 420886 9947 5468 IGFALS ALS ALS 14 0.3 improvement was observed in patients treated with NAC segregation of ALS cases into bulbar and limb onset groups is informative 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000941536966293652<>ScoreDetail__5468|IGFALS|0.000832372903060571__11179|SOD1|0.000941536966293652__ 0 0 0 0 0 295139 8922414 420887 9947 5468 IGFALS ALS ALS 1 0.3 In ALS cases of bulbar onset NAC did not improve survival 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000941536966293652<>ScoreDetail__5468|IGFALS|0.000832372903060571__11179|SOD1|0.000941536966293652__ 0 0 0 0 0 295140 8922414 420887 14452 14374 NLRP1 NAC NAC 6 0.3 In ALS cases of bulbar onset NAC did not improve survival 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295141 8922414 420888 14452 14374 NLRP1 NAC NAC 8 0.3 However in patients with the limb onset form NAC does seem to improve survival (NAC NAC 74% 28/38; 28 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295142 8922414 420888 14452 14374 NLRP1 NAC NAC 14 0.3 limb onset form NAC does seem to improve survival (NAC NAC 74% 28/38; 28 38 vehicle 51% 22/43) 22 43 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295143 8922414 420890 14452 14374 NLRP1 NAC NAC 10 0.3 It is interesting to speculate that the differential availability of NAC to these two neural populations may underlie the differences in 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295144 8922414 420891 9947 5468 IGFALS ALS ALS 9 0.3 For comparison one current therapy that shows promise for ALS patients is studies with the glutamate antagonist riluzole (100 100 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000941536966293652<>ScoreDetail__5468|IGFALS|0.000832372903060571__11179|SOD1|0.000941536966293652__ 0 0 0 0 0 295145 8922414 420892 9947 5468 IGFALS ALS ALS 17 0.3 month period there are some indications of clinical improvements in ALS patients suggesting that aberrant glutamate metabolism (and and perhaps ROS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000941536966293652<>ScoreDetail__5468|IGFALS|0.000832372903060571__11179|SOD1|0.000941536966293652__ 0 0 0 0 0 295146 8922414 420892 18723 10261 ROS1 ROS ROS 26 0.0 ALS patients suggesting that aberrant glutamate metabolism (and and perhaps ROS may play a role in this disorder (Bensimon Bensimon et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295147 8922414 420893 4649 2169 CNTF CNTF CNTF 14 0.3 wobbler mice has been treated previously with a combination of CNTF (1 1 mg/kg) mg kg and BDNF (5 5 mg/kg) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295148 8922414 420893 1624 1033 BDNF BDNF BDNF 18 0.3 a combination of CNTF (1 1 mg/kg) mg kg and BDNF (5 5 mg/kg) mg kg by subcutaneous injection three times 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 295149 8922414 420895 14452 14374 NLRP1 NAC NAC 34 0.3 function over a similar time frame than those treated with NAC 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295150 8922414 420897 14452 14374 NLRP1 NAC NAC 8 0.3 For example to be accessible to motor neurons NAC must be taken up via contact with somatic tissue through 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295151 8922414 420898 14452 14374 NLRP1 NAC NAC 3 0.3 Oral administration of NAC does result in enhanced GPx activity in the cervical spinal 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295152 8922414 420899 14452 14374 NLRP1 NAC NAC 26 0.3 axonal transport may be impaired in their ability to accumulate NAC and its metabolites thus limiting its potential therapeutic effects 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295153 8922414 420902 14452 14374 NLRP1 NAC NAC 8 0.3 In addition it is important to realize that NAC may be affecting only a portion of the pathways involved 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295154 8922414 420904 14452 14374 NLRP1 NAC NAC 8 0.3 Despite this the use of agents such as NAC would seem to be a practical approach to enhancing cell 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295155 8922414 420905 14452 14374 NLRP1 NAC NAC 20 0.3 intrathecal implantation of proteins which are quite labile in vivo NAC can be given per os over dispersed intervals 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295156 8922414 420906 14452 14374 NLRP1 NAC NAC 0 0.3 NAC is also an inexpensive drug possessing few side effects and 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295157 8922414 420907 14452 14374 NLRP1 NAC NAC 19 0.3 to that of several human neurodegenerative disorders the application of NAC may prove useful in treating other mammalian neurodegenerative diseases 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295158 8922414 420916 14452 14374 NLRP1 NAC NAC 0 0.3 NAC reduces axonal loss in wobbler facial nerve 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295159 8922414 420920 14452 14374 NLRP1 NAC NAC-treated 6 0.3 Control-treated wr/wr wr wr mice n = 17 NAC-treated wr/wr wr wr mice n = 11 NW mice n 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295160 8922414 420922 8306 4268 GIF GIF GIF 25 0.0 _lt_ 0.030 View Larger Version of this Image (61K 61K GIF file 1 JUMiner_v2.2 1 0 0 2 4268 TotalCon:3<>4268|GIF|2694|Complete__7097|MIF|4282|Complete__7408|MT3|4504|Complete__<>AvaiableGeneRif=3<>BEST:4268|GIF|0.000666666666666667<>ScoreDetail__7097|MIF|0.0001038316122115__7408|MT3|0.000280701754385965__4268|GIF|0.000666666666666667__ 0 0 0 0 0 295161 8922414 420924 14452 14374 NLRP1 NAC NAC 0 0.3 NAC prevents losses in axon caliber in wobbler mice 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295162 8922414 420928 14452 14374 NLRP1 NAC NAC-treated 5 0.3 C Axon distribution of NAC-treated wr/wr wr wr mice n = 6 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295163 8922414 420931 8306 4268 GIF GIF GIF 24 0.0 the mean View Larger Version of this Image (43K 43K GIF file 1 JUMiner_v2.2 1 0 0 2 4268 TotalCon:3<>4268|GIF|2694|Complete__7097|MIF|4282|Complete__7408|MT3|4504|Complete__<>AvaiableGeneRif=3<>BEST:4268|GIF|0.000666666666666667<>ScoreDetail__7097|MIF|0.0001038316122115__7408|MT3|0.000280701754385965__4268|GIF|0.000666666666666667__ 0 0 0 0 0 295164 8922414 420933 14452 14374 NLRP1 NAC NAC 0 0.3 NAC reduces the loss of ChAT-positive neurons in the cervical spinal 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295165 8922414 420936 8306 4268 GIF GIF GIF 28 0.0 wr group View Larger Version of this Image (65K 65K GIF file 1 JUMiner_v2.2 1 0 0 2 4268 TotalCon:3<>4268|GIF|2694|Complete__7097|MIF|4282|Complete__7408|MT3|4504|Complete__<>AvaiableGeneRif=3<>BEST:4268|GIF|0.000666666666666667<>ScoreDetail__7097|MIF|0.0001038316122115__7408|MT3|0.000280701754385965__4268|GIF|0.000666666666666667__ 0 0 0 0 0 295166 8922414 420938 14452 14374 NLRP1 NAC NAC 0 0.3 NAC reduces the atrophy of forelimb muscles in wobbler mice 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295167 8922414 420949 8306 4268 GIF GIF GIF 31 0.0 _lt_ 0.001 View Larger Version of this Image (50K 50K GIF file 1 JUMiner_v2.2 1 0 0 2 4268 TotalCon:3<>4268|GIF|2694|Complete__7097|MIF|4282|Complete__7408|MT3|4504|Complete__<>AvaiableGeneRif=3<>BEST:4268|GIF|0.000666666666666667<>ScoreDetail__7097|MIF|0.0001038316122115__7408|MT3|0.000280701754385965__4268|GIF|0.000666666666666667__ 0 0 0 0 0 295168 8922414 420951 14452 14374 NLRP1 NAC NAC 0 0.3 NAC reduces functional losses in the forelimb of wobbler mice 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295169 8922414 420957 8306 4268 GIF GIF GIF 35 0.0 _lt_ 0.001 View Larger Version of this Image (55K 55K GIF file 1 JUMiner_v2.2 1 0 0 2 4268 TotalCon:3<>4268|GIF|2694|Complete__7097|MIF|4282|Complete__7408|MT3|4504|Complete__<>AvaiableGeneRif=3<>BEST:4268|GIF|0.000666666666666667<>ScoreDetail__7097|MIF|0.0001038316122115__7408|MT3|0.000280701754385965__4268|GIF|0.000666666666666667__ 0 0 0 0 0 295170 8922414 420959 14452 14374 NLRP1 NAC NAC 0 0.3 NAC treatment augments glutathione peroxidase (GPx) GPx levels in the cervical 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 295171 8922414 420964 8306 4268 GIF GIF GIF 42 0.0 _lt_ 0.01 View Larger Version of this Image (66K 66K GIF file 1 JUMiner_v2.2 1 0 0 2 4268 TotalCon:3<>4268|GIF|2694|Complete__7097|MIF|4282|Complete__7408|MT3|4504|Complete__<>AvaiableGeneRif=3<>BEST:4268|GIF|0.000666666666666667<>ScoreDetail__7097|MIF|0.0001038316122115__7408|MT3|0.000280701754385965__4268|GIF|0.000666666666666667__ 0 0 0 0 0 297782 9044305 425433 20996 11179 SOD1 SOD SOD 10 0.9 supports the concept that decreases in Cu Zn-superoxide dismutase (SOD) SOD activity causes apoptotic cell death in neuronal cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294098 9092140 418545 20996 11179 SOD1 ALS ALS 16 1.4 dismutase (CuZn-SOD) CuZn-SOD are associated with amyotrophic lateral sclerosis (ALS) ALS suggests that the disease arises from a perturbation of the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00171478594850555<>ScoreDetail__5468|IGFALS|0.000241298184231164__11179|SOD1|0.00171478594850555__ 0 0 0 0 0 294099 9092140 418549 20996 11179 SOD1 SOD SOD 0 1.4 SOD research is an important step for a better understanding of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294100 9092140 418549 20996 11179 SOD1 ALS ALS 14 1.4 important step for a better understanding of the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00171478594850555<>ScoreDetail__5468|IGFALS|0.000241298184231164__11179|SOD1|0.00171478594850555__ 0 0 0 0 0 294634 9172131 419809 20996 11179 SOD1 ALS ALS 16 2.7 central role in the pathogenesis of amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294635 9172131 419810 18723 10261 ROS1 ROS ROS 21 0.0 cells counteract the deleterious effects of reactive oxygen species (ROS) ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294636 9172131 419811 18723 10261 ROS1 ROS ROS-induced 6 0.0 Neurons may be particularly vulnerable to ROS-induced oxidative DNA damage this is repaired by the base-excision repair 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294637 9172131 419812 878 587 APEX1 APE APE 12 3.9 of the pivotal BER protein apurinic/apyrimidinic apurinic apyrimidinic endonuclease (APE) APE were determined in 11 patients with sporadic ALS and six 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294638 9172131 419812 20996 11179 SOD1 ALS ALS 20 2.7 endonuclease (APE) APE were determined in 11 patients with sporadic ALS and six age-matched control subjects 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294639 9172131 419813 878 587 APEX1 APE APE 0 3.9 APE levels ( p _amp_#60 0.003 and activity ( p _amp_#60 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294640 9172131 419813 20996 11179 SOD1 ALS ALS 16 2.7 and activity ( p _amp_#60 0.000007 were significantly lower in ALS subjects than in controls 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294641 9172131 419814 20996 11179 SOD1 ALS ALS 4 2.7 These findings suggest that ALS brain tissue is inefficient in repairing oxidative DNA damage 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294642 9172131 419815 20996 11179 SOD1 ALS ALS 3 2.7 Amyotrophic lateral sclerosis (ALS) ALS is a progressive age-related neurological disorder of unknown etiology associated 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294643 9172131 419815 20996 11179 SOD1 ALS ALS 28 2.7 motor neurons in the motor cortex and spinal cord 1 ALS occurs in both sporadic (~80-90_amp_#37; ~80-90_amp_#37 cases and familial (5-10_amp_#37; 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294644 9172131 419815 20996 11179 SOD1 SOD1 SOD1 65 2.9 major cellular antioxidant enzyme Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 in familial ALS subjects 3 has initiated an intense investigation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294645 9172131 419815 20996 11179 SOD1 ALS ALS 68 2.7 enzyme Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 in familial ALS subjects 3 has initiated an intense investigation into the role 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294646 9172131 419815 20996 11179 SOD1 ALS ALS 86 2.7 into the role of oxidative stress in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294647 9172131 419816 20996 11179 SOD1 ALS ALS 23 2.7 oxidative damage to protein 4 5 have been identified in ALS subjects 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294648 9172131 419817 20996 11179 SOD1 ALS ALS 15 2.7 i.e 8-oxodeoxyguanosine has been detected in spinal cord tissue of ALS subjects 6 While these findings strongly support a role for 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294649 9172131 419817 20996 11179 SOD1 ALS ALS 39 2.7 mitochondrial dysfunction in the disease fewer than 20_amp_#37 of familial ALS cases map to the SOD1 gene 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294650 9172131 419817 20996 11179 SOD1 SOD1 SOD1 44 2.9 fewer than 20_amp_#37 of familial ALS cases map to the SOD1 gene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294651 9172131 419818 20996 11179 SOD1 ALS ALS 7 2.7 Moreover the etiology and pathogenesis of sporadic ALS are unknown and Guam ALS has been epidemiologically associated with 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294652 9172131 419818 20996 11179 SOD1 ALS ALS 12 2.7 etiology and pathogenesis of sporadic ALS are unknown and Guam ALS has been epidemiologically associated with exposure to the DNAdamaging agent 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294653 9172131 419819 20996 11179 SOD1 ALS ALS 14 2.7 the hypothesis originally proposed by Bradley and Krasin 8 that ALS subjects have an abnormality (either either acquired or inherited in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294654 9172131 419820 20996 11179 SOD1 ALS ALS 11 2.7 levels of oxidative DNA damage in spinal cord tissue of ALS subjects 6 suggests that repair of oxidative DNA damage may 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294655 9172131 419821 878 587 APEX1 APE APE 43 3.9 abasic site is repaired by apurinic/apyrimidinic apurinic apyrimidinic endonuclease (APE) APE 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294656 9172131 419822 878 587 APEX1 APE APE 0 3.9 APE the pivotal step in BER is found in both the 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294657 9172131 419822 878 587 APEX1 APE APE 26 3.9 mitochondria (~65 ~65 kDa 10 A reduction or loss of APE would be extremely detrimental to a neuron and could conceivably 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294658 9172131 419822 20996 11179 SOD1 ALS ALS 73 2.7 cytoskeletal proteins and membrane (e.g e.g lipids all features of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294659 9172131 419823 878 587 APEX1 APE APE 0 3.9 APE is a bifunctional protein with separate domains for DNA repair 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294660 9172131 419824 878 587 APEX1 APE APE 1 3.9 Therefore APE possesses multiple cellular functions and its deficiency could have profound 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294661 9172131 419825 878 587 APEX1 APE APE 5 3.9 In fact lack of the APE gene is lethal to embryonic mutant mice (gestational gestational day 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294662 9172131 419826 878 587 APEX1 APE APE 10 3.9 The present study aimed to determine whether the BER protein APE is deficient in the brains of ALS subjects 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294663 9172131 419826 20996 11179 SOD1 ALS ALS 17 2.7 the BER protein APE is deficient in the brains of ALS subjects 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294664 9172131 419828 20996 11179 SOD1 ALS ALS 13 2.7 first time that DNA repair has been directly examined in ALS brain tissue 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294665 9172131 419829 20996 11179 SOD1 ALS ALS 26 2.7 _amp_#177 4.8 years n _amp_#61 6 and subjects with sporadic ALS (66.4 66.4 _amp_#177 3.4 years n _amp_#61 11 was obtained 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294666 9172131 419832 878 587 APEX1 APE APE 0 3.9 APE levels were determined in human brain tissue extracts and compared 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294667 9172131 419832 878 587 APEX1 APE APE 24 3.9 of HeLa cells (positive positive control and with recombinant human APE (a a hist_amp_#237 dine-tagged full-length human protein provided by Dr 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294668 9172131 419836 3778 10620 CCL21 ECL ECL 21 0.0 using a HRP-conjugated goat anti-rabbit antibody and enhanced chemiluminescence (ECL, ECL Amersham according to the manufacturer_amp_#39 s instructions 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294669 9172131 419840 878 587 APEX1 APE APE 0 3.9 APE activity was determined in human brain tissue extracts by measuring 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294670 9172131 419842 19573 10691 SDS SDS SDS 11 0.0 reaction was stopped by the addition of loading buffer containing SDS and chilling samples were loaded onto a 0.9_amp_#37 agarose gel 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000519714331184849<>ScoreDetail__10691|SDS|0.000264830508474576__19440|SBDS|0.000519714331184849__ 0 0 0 0 0 294671 9172131 419844 878 587 APEX1 APE APE 0 3.9 APE levels and activity (ability ability to repair apurinic sites in 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294672 9172131 419844 20996 11179 SOD1 ALS ALS 27 2.7 extracts prepared from the frontal cortex of patients with sporadic ALS and age-matched controls with non-neurological disease 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294673 9172131 419845 878 587 APEX1 APE APE 10 3.9 There was no significant correlation between post mortem interval and APE levels in control ( r _amp_#61 _amp_#45 0.5 or ALS 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294674 9172131 419845 20996 11179 SOD1 ALS ALS 19 2.7 APE levels in control ( r _amp_#61 _amp_#45 0.5 or ALS ( r _amp_#61 _amp_#45 0.2 tissue 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294675 9172131 419846 878 587 APEX1 APE APE 1 3.9 Cortical APE levels were reduced by 3-4_amp_#215 3 ( p _amp_#60 0.003 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294676 9172131 419846 20996 11179 SOD1 ALS ALS 12 2.7 were reduced by 3-4_amp_#215 3 ( p _amp_#60 0.003 in ALS subjects compared with those in age-matched controls ( Fig 1 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294677 9172131 419847 20996 11179 SOD1 ALS ALS 14 2.7 50 microg from several control ( n _amp_#61 4 and ALS ( n _amp_#61 3 subjects were analyzed by Western blotting 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294678 9172131 419847 13410 7211 MPG MPG MPG 38 1.1 to the human BER protein N -methylpurine DNA glycosylase (MPG) MPG and purified human MPG (positive positive control (both both provided 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294679 9172131 419847 13410 7211 MPG MPG MPG 42 1.1 protein N -methylpurine DNA glycosylase (MPG) MPG and purified human MPG (positive positive control (both both provided by Dr Sankar Mitra 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294680 9172131 419848 878 587 APEX1 APE APE 3 3.9 In contrast to APE levels cortical MPG levels in ALS subjects were not significantly 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294681 9172131 419848 13410 7211 MPG MPG MPG 6 1.1 In contrast to APE levels cortical MPG levels in ALS subjects were not significantly different ( p 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294682 9172131 419848 20996 11179 SOD1 ALS ALS 9 2.7 In contrast to APE levels cortical MPG levels in ALS subjects were not significantly different ( p _amp_#60 0.47 from 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294683 9172131 419850 878 587 APEX1 APE APE 1 3.9 Like APE levels APE activity was significantly lower ( p _amp_#60 0.000007 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294684 9172131 419850 878 587 APEX1 APE APE 3 3.9 Like APE levels APE activity was significantly lower ( p _amp_#60 0.000007 in ALS 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294685 9172131 419850 20996 11179 SOD1 ALS ALS 13 2.7 APE activity was significantly lower ( p _amp_#60 0.000007 in ALS subjects than in age-matched controls 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294686 9172131 419851 20996 11179 SOD1 ALS ALS 21 2.7 species ROS plays a central role in the pathogenesis of ALS 18 The hypothesis under study is that the variety of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294687 9172131 419851 20996 11179 SOD1 ALS ALS 39 2.7 the variety of biochemical and neuropathological changes that occur in ALS results from an underlying abnormality in repair of oxidative DNA 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294688 9172131 419851 18723 10261 ROS1 ROS ROS 12 0.0 to suggest that oxidative stress (e.g e.g reactive oxygen species ROS plays a central role in the pathogenesis of ALS 18 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294689 9172131 419852 13410 7211 MPG MPG MPG 41 1.1 removed by a DNA glycosylase (e.g e.g formamidopyrimidine DNA glycosylase MPG 20 21 and the resulting apurinic site repaired by APE 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294690 9172131 419852 878 587 APEX1 APE APE 50 3.9 MPG 20 21 and the resulting apurinic site repaired by APE 8-Oxodeoxyguanosine levels are elevated in ALS spinal cord tissue 6 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294691 9172131 419852 20996 11179 SOD1 ALS ALS 56 2.7 apurinic site repaired by APE 8-Oxodeoxyguanosine levels are elevated in ALS spinal cord tissue 6 suggesting that repair of oxidative DNA 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294692 9172131 419852 18723 10261 ROS1 ROS ROS 3 0.0 Oxidative damage by ROS induces DNA strand breaks (e.g e.g apurinic sites DNA adduct 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294693 9172131 419853 878 587 APEX1 APE APE 11 3.9 from the present studies indicate that the pivotal BER protein APE is severely deficient in ALS brain tissue 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294694 9172131 419853 20996 11179 SOD1 ALS ALS 16 2.7 that the pivotal BER protein APE is severely deficient in ALS brain tissue 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294695 9172131 419854 13410 7211 MPG MPG MPG 10 1.1 The lack of a similar reduction in the BER protein MPG in ALS brain tissue suggests a selective abnormality in APE 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 294696 9172131 419854 20996 11179 SOD1 ALS ALS 12 2.7 of a similar reduction in the BER protein MPG in ALS brain tissue suggests a selective abnormality in APE 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294697 9172131 419854 878 587 APEX1 APE APE 20 3.9 MPG in ALS brain tissue suggests a selective abnormality in APE 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294698 9172131 419855 878 587 APEX1 APE APE 1 3.9 Interestingly APE activity has also been examined in lymphocytes from patients with 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294699 9172131 419855 20996 11179 SOD1 ALS ALS 23 2.7 ( n _amp_#61 3 and familial ( n _amp_#61 2 ALS using a double-stranded oligonucleotide probe containing a single AP site 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294700 9172131 419855 878 587 APEX1 APE APE 35 3.9 a double-stranded oligonucleotide probe containing a single AP site 22 APE activity was shown to be similarly reduced in lymphocytes of 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294701 9172131 419855 20996 11179 SOD1 ALS ALS 49 2.7 to be similarly reduced in lymphocytes of sporadic and familial ALS subjects when compared with age-matched nonneurological controls 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294702 9172131 419856 878 587 APEX1 APE APE 4 3.9 A similar reduction of APE in both ALS brain and lymphocyte tissue 22 suggests that 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294703 9172131 419856 20996 11179 SOD1 ALS ALS 7 2.7 A similar reduction of APE in both ALS brain and lymphocyte tissue 22 suggests that the DNA repair 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294704 9172131 419856 878 587 APEX1 APE APE 28 3.9 deficit is systemic and possibly due to an abnormality in APE regulation or a gene mutation 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294705 9172131 419857 878 587 APEX1 APE APE 4 3.9 Detection of several missense APE gene mutations 22 in lymphocyte DNA from patients with sporadic 1 JUMiner_v2.2 1 0 0 2 587 TotalCon:2<>587|APEX1|328|Complete__25523|CCDC88A|55704|Complete__<>AvaiableGeneRif=2<>BEST:587|APEX1|0.00120378405049938<>ScoreDetail__25523|CCDC88A|0.000799200799200799__587|APEX1|0.00120378405049938__ 0 0 0 0 0 294706 9172131 419857 20996 11179 SOD1 ALS ALS 17 2.7 22 in lymphocyte DNA from patients with sporadic and familial ALS suggests the latter may be the more likely mechanism 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294707 9172131 419858 20996 11179 SOD1 ALS ALS 10 2.7 The present findings and those of other investigators indicate that ALS brain and lymphocyte tissue are likely to be inefficient in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294708 9172131 419860 20996 11179 SOD1 ALS ALS 15 2.7 may explain the unexpected death of a significant number of ALS patients 2 years after they received irradiation therapy of the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 294709 9172131 419861 20996 11179 SOD1 ALS ALS 18 2.7 of BER in maintaining neuronal integrity and its importance in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000811179968626422<>ScoreDetail__5468|IGFALS|0.000600655497956466__11179|SOD1|0.000811179968626422__ 0 0 0 0 0 293238 9337068 416912 926 620 APP amyloid amyloid 20 1.3 disease has not been reached yet the involvement of the amyloid precursor protein (APP) APP and betaA4 (A A beta in 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 293239 9337068 416912 926 620 APP APP APP 23 0.6 reached yet the involvement of the amyloid precursor protein (APP) APP and betaA4 (A A beta in the pathologic changes advances 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293240 9337068 416914 926 620 APP APP APP 34 0.6 oxidation and that free oxygen radicals may be involved in APP metabolism 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293241 9337068 416917 926 620 APP APP APP 9 0.6 reduction of Cu(II) Cu II to Cu(I) Cu I by APP involves an electron-transfer reaction and could also lead to a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293717 9350962 417499 20996 11179 SOD1 ALS ALS 20 2.2 the spinal cord of transgenic familial amyotrophic lateral sclerosis (ALS) ALS mice and (2) 2 in the selectively vulnerable gerbil hippocampal 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00101682528081854<>ScoreDetail__5468|IGFALS|0.000274530069116982__11179|SOD1|0.00101682528081854__ 0 0 0 0 0 293718 9350962 417499 3353 1368 CA1 CA1 CA1 30 0.0 mice and (2) 2 in the selectively vulnerable gerbil hippocampal CA1 region after a 5 min episode of forebrain ischemia and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293719 9350962 417503 20996 11179 SOD1 ALS ALS 36 2.2 1992 Smith et al. 1994 and amyotrophic lateral sclerosis (ALS) ALS ( Rosen et al. 1993 Gurney et al. 1996 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00101682528081854<>ScoreDetail__5468|IGFALS|0.000274530069116982__11179|SOD1|0.00101682528081854__ 0 0 0 0 0 293720 9350962 417511 20996 11179 SOD1 ALS ALS 38 2.2 demonstrated its applicability in a transgenic mouse model of familial ALS and the gerbil model of transient forebrain ischemia 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00101682528081854<>ScoreDetail__5468|IGFALS|0.000274530069116982__11179|SOD1|0.00101682528081854__ 0 0 0 0 0 293721 9350962 417519 8255 4236 GFER HPO HPO 14 0.0 ml of phosphate-buffered saline (PBS; PBS 10 mM Na 2 HPO 4 containing 0.9% NaCl and 0.01% EDTA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293722 9350962 417532 19988 17710 SIT1 sit sit 30 0.0 as a 3.34 mg/ml mg ml stock and allowed to sit at room temperature for 30 min 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>17710|SIT1|27240|No_GeneRif__18270|HHAT|55733|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 293723 9350962 417535 19988 17710 SIT1 sit sit 20 0.0 dilutions (1:125_amp_#x2013;1:10_amp_#xa0;000) 1 125_amp_#x2013 1 10_amp_#xa0 000 and allowed to sit for 45 min followed by two washes with 200 _amp_#x3bc 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>17710|SIT1|27240|No_GeneRif__18270|HHAT|55733|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 293724 9350962 417536 19988 17710 SIT1 sit sit 27 0.0 in 1% BSA/PBS BSA PBS and the plate allowed to sit at room temperature for 30 min 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>17710|SIT1|27240|No_GeneRif__18270|HHAT|55733|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 293725 9350962 417541 20996 11179 SOD1 ALS ALS 2 2.2 Transgenic familial ALS mice (G1H/+ G1H strain which highly express a mutant human 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00101682528081854<>ScoreDetail__5468|IGFALS|0.000274530069116982__11179|SOD1|0.00101682528081854__ 0 0 0 0 0 293726 9350962 417552 20996 11179 SOD1 ALS ALS 2 2.2 The transgenic ALS mice and the gerbils subjected to forebrain ischemia were deeply 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00101682528081854<>ScoreDetail__5468|IGFALS|0.000274530069116982__11179|SOD1|0.00101682528081854__ 0 0 0 0 0 293727 9350962 417552 3357 1377 CA5A CAVA cava 37 1.0 pH 7.2 until the venous effluent (sectioned sectioned superior vena cava was cleared of blood 14 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 293728 9350962 417565 3353 1368 CA1 CA1 CA1 32 0.0 counted over a 310 _amp_#x3bc m length of the hippocampal CA1 region 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293729 9350962 417569 20996 11179 SOD1 ALS ALS 23 2.2 various proteins in the spinal cords from the transgenic familial ALS and non-transgenic mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00101682528081854<>ScoreDetail__5468|IGFALS|0.000274530069116982__11179|SOD1|0.00101682528081854__ 0 0 0 0 0 293730 9350962 417575 830 536 ANXA13 ISA ISA 12 0.0 proteins were separated on 4_amp_#x2013 20% gradient SDS-PAGE gels (ISA, ISA Natick MA at 10 _amp_#x3bc g of protein per lane 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293731 9350962 417580 19329 10524 SALL1 TBS TBS 6 0.0 The membranes were then washed in TBS (6_amp_#xd7;5 6_amp_#xd7 5 min and then treated with enhanced chemiluminescence 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293732 9350962 417580 3778 10620 CCL21 ECL ECL 16 0.0 5 min and then treated with enhanced chemiluminescence reagents (ECL, ECL Amersham Buckinghamshire UK 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293733 9350962 417594 20996 11179 SOD1 ALS ALS 14 2.2 increase in MDA-derived immunostaining in the ventral horns of transgenic ALS mice at 120 days of age in comparison with that 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00101682528081854<>ScoreDetail__5468|IGFALS|0.000274530069116982__11179|SOD1|0.00101682528081854__ 0 0 0 0 0 293734 9350962 417598 20996 11179 SOD1 ALS ALS 17 2.2 of spinal cord proteins from a non-transgenic and a transgenic ALS mouse (both both at 120 days of age shows that 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00101682528081854<>ScoreDetail__5468|IGFALS|0.000274530069116982__11179|SOD1|0.00101682528081854__ 0 0 0 0 0 293735 9350962 417601 3353 1368 CA1 CA1 CA1 15 0.0 immunostaining (compared compared with cresyl violet-stained sections in the hippocampal CA1 region of gerbils subjected to 5 min of near complete 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293736 9350962 417604 3353 1368 CA1 CA1 CA1 14 0.0 figure the immunostaining was not confined to the more vulnerable CA1 region of the hippocampal formation but was also observed in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293737 9350962 417604 3355 1374 CA3 CA3 CA3 26 0.0 of the hippocampal formation but was also observed in the CA3 and CA4 subfields and the dentate gyrus 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293738 9350962 417604 3356 1375 CA4 CA4 CA4 26 0.0 of the hippocampal formation but was also observed in the CA3 and CA4 subfields and the dentate gyrus 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293739 9350962 417604 3356 1375 CA4 CA4 CA4 28 0.0 hippocampal formation but was also observed in the CA3 and CA4 subfields and the dentate gyrus 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293740 9350962 417605 3353 1368 CA1 CA1 CA1 18 0.0 the MDA immunostaining is more widespread among the population of CA1 neurons compared with other hippocampal areas 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293741 9350962 417606 3353 1368 CA1 CA1 CA1 16 0.0 between the intensity of MDA-derived immunostaining and the loss of CA1 neurons as a function of the first 72 h after 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293742 9350962 417607 3353 1368 CA1 CA1 CA1 15 0.0 immunostaining is observed by 48 h when the loss of CA1 neurons is approximately 50% 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293743 9350962 417608 3353 1368 CA1 CA1 CA1 17 0.0 of increased MDA-related immunostaining is simultaneous with that of post-ischemic CA1 neuronal degeneration 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293744 9350962 417620 3353 1368 CA1 CA1 CA1 13 0.0 scavenging or LP-inhibiting compounds are known to attenuate post-ischemic hippocampal CA1 degeneration ( Hall 1996 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293745 9350962 417621 20996 11179 SOD1 ALS ALS 6 2.2 Moreover recent studies with the transgenic ALS mouse model have shown a relative depletion in spinal cord 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00101682528081854<>ScoreDetail__5468|IGFALS|0.000274530069116982__11179|SOD1|0.00101682528081854__ 0 0 0 0 0 293746 9350962 417624 3353 1368 CA1 CA1 CA1 19 0.0 ischemia model suggest that the time course of increasing hippocampal CA1 MDA-related immunostaining correlates with the progressive loss of neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293747 9350962 417625 3353 1368 CA1 CA1 CA1 15 0.0 significantly at the time point at which 50% of the CA1 neurons are lost 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293748 9350962 417640 20996 11179 SOD1 ALS ALS 15 2.2 the ventral horn of normal non-transgenic (A) A and transgenic ALS mice (B) B at 120 days of age 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00101682528081854<>ScoreDetail__5468|IGFALS|0.000274530069116982__11179|SOD1|0.00101682528081854__ 0 0 0 0 0 293749 9350962 417641 20996 11179 SOD1 ALS ALS 15 2.2 of the ventral horn of the spinal cord of an ALS mouse showing that pre-adsorption of the primary anti-MDA antibody with 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00101682528081854<>ScoreDetail__5468|IGFALS|0.000274530069116982__11179|SOD1|0.00101682528081854__ 0 0 0 0 0 293750 9350962 417643 20996 11179 SOD1 ALS ALS 8 2.2 Fig 5.Immunoblots of spinal cord proteins from transgenic ALS (G1H/+) G1H and non-transgenic ALS mice with anti-MDA-RSA antibody 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00101682528081854<>ScoreDetail__5468|IGFALS|0.000274530069116982__11179|SOD1|0.00101682528081854__ 0 0 0 0 0 293751 9350962 417643 20996 11179 SOD1 ALS ALS 12 2.2 spinal cord proteins from transgenic ALS (G1H/+) G1H and non-transgenic ALS mice with anti-MDA-RSA antibody 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00101682528081854<>ScoreDetail__5468|IGFALS|0.000274530069116982__11179|SOD1|0.00101682528081854__ 0 0 0 0 0 293752 9350962 417648 3353 1368 CA1 CA1 CA1 7 0.0 Also shown are examples of cresyl violet-stained CA1 neurons in a sham (C) C and a 48 h 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293753 9350962 417650 3353 1368 CA1 CA1 CA1 12 0.0 comparison of the time courses of the loss of hippocampal CA1 neurons (counts counts of cresyl violet stained neurons in a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 293754 9350962 417650 3353 1368 CA1 CA1 CA1 28 0.0 stained neurons in a 315 micron segment of the medial CA1 region and the appearance of increased MDA-derived immunostaining (semi-quantitative semi-quantitative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 290822 9437657 411969 20996 11179 SOD1 ALS ALS 22 0.0 neurodegenerative diseases including Alzheimer disease and amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000654854754686994<>ScoreDetail__5468|IGFALS|0.00029915041282757__11179|SOD1|0.000654854754686994__ 0 0 0 0 0 290823 9437657 411975 18723 10261 ROS1 ROS ROS 6 0.0 The production of reactive oxygen species (ROS) ROS was examined using the fluorescent probe dichlorofluorescin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 290824 9437657 411976 18723 10261 ROS1 ROS ROS 7 0.0 By itself AlCl3 had little effect on ROS production 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 290825 9437657 411977 18723 10261 ROS1 ROS ROS 5 0.0 However AlCl3 pretreatment potentiated the ROS production induced by 50 microM Fe2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 290826 9437657 411978 18723 10261 ROS1 ROS ROS 12 0.0 suggest that aluminum may facilitate increases in intracellular Ca2 and ROS and potentially contribute to neurotoxicity induced by other neurotoxicants 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 290827 9441250 411984 20996 11179 SOD1 ALS ALS 10 0.9 presently the etiology and pathogenesis of amyotrophic lateral sclerosis (ALS) ALS are unknown 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00160649814407188<>ScoreDetail__5468|IGFALS|8.02117590438758e-05__11179|SOD1|0.00160649814407188__ 0 0 0 0 0 290828 9441250 411986 20996 11179 SOD1 ALS ALS 21 0.9 of the pathogenesis of the familial and sporadic forms of ALS and thus provide a basis for rational therapeutic approaches 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00160649814407188<>ScoreDetail__5468|IGFALS|8.02117590438758e-05__11179|SOD1|0.00160649814407188__ 0 0 0 0 0 290829 9441250 411987 20996 11179 SOD1 ALS ALS 13 0.9 recent findings on the pathogenesis of the familial form of ALS and their implications for the sporadic form are discussed 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00160649814407188<>ScoreDetail__5468|IGFALS|8.02117590438758e-05__11179|SOD1|0.00160649814407188__ 0 0 0 0 0 291073 9462746 412764 18723 10261 ROS1 ROS ROS 3 0.0 Reactive oxygen species (ROS) ROS have been implicated in a wide range of degenerative processes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 291074 9462746 412765 18723 10261 ROS1 ROS ROS 0 0.0 ROS are generated by mitochondria as the toxic by-products of oxidative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 291075 9462746 412767 20996 11179 SOD1 SOD SOD 8 0.9 We report that treatment with the superoxide dismutase (SOD) SOD mimetic Manganese 5 10 15 20-tetrakis (4-benzoic 4-benzoic acid porphyrin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 291076 9462746 412770 18723 10261 ROS1 ROS ROS 24 0.0 barrier progressive neuropathology is caused by excessive mitochondrial production of ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 289757 9620775 410130 20996 11179 SOD1 SOD1 SOD1 8 2.0 Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 289758 9620775 410133 20996 11179 SOD1 SOD1 SOD1 16 2.0 encoding the oxygen radical metabolizing enzyme CuZn superoxide dismutase (SOD1) SOD1 and loss of motorneurons in the brain and spinal cord 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 289759 9620775 410134 20996 11179 SOD1 SOD1 SOD1 11 2.0 test this hypothesis we generated transgenic Drosophila which express human SOD1 specifically in adult motorneurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 289760 9620775 410135 20996 11179 SOD1 SOD1 SOD1 8 2.0 We show that overexpression of a single gene SOD1 in a single cell type the motorneuron extends normal lifespan 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 289761 9620775 410137 20996 11179 SOD1 SOD SOD 4 1.7 These results show that SOD activity in motorneurons is an important factor in ageing and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 290126 9633809 410560 20996 11179 SOD1 ALS ALS 17 2.2 disease onset and progression in a transgenic model of familial ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124993433595886<>ScoreDetail__5468|IGFALS|0.000593615337261455__11179|SOD1|0.00124993433595886__ 0 0 0 0 0 290127 9633809 410561 20996 11179 SOD1 SOD1 SOD1 11 2.2 that highly over-express a mutated human CuZn superoxide dismutase (SOD1) SOD1 gene gly93-->ala TgN(SOD1-G93A)G1H TgN SOD1-G93A G1H line found in some 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 290128 9633809 410561 22055 11764 TG TGN TgN 14 0.3 mutated human CuZn superoxide dismutase (SOD1) SOD1 gene gly93-->ala TgN(SOD1-G93A)G1H TgN SOD1-G93A G1H line found in some patients with familial ALS 3 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 290129 9633809 410561 20996 11179 SOD1 ALS ALS 22 2.2 TgN SOD1-G93A G1H line found in some patients with familial ALS (FALS) FALS have been shown to develop motor neuron disease 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124993433595886<>ScoreDetail__5468|IGFALS|0.000593615337261455__11179|SOD1|0.00124993433595886__ 0 0 0 0 0 290130 9633809 410562 20996 11179 SOD1 SOD SOD 3 2.2 The mutant Cu Zn SOD exhibits essentially normal SOD activity but also generates toxic oxygen 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 290131 9633809 410562 20996 11179 SOD1 SOD SOD 7 2.2 The mutant Cu Zn SOD exhibits essentially normal SOD activity but also generates toxic oxygen radicals as a result 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 290132 9633809 410564 22055 11764 TG TGN TgN 34 0.3 to the course of motor neuron disease in the TgN(SOD1-G93A)G1H TgN SOD1-G93A G1H FALS mice 3 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 290133 9633809 410566 22055 11764 TG TGN TgN 5 0.3 Compared to non-transgenic littermates the TgN(SOD1-G93A)G1H TgN SOD1-G93A G1H mice showed significantly increased numbers of activated astrocytes 3 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 285024 9675268 403033 18723 10261 ROS1 ROS ROS 8 0.3 Previous studies have implicated mitochondria-derived reactive oxygen species (ROS) ROS in both the aging process and age-related diseases such as 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 285025 9675268 403056 24185 29175 WDTC1 ADP ADP 34 0.0 water with a simultaneous production of ATP through phosphorylation of ADP 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 285026 9675268 403058 18723 10261 ROS1 ROS ROS 33 0.3 been well established that mitochondrial macromolecules undergo damage by self-generated ROS 11 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 285027 9675268 403059 18723 10261 ROS1 ROS ROS 25 0.3 under induced metabolic stress tend to form higher levels of ROS 3 4 12 13 14 and 15 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 285028 9675268 403060 18723 10261 ROS1 ROS ROS 1 0.3 These ROS can contribute to oxidative damage of mitochondrial lipids proteins and 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 285029 9675268 403086 6791 3467 ESR1 ESR ESR 4 0.0 Succinate-induced mitochondrial stimulation and ESR spin labeling 2.4.1 5-NS lipid spin labeling 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 285030 9675268 403167 18723 10261 ROS1 ROS ROS 19 0.3 of oxidative events thought to occur in the membrane following ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 285031 9675268 403182 12261 6817 MAL MAL MAL-6-linked 12 0.6 in our laboratory of the W / S ratio of MAL-6-linked synaptosomal membrane following 4-HNE treatment have shown that this toxic 11 JUMiner_v2.2 1 0 0 2 6817 TotalCon:3<>6817|MAL|4118|Complete__14334|MKL1|57591|Complete__1706|CD8A|925|Complete__<>AvaiableGeneRif=3<>BEST:6817|MAL|0.000487439070116235<>ScoreDetail__1706|CD8A|0.000319447248581107__6817|MAL|0.000487439070116235__14334|MKL1|0.000361682019572943__ 0 0 0 0 0 285032 9675268 403182 12261 6817 MAL MAL MAL-6-spin 44 0.6 as monitored by a reduced W / S ratio of MAL-6-spin labeled synaptosomal membranes 36 11 JUMiner_v2.2 1 0 0 2 6817 TotalCon:3<>6817|MAL|4118|Complete__14334|MKL1|57591|Complete__1706|CD8A|925|Complete__<>AvaiableGeneRif=3<>BEST:6817|MAL|0.000487439070116235<>ScoreDetail__1706|CD8A|0.000319447248581107__6817|MAL|0.000487439070116235__14334|MKL1|0.000361682019572943__ 0 0 0 0 0 285033 9675268 403185 6554 3309 ELA2 HNE HNE 1 0.0 Since HNE adducts protrude from proteins into the hydrophobic domain of bilayers 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 285034 9675268 403187 18723 10261 ROS1 ROS ROS 7 0.3 This study also investigated the effect of ROS as generated by metabolic stimulation of mitochondria on cytoskeletal and 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 285035 9675268 403189 12261 6817 MAL MAL MAL-6-labeled 24 0.6 generation 21 in which the W / S ratio of MAL-6-labeled neocortical or erythrocyte membranes was reduced 21 30 31 32 11 JUMiner_v2.2 1 0 0 2 6817 TotalCon:3<>6817|MAL|4118|Complete__14334|MKL1|57591|Complete__1706|CD8A|925|Complete__<>AvaiableGeneRif=3<>BEST:6817|MAL|0.000487439070116235<>ScoreDetail__1706|CD8A|0.000319447248581107__6817|MAL|0.000487439070116235__14334|MKL1|0.000361682019572943__ 0 0 0 0 0 285036 9675268 403189 18723 10261 ROS1 ROS ROS 60 0.3 in cytoskeletal and transmembrane proteins due to an onslaught by ROS generated following succinate-induced stimulation of mitochondrial respiration 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 285037 9675268 403190 18723 10261 ROS1 ROS ROS 11 0.3 of proteins can be a result of direct interaction with ROS like OH* radicals or possibly by interaction with toxic aldehydic 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 285038 9675268 403193 18723 10261 ROS1 ROS ROS 16 0.3 AD amyotrophic lateral sclerosis and Parkinson_amp_#x2019 s disease have implicated ROS in their pathogenesis 37 40 41 and 42 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 285039 9675268 403196 926 620 APP amyloid amyloid 29 1.0 and peptides (e.g e.g nitric oxide synthase xanthine oxidase _amp_#x3b2 -amyloid etc. present in the brain 11 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 285040 9675268 403196 18723 10261 ROS1 ROS ROS-generating 19 0.0 redox metal ions (i.e i.e iron and copper and particular ROS-generating enzymes and peptides (e.g e.g nitric oxide synthase xanthine oxidase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 285041 9675268 403245 18723 10261 ROS1 ROS ROS 16 0.3 spin probe intercalated within it is susceptible to attack by ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 285042 9675268 403246 18723 10261 ROS1 ROS ROS 11 0.3 resultant more polar lipid hydroperoxides formed due to interaction with ROS move towards the aqueous phase creating a void in the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 286045 9711902 404620 20996 11179 SOD1 ALS ALS 34 0.0 conditions including Alzheimer's disease (AD), AD amyotrophic lateral sclerosis (ALS), ALS Parkinson's disease (PD), PD and ischemia 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000527289207775843<>ScoreDetail__5468|IGFALS|0.000158679784195493__11179|SOD1|0.000527289207775843__ 0 0 0 0 0 286046 9711902 404622 11961 6679 LPP LPP LPP 29 0.0 give rise to a variety of lipid peroxidation products (LPP), LPP including 4-hydroxynonenal (HNE) HNE and malondialdehyde (MD) MD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286047 9711902 404622 6554 3309 ELA2 HNE HNE 32 0.0 variety of lipid peroxidation products (LPP), LPP including 4-hydroxynonenal (HNE) HNE and malondialdehyde (MD) MD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286048 9711902 404624 11961 6679 LPP LPP LPP 6 0.0 Emerging data suggest that LP and LPP may underlie the neuronal alterations and neurotoxicity observed in numerous 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286049 9711902 404625 11961 6679 LPP LPP LPP 12 0.0 this involvement include the detection of LP and formation of LPP in a variety of neuropathological conditions including AD ALS PD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286050 9711902 404625 20996 11179 SOD1 ALS ALS 21 0.0 of LPP in a variety of neuropathological conditions including AD ALS PD and ischemia 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000527289207775843<>ScoreDetail__5468|IGFALS|0.000158679784195493__11179|SOD1|0.000527289207775843__ 0 0 0 0 0 286051 9711902 404626 11961 6679 LPP LPP LPP 4 0.0 Secondly direct application of LPP either in vivo or in vitro has been shown to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286052 9711902 404627 11961 6679 LPP LPP LPP 6 0.0 Furthermore prevention of LP and subsequent LPP formation have been demonstrated to be neuroprotective in a variety 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286053 9711902 404628 11961 6679 LPP LPP LPP 3 0.0 Additionally LP and LPP have been implicated in the modulation of a wide array 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286907 9745361 405674 20017 10940 SLC1A2 GLT1 GLT1 19 2.3 in the structures of at least three transporter subtypes (GLT1, GLT1 GLAST and EAAC1 and shown to regulate transport rate via 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286908 9745361 405674 20018 10941 SLC1A3 GLAST GLAST 20 2.5 the structures of at least three transporter subtypes (GLT1, GLT1 GLAST and EAAC1 and shown to regulate transport rate via thiol-disulphide 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286909 9745361 405674 20016 10939 SLC1A1 EAAC1 EAAC1 22 3.0 of at least three transporter subtypes (GLT1, GLT1 GLAST and EAAC1 and shown to regulate transport rate via thiol-disulphide redox interconversion 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286910 9745361 405679 20018 10941 SLC1A3 GLAST GLAST 15 2.5 (or or excitatory amino acid carriers have now been identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286911 9745361 405679 20018 10941 SLC1A3 EAAT1 EAAT1 16 2.5 excitatory amino acid carriers have now been identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286912 9745361 405679 20017 10940 SLC1A2 GLT1 GLT1 17 2.3 amino acid carriers have now been identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286913 9745361 405679 20017 10940 SLC1A2 EAAT2 EAAT2 18 1.5 carriers have now been identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs 1 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286914 9745361 405679 20016 10939 SLC1A1 EAAC1 EAAC1 19 3.0 have now been identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs 1 2 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286915 9745361 405679 20016 10939 SLC1A1 EAAT3 EAAT3 20 2.5 been identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs 1 2 3 4 5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286916 9745361 405679 20021 10944 SLC1A6 EAAT4 EAAT4 21 1.0 identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs 1 2 3 4 5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286917 9745361 405679 20022 10945 SLC1A7 EAAT5 EAAT5 21 1.0 identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs 1 2 3 4 5 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286918 9745361 405679 20022 10945 SLC1A7 EAAT5 EAAT5 23 1.0 (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs 1 2 3 4 5 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286919 9745361 405686 20021 10944 SLC1A6 EAAT4 EAAT4 0 1.0 EAAT4 and EAAT5 have the highest Cl _amp_#x2212 conductances 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286920 9745361 405686 20022 10945 SLC1A7 EAAT5 EAAT5 0 1.0 EAAT4 and EAAT5 have the highest Cl _amp_#x2212 conductances 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286921 9745361 405686 20022 10945 SLC1A7 EAAT5 EAAT5 2 1.0 EAAT4 and EAAT5 have the highest Cl _amp_#x2212 conductances 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286922 9745361 405687 20017 10940 SLC1A2 GLT1 GLT1 6 2.3 In studies to localize the isoforms GLT1 and GLAST appear to be restricted to brain astrocytes 11 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286923 9745361 405687 20018 10941 SLC1A3 GLAST GLAST 8 2.5 In studies to localize the isoforms GLT1 and GLAST appear to be restricted to brain astrocytes 11 12 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286924 9745361 405688 20017 10940 SLC1A2 GLT1 GLT1 0 2.3 GLT1 is the most abundant glutamate transporter and represents about 1% 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286925 9745361 405689 20018 10941 SLC1A3 GLAST GLAST 4 2.5 The highest concentration of GLAST is found in the Bergmann glia of the cerebellar molecular 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286926 9745361 405690 20017 10940 SLC1A2 GLT1 GLT1 3 2.3 In astrocytic membranes GLT1 and GLAST localize preferentially to the parts of the plasma 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286927 9745361 405690 20018 10941 SLC1A3 GLAST GLAST 5 2.5 In astrocytic membranes GLT1 and GLAST localize preferentially to the parts of the plasma membrane that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286928 9745361 405691 20017 10940 SLC1A2 GLT1 GLT1 4 2.3 Moreover the expression of GLT1 and GLAST is under the control of neuronal soluble factors 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286929 9745361 405691 20018 10941 SLC1A3 GLAST GLAST 6 2.5 Moreover the expression of GLT1 and GLAST is under the control of neuronal soluble factors including glutamate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286930 9745361 405692 20016 10939 SLC1A1 EAAC1 EAAC1 4 3.0 In the brain the EAAC1 protein and mRNA are found in neurones 15 16 where 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286931 9745361 405693 20016 10939 SLC1A1 EAAC1 EAAC1 0 3.0 EAAC1 is not restricted to glutamatergic neurones and has now also 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286932 9745361 405694 20021 10944 SLC1A6 EAAT4 EAAT4 3 1.0 The fourth subtype EAAT4 is concentrated in the spines of Purkinje cells predominantly extrasynaptically 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286933 9745361 405695 20022 10945 SLC1A7 EAAT5 EAAT5 0 1.0 EAAT5 appears to be a retinal protein 5 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286934 9745361 405710 20017 10940 SLC1A2 GLT1 GLT1 19 2.3 tissue damage resulted from loss of the glial transporters particularly GLT1 (Ref Ref 25 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286935 9745361 405711 20017 10940 SLC1A2 GLT1 GLT1 4 2.3 Indeed knockout mice lacking GLT1 undergo lethal spontaneous seizures increased susceptibility to acute brain injury 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286936 9745361 405712 20016 10939 SLC1A1 EAAC1 EAAC1-knockout 2 2.5 In contrast EAAC1-knockout mice develop dicarboxylic aminoaciduria and no sign of neurodegeneration during 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286937 9745361 405727 20017 10940 SLC1A2 GLT1 GLT1 5 2.3 Indeed the transport activities of GLT1 EAAC1 and GLAST are equally inhibited by oxidants via a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286938 9745361 405727 20016 10939 SLC1A1 EAAC1 EAAC1 6 3.0 Indeed the transport activities of GLT1 EAAC1 and GLAST are equally inhibited by oxidants via a direct 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286939 9745361 405727 20018 10941 SLC1A3 GLAST GLAST 8 2.5 Indeed the transport activities of GLT1 EAAC1 and GLAST are equally inhibited by oxidants via a direct action on 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286940 9745361 405742 20016 10939 SLC1A1 EAAC1 EAAC1 0 3.0 EAAC1 GLT1 and GLAST exhibit redox-sensing properties 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286941 9745361 405742 20017 10940 SLC1A2 GLT1 GLT1 1 2.3 EAAC1 GLT1 and GLAST exhibit redox-sensing properties 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286942 9745361 405742 20018 10941 SLC1A3 GLAST GLAST 3 2.5 EAAC1 GLT1 and GLAST exhibit redox-sensing properties 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286943 9745361 405743 20021 10944 SLC1A6 EAAT4 EAAT4 7 1.0 At present no information is available for EAAT4 and EAAT5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286944 9745361 405743 20022 10945 SLC1A7 EAAT5 EAAT5 7 1.0 At present no information is available for EAAT4 and EAAT5 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286945 9745361 405743 20022 10945 SLC1A7 EAAT5 EAAT5 9 1.0 At present no information is available for EAAT4 and EAAT5 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286946 9745361 405745 20016 10939 SLC1A1 EAAC1 EAAC1 0 3.0 EAAC1 GLAST GLT1 EAAT4 and EAAT5 carry different cysteine residues in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286947 9745361 405745 20018 10941 SLC1A3 GLAST GLAST 1 2.5 EAAC1 GLAST GLT1 EAAT4 and EAAT5 carry different cysteine residues in their 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286948 9745361 405745 20017 10940 SLC1A2 GLT1 GLT1 2 2.3 EAAC1 GLAST GLT1 EAAT4 and EAAT5 carry different cysteine residues in their sequences 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286949 9745361 405745 20021 10944 SLC1A6 EAAT4 EAAT4 3 1.0 EAAC1 GLAST GLT1 EAAT4 and EAAT5 carry different cysteine residues in their sequences ranging 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286950 9745361 405745 20022 10945 SLC1A7 EAAT5 EAAT5 3 1.0 EAAC1 GLAST GLT1 EAAT4 and EAAT5 carry different cysteine residues in their sequences ranging 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286951 9745361 405745 20022 10945 SLC1A7 EAAT5 EAAT5 5 1.0 EAAC1 GLAST GLT1 EAAT4 and EAAT5 carry different cysteine residues in their sequences ranging from a 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286952 9745361 405745 20021 10944 SLC1A6 EAAT4 EAAT4 20 1.0 in their sequences ranging from a minimum of two for EAAT4 to a maximum of 11 for EAAT5 (Ref Ref 5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286953 9745361 405745 20022 10945 SLC1A7 EAAT5 EAAT5 27 1.0 of two for EAAT4 to a maximum of 11 for EAAT5 (Ref Ref 5 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286954 9745361 405746 20022 10945 SLC1A7 EAAT5 EAAT5 12 1.0 residues two are conserved among all the transporter subtypes except EAAT5 which has only one conserved cysteine 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286955 9745361 405750 19573 10691 SDS SDS SDS 24 0.0 gel electrophoresis (SDS-PAGE) SDS-PAGE if electrophoresed immediately after solubilization in SDS even when reducing agents are omitted ( Fig 3 lane 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000269526876667266<>ScoreDetail__10691|SDS|4.08897612037946e-05__19440|SBDS|0.000269526876667266__ 0 0 0 0 0 286956 9745361 405752 6181 3058 DTNB DTNB DTNB 43 0.0 the sulphydryl-specific oxidant 5,5_amp_#x2032;-dithio-bis(2-nitrobenzoic) 5 5_amp_#x2032 -dithio-bis 2-nitrobenzoic acid (DTNB) DTNB (lane lane 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286957 9745361 405765 20996 11179 SOD1 ALS ALS 27 1.4 others e.g spinal motoneurone synapses in amyotrophic lateral sclerosis (ALS)] ALS 47 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00169113875352655<>ScoreDetail__5468|IGFALS|0.000410583941605839__11179|SOD1|0.00169113875352655__ 0 0 0 0 0 286958 9745361 405768 20016 10939 SLC1A1 EAAC1 EAAC1 8 3.0 Glutamate transporters located in the postsynaptic compartment (e.g e.g EAAC1 or EAAT4 have an increased chance of exposure to noxious 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286959 9745361 405768 20021 10944 SLC1A6 EAAT4 EAAT4 10 1.0 transporters located in the postsynaptic compartment (e.g e.g EAAC1 or EAAT4 have an increased chance of exposure to noxious amounts of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286960 9745361 405780 20996 11179 SOD1 ALS ALS 3 1.4 The case of ALS illustrates the involvement of glutamate transporters in a neurodegenerative pathology 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00169113875352655<>ScoreDetail__5468|IGFALS|0.000410583941605839__11179|SOD1|0.00169113875352655__ 0 0 0 0 0 286961 9745361 405781 20996 11179 SOD1 ALS ALS 5 1.4 In the sporadic form of ALS (sALS), sALS a direct link between transporter defect and neurodegeneration 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00169113875352655<>ScoreDetail__5468|IGFALS|0.000410583941605839__11179|SOD1|0.00169113875352655__ 0 0 0 0 0 286962 9745361 405781 20017 10940 SLC1A2 GLT1 GLT1 42 2.3 glutamate uptake activity apparently owing to a selective loss of GLT1 in the spinal cord and motor cortex of patients with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286963 9745361 405782 20017 10940 SLC1A2 GLT1 GLT1 6 2.3 The mechanism(s) mechanism s leading to loss of GLT1 are not fully understood 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286964 9745361 405783 20017 10940 SLC1A2 GLT1 GLT1 4 2.3 The steady-state level of GLT1 mRNA was apparently unchanged leading investigators initially to suspect a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286965 9745361 405783 20017 10940 SLC1A2 GLT1 GLT1 26 2.3 or the internalization and/or and or degradation of post-translationally damaged GLT1 (Ref Ref 51 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286966 9745361 405784 20017 10940 SLC1A2 GLT1 GLT1 33 2.3 and/or and or producing a dominant negative effect on normal GLT1 (Ref Ref 52 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286967 9745361 405785 20996 11179 SOD1 ALS ALS 9 1.4 Studies by Rosen and colleagues 53 linked ALS to reactive oxygen species toxicity since they showed that 15_amp_#x2013 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00169113875352655<>ScoreDetail__5468|IGFALS|0.000410583941605839__11179|SOD1|0.00169113875352655__ 0 0 0 0 0 286968 9745361 405785 20996 11179 SOD1 SOD1 SOD1 37 1.4 gene encoding Cu 2 /Zn Zn 2 superoxide dismutase ( SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286969 9745361 405786 20996 11179 SOD1 SOD1 SOD1 5 1.4 Mice made transgenic for mutant SOD1 developed selective motoneurone pathology strongly resembling human ALS (Ref Ref 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286970 9745361 405786 20996 11179 SOD1 ALS ALS 13 1.4 for mutant SOD1 developed selective motoneurone pathology strongly resembling human ALS (Ref Ref 54 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00169113875352655<>ScoreDetail__5468|IGFALS|0.000410583941605839__11179|SOD1|0.00169113875352655__ 0 0 0 0 0 286971 9745361 405787 20996 11179 SOD1 SOD1 SOD1-dependent 25 1.4 aetiology of sporadic forms may involve mechanisms similar to the SOD1-dependent defects of fALS (Ref Ref 55 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286972 9745361 405788 20996 11179 SOD1 SOD1 SOD1 2 1.4 Mutations in SOD1 not only reduce the capacity to detoxify superoxide but actually 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286973 9745361 405790 20996 11179 SOD1 SOD1 SOD1 2 1.4 Abnormalities of SOD1 may result in defective glutamate transport since transgenic mice expressing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286974 9745361 405790 20996 11179 SOD1 ALS ALS-linked 14 1.4 result in defective glutamate transport since transgenic mice expressing an ALS-linked SOD1 mutation show increased tyrosine nitration of glutamate transporters 43 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00169113875352655<>ScoreDetail__5468|IGFALS|0.000410583941605839__11179|SOD1|0.00169113875352655__ 0 0 0 0 0 286975 9745361 405790 20996 11179 SOD1 SOD1 SOD1 15 1.4 in defective glutamate transport since transgenic mice expressing an ALS-linked SOD1 mutation show increased tyrosine nitration of glutamate transporters 43 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286976 9745361 405790 20017 10940 SLC1A2 GLT1 GLT1 30 2.3 tyrosine nitration of glutamate transporters 43 and marked loss of GLT1 in the spinal cord 58 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286977 9745361 405794 926 620 APP amyloid amyloid 3 1.0 A fragment of _amp_#x3b2 -amyloid (A_amp_#x3b2;), A_amp_#x3b2 the central constituent of neuritic plaques in Alzheimer's 11 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 286978 9745361 405807 20017 10940 SLC1A2 GLT1 GLT1 33 2.3 shown to form adducts with a number of proteins including GLT1 by reaction at sulphydryls or other vulnerable groups 66 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286979 9745361 405816 20017 10940 SLC1A2 GLT1 GLT1 4 2.3 As the glutamate transporters GLT1 in particular are crucial in maintaining glutamate homeostasis 6 32 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286980 9745361 405823 18723 10261 ROS1 ROS ROS 9 0.0 The reciprocal interactions between glutamate and reactive oxygen species (ROS)-mediated ROS -mediated events might start a vicious amplifying cycle of the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286981 9745361 405828 18723 10261 ROS1 ROS ROS 0 0.0 ROS are among the products and mediators of these enzymatic processes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286982 9745361 405830 20996 11179 SOD1 SOD1 SOD1 25 1.4 a result of altered function of mutant superoxide dismutase (SOD1) SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286983 9745361 405830 18723 10261 ROS1 ROS ROS 11 0.0 amyotrophic lateral sclerosis peroxynitrite (ONOO ONOO _amp_#x2212 or other noxious ROS can be formed as a result of altered function of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286984 9745361 405831 18723 10261 ROS1 ROS ROS 6 0.0 In addition to being directly neurotoxic ROS oxidize proteins crucial for excitatory synapse function such as the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286985 9745361 405838 6181 3058 DTNB DTNB DTNB 23 0.0 or saline plus 5,5_amp_#x2032;-dithio-bis(2-nitrobenzoic) 5 5_amp_#x2032 -dithio-bis 2-nitrobenzoic acid (DTNB; DTNB 500 _amp_#x3bc 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286986 9745361 405840 6181 3058 DTNB DTNB DTNB 10 0.0 As shown at the top of the figure DTT and DTNB act specifically on the redox equilibrium of sulphydryl groups shifting 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286987 9745361 405840 6181 3058 DTNB DTNB DTNB 33 0.0 fully reduced (DTT) DTT or the fully oxidized state (DTNB) DTNB 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286988 9745361 405842 6181 3058 DTNB DTNB DTNB 18 0.0 changes if the cells had been exposed to DTT and DTNB in sequence b Biological oxidants interact with the redox regulatory 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286989 9745361 405843 6181 3058 DTNB DTNB DTNB 33 0.0 and peroxynitrite (ONOO ONOO _amp_#x2212 nominally 300 _amp_#x3bc instead of DTNB 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286990 9745361 405844 6181 3058 DTNB DTNB DTNB 10 0.0 Both H 2 O 2 and ONOO _amp_#x2212 like DTNB reversed DTT potentiation bringing the uptake current below control level 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286991 9745361 405848 19573 10691 SDS SDS SDS 26 0.0 solubilized with 10 mg ml -1 sodium dodecyl sulphate (SDS), SDS (lane lane 2 incubated 2 h on ice before solubilization 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000269526876667266<>ScoreDetail__10691|SDS|4.08897612037946e-05__19440|SBDS|0.000269526876667266__ 0 0 0 0 0 286992 9745361 405848 19573 10691 SDS SDS SDS 37 0.0 lane 2 incubated 2 h on ice before solubilization in SDS (lane lane 3 incubated for 2 h on ice with 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000269526876667266<>ScoreDetail__10691|SDS|4.08897612037946e-05__19440|SBDS|0.000269526876667266__ 0 0 0 0 0 286993 9745361 405848 6181 3058 DTNB DTNB DTNB 51 0.0 with 2 m 5,5_amp_#x2032;-dithio-bis(2-nitrobenzoic) 5 5_amp_#x2032 -dithio-bis 2-nitrobenzoic acid (DTNB) DTNB before solubilization in SDS (lane lane 4 incubated for 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286994 9745361 405848 19573 10691 SDS SDS SDS 55 0.0 5 5_amp_#x2032 -dithio-bis 2-nitrobenzoic acid (DTNB) DTNB before solubilization in SDS (lane lane 4 incubated for 2 h on ice with 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000269526876667266<>ScoreDetail__10691|SDS|4.08897612037946e-05__19440|SBDS|0.000269526876667266__ 0 0 0 0 0 286995 9745361 405848 19573 10691 SDS SDS SDS 72 0.0 ice with 30 m dithiothreitol (DTT) DTT before solubilization in SDS or (lane lane 5 incubated for 2 h on ice 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000269526876667266<>ScoreDetail__10691|SDS|4.08897612037946e-05__19440|SBDS|0.000269526876667266__ 0 0 0 0 0 286996 9745361 405848 6181 3058 DTNB DTNB DTNB 85 0.0 5 incubated for 2 h on ice with 2 mM DTNB and then for 30 min with 30 mM DTT before 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 286997 9745361 405848 19573 10691 SDS SDS SDS 98 0.0 for 30 min with 30 mM DTT before solubilization in SDS 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000269526876667266<>ScoreDetail__10691|SDS|4.08897612037946e-05__19440|SBDS|0.000269526876667266__ 0 0 0 0 0 286998 9745361 405850 19573 10691 SDS SDS SDS-resistant 7 0.5 Note that the oxidation dependent formation of SDS-resistant protein complexes shown here is different from the oxidation independent 3 JUMiner_v2.2 1 2 sds 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000269526876667266<>ScoreDetail__10691|SDS|4.08897612037946e-05__19440|SBDS|0.000269526876667266__ 0 0 0 0 0 284176 9856861 401486 18723 10261 ROS1 ROS ROS 7 0.0 Evidence is growing that reactive oxygen species (ROS), ROS by-products of (normal) normal cellular aerobic metabolism are involved in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 284177 9856861 401487 20996 11179 SOD1 ALS ALS 8 0.8 One of these diseases is amyotrophic lateral sclerosis (ALS), ALS in which motoneurons die leading to paralysis and death 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000780065312741185<>ScoreDetail__5468|IGFALS|0.00016818594638232__11179|SOD1|0.000780065312741185__ 0 0 0 0 0 284178 9856861 401488 20996 11179 SOD1 ALS ALS 13 0.8 ROS are the cause of (apoptotic) apoptotic motoneuron death in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000780065312741185<>ScoreDetail__5468|IGFALS|0.00016818594638232__11179|SOD1|0.000780065312741185__ 0 0 0 0 0 284179 9856861 401488 18723 10261 ROS1 ROS ROS 4 0.0 It remains uncertain whether ROS are the cause of (apoptotic) apoptotic motoneuron death in ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 284180 9856861 401489 18723 10261 ROS1 ROS ROS 6 0.0 To further understand the role of ROS in motoneuron death we investigated the effects of ROS on 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 284181 9856861 401489 18723 10261 ROS1 ROS ROS 15 0.0 of ROS in motoneuron death we investigated the effects of ROS on isolated spinal rat motoneurons in culture 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 284182 9856861 401490 18723 10261 ROS1 ROS ROS 0 0.0 ROS were generated with a combination of iron(III) iron III and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 284183 9856861 401492 20996 11179 SOD1 SOD1 SOD1 20 0.8 enzyme catalase and partially prevented with the antioxidant vitamin E SOD1 the enzyme that removes superoxide did not protect against iron(III)/ascorbate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 284184 9856861 401493 18723 10261 ROS1 ROS ROS 0 0.0 ROS treatment caused apoptotic motoneuron death low doses of iron(III)/ iron 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 284185 9856861 401493 18723 10261 ROS1 ROS ROS 26 0.0 complete apoptosis ending in nuclear fragmentation while high doses of ROS resulted in incomplete apoptosis (nuclear nuclear condensation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 284186 9856861 401494 18723 10261 ROS1 ROS ROS 6 0.0 Thus depending on the dose of ROS the motoneurons complete the apoptotic pathway (low low dose or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280270 10077670 394958 20996 11179 SOD1 SOD SOD 17 3.2 (FALS)-associated FALS -associated mutant Cu/Zn Cu Zn superoxide dismutase-1 (SOD) SOD induces apoptosis of neuronal cells in culture associated with an 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280271 10077670 394959 20996 11179 SOD1 SOD SOD 0 3.2 SOD recently has been shown to prevent calcineurin inactivation initiating the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280272 10077670 394959 20996 11179 SOD1 SOD SOD-induced 20 2.4 the present investigations examining the role of calcineurin in mutant SOD-induced cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280273 10077670 394960 20996 11179 SOD1 SOD SOD 3 3.2 Wild-type or mutant SOD was expressed in neuronal cells by infection with replication-deficient adenoviruses 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280274 10077670 394961 20996 11179 SOD1 SOD SOD 5 3.2 PC12 cells overexpressing human wild-type SOD exhibited higher calcineurin activity than cells expressing FALS-related mutant SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280275 10077670 394961 20996 11179 SOD1 SOD SOD 15 3.2 SOD exhibited higher calcineurin activity than cells expressing FALS-related mutant SOD (SODV148G); SODV148G however cells expressing SODV148G had calcineurin activity equal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280276 10077670 394961 20996 11179 SOD1 SOD SOD 35 3.2 to mock-infected cells suggesting that cell death induced by mutant SOD was not related to a decrease in calcineurin activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280277 10077670 394963 5344 2595 CYP1A1 CYP CyP 11 0.0 groups of drugs inhibit the rotamase activity of cyclophilins (CyP), CyP but only the immunosuppressant analogs inhibit calcineurin activity these data 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280278 10077670 394964 20996 11179 SOD1 SOD SOD-mediated 7 2.4 The importance of rotamase activity in mutant SOD-mediated apoptosis was supported by experiments showing that overexpressed wild-type cyclophilin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280279 10077670 394964 17055 9253 PPIA CYPA CyPA 19 1.3 supported by experiments showing that overexpressed wild-type cyclophilin A (CyPA), CyPA but not CyPA with a rotamase active site point mutation 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280280 10077670 394964 17055 9253 PPIA CYPA CyPA 22 1.3 showing that overexpressed wild-type cyclophilin A (CyPA), CyPA but not CyPA with a rotamase active site point mutation protected cells from 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280281 10077670 394965 20996 11179 SOD1 SOD SOD 5 3.2 These data suggest that mutant SOD produces a greater need for rotamase and also highlights possible 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280282 10077670 394968 20996 11179 SOD1 SOD SOD 26 3.2 preparation of adenoviruses (AdVs) AdVs expressing wild type or mutant SOD have been described previously ( 12 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280283 10077670 394972 20996 11179 SOD1 SOD SOD 2 3.2 Expression of SOD and calcineurin A was analyzed by Western blot analysis as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280284 10077670 394974 20996 11179 SOD1 SOD SOD 10 3.2 A previously described method was followed for immunohistochemical detection of SOD ( 12 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280285 10077670 394975 17055 9253 PPIA CYPA CyPA 0 1.3 CyPA (histidine-tagged) histidine-tagged ( 17 expression was detected by immunostaining with 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280286 10077670 394977 20996 11179 SOD1 SOD SOD 8 3.2 The effect of wild-type (WT) WT or FALS-linked mutant SOD gene expression on viability of cells was determined as reported 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280287 10077670 394982 17055 9253 PPIA CYPA CyPA 4 1.3 For some experiments involving CyPA we used a wild-type CyPA (CyPAWT) CyPAWT cDNA or isomerase-deficient 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280288 10077670 394982 17055 9253 PPIA CYPA CyPA 9 1.3 For some experiments involving CyPA we used a wild-type CyPA (CyPAWT) CyPAWT cDNA or isomerase-deficient mutant CyPA(R55A) CyPA R55A cDNA 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280289 10077670 394982 17055 9253 PPIA CYPA CyPA 15 1.3 a wild-type CyPA (CyPAWT) CyPAWT cDNA or isomerase-deficient mutant CyPA(R55A) CyPA R55A cDNA isolated from rat brain and cloned into pcDNA1/AMP 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280290 10077670 394983 17055 9253 PPIA CYPA CyPA 13 1.3 PC12 cells were transfected with either CyPAWT cDNA or CyPA(R55A) CyPA R55A cDNA by using polyethylenimine as described ( 18 19 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280291 10077670 394984 3870 1706 CD8A CD8 CD8 11 0.0 a control for these experiments some cells were transfected with CD8 cDNA (a a gift from Jeff Bluestone University of Chicago 1 JUMiner_v2.2 1 1 cd8; 0 0 0 0 0 0 0 0 280292 10077670 394986 6741 3439 ERCC8 CSA CsA 5 0.0 Drugs included NMDA the immunosuppressants CsA (1 1 _amp_#x003bc M CsG (Nva-2-Cs, Nva-2-Cs 1 _amp_#x003bc M 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280293 10077670 394994 20247 20116 SLC25A29 CACL CaCl 39 1.0 calmodulin and 25 nM calyculin A and either 0.5 mM CaCl 2 or 1 mM EGTA without CaCl 2 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 280294 10077670 394994 20247 20116 SLC25A29 CACL CaCl 46 1.0 either 0.5 mM CaCl 2 or 1 mM EGTA without CaCl 2 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 280295 10077670 394997 14373 7808 NGF NGF NGF 11 1.2 phosphatase activity in cells expressing SODV148G or SODWT or after NGF withdrawal was normalized to activity of mock-infected cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280296 10077670 395000 6741 3439 ERCC8 CSA CsA 6 0.0 Cells were treated with 1 _amp_#x003bc M CsA 48 hr after infection and were harvested 24 hr later 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280297 10077670 395002 20996 11179 SOD1 SOD SOD 0 3.2 SOD Activity Assay 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280298 10077670 395003 6741 3439 ERCC8 CSA CsA 4 0.0 Cells were treated with CsA and were harvested as described above for the rotamase assay 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280299 10077670 395004 20996 11179 SOD1 SOD SOD 0 3.2 SOD activity was determined in triplicate by using a colorimetric assay 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280300 10077670 395006 20996 11179 SOD1 SOD SOD 6 3.2 Overexpression of WT- and FALS-Associated Mutant SOD with Replication-Deficient Adenoviruses 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280301 10077670 395007 20996 11179 SOD1 SOD SOD 0 3.2 SOD expression in PC12 cells was determined by Western blot analysis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280302 10077670 395008 20996 11179 SOD1 SOD SOD 2 3.2 Endogenous rodent SOD was present in both the mock-infected (Fig Fig 1 A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280303 10077670 395009 20996 11179 SOD1 SOD SOD 14 3.2 of slower electrophoretic mobility consistent with that expected for human SOD was present in extracts from cells infected with AdSODWT AdSODV148G 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280304 10077670 395010 20996 11179 SOD1 SOD SOD 2 3.2 The human SOD level in cells expressing SODWT SODV148G and SODA4V was similar 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280305 10077670 395010 20996 11179 SOD1 SOD SOD 15 3.2 cells expressing SODWT SODV148G and SODA4V was similar to endogenous SOD seen in mock cells (Fig Fig 1 A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280306 10077670 395014 20996 11179 SOD1 SOD SOD 5 3.2 Effect of Overexpression of Mutant SOD on Neural Cell Viability 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280307 10077670 395015 20996 11179 SOD1 SOD SOD 10 3.2 We determined the effect of expression of WT and mutant SOD on differentiated PC12 cells a model system for postmitotic neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280308 10077670 395020 20996 11179 SOD1 SOD SOD 14 3.2 that the cells that died were the ones expressing mutant SOD and that these cells died by apoptosis ( 12 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280309 10077670 395021 20996 11179 SOD1 SOD SOD 5 3.2 Effect of Overexpression of Mutant SOD on Calcineurin Activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280310 10077670 395022 20996 11179 SOD1 SOD SOD 8 3.2 We examined the effects of WT and mutant SOD overexpression on calcineurin activity in differentiated PC12 cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280311 10077670 395025 14373 7808 NGF NGF NGF-removal 12 1.2 was no decline in calcineurin activity of PC12 cells after NGF-removal a procedure that also leads to apoptotic cell death (Fig 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280312 10077670 395026 6741 3439 ERCC8 CSA CsA 4 0.0 As expected treatment with CsA a calcineurin inhibitor dramatically decreased calcineurin in all cases by 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280313 10077670 395028 20996 11179 SOD1 SOD SOD 7 3.2 We next tested whether the effects of SOD overexpression on calcineurin activity were related to a change in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280314 10077670 395029 14373 7808 NGF NGF NGF 30 1.2 after mock infection (Fig Fig 2 C lane 1 after NGF removal (Fig Fig 2 C lane 2 or 72 hr 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280315 10077670 395031 20996 11179 SOD1 SOD SOD 12 3.2 CsA and CsA Analogs on Cell Death Induced by Mutant SOD Expression or NGF Withdrawal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280316 10077670 395031 14373 7808 NGF NGF NGF 15 1.2 Analogs on Cell Death Induced by Mutant SOD Expression or NGF Withdrawal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280317 10077670 395031 6741 3439 ERCC8 CSA CsA 2 0.0 Effect of CsA and CsA Analogs on Cell Death Induced by Mutant SOD 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280318 10077670 395031 6741 3439 ERCC8 CSA CsA 4 0.0 Effect of CsA and CsA Analogs on Cell Death Induced by Mutant SOD Expression or 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280319 10077670 395032 20996 11179 SOD1 SOD SOD 5 3.2 To assess the relationship between SOD expression calcineurin activity and cell death cells were treated with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280320 10077670 395033 6741 3439 ERCC8 CSA CsA 9 0.0 In preliminary studies we treated cells expressing SODV148G with CsA and found that 1 and 3 _amp_#x003bc M concentrations significantly 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280321 10077670 395034 6741 3439 ERCC8 CSA CsA 5 0.0 Fig 3 A shows that CsA CsG and FK506 immunosuppressant drugs known to inhibit calcineurin and 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280322 10077670 395035 6741 3439 ERCC8 CSA CsA 6 0.0 The potentiation of cell death by CsA did not reach 100_amp_#x00025 because the viral infection efficiency was 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280323 10077670 395038 20996 11179 SOD1 SOD SOD-expressing 9 2.4 Although cell death was enhanced after treatment of mutant SOD-expressing cells (Fig Fig 3 A CsA dramatically decreased calcineurin activity 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 280324 10077670 395038 6741 3439 ERCC8 CSA CsA 15 0.0 after treatment of mutant SOD-expressing cells (Fig Fig 3 A CsA dramatically decreased calcineurin activity in all cases (Fig Fig 2 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280325 10077670 395039 20996 11179 SOD1 SOD SOD-induced 8 2.4 As previously noted these results indicate that mutant SOD-induced cell death is not related to calcineurin inhibition 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280326 10077670 395041 6741 3439 ERCC8 CSA CsA 12 0.0 the effect of PKF 211_amp_#x02013 811 and PSC 833 nonimmunosuppressant CsA analogs that inhibit cyclophilin rotamase activity but not calcineurin ( 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280327 10077670 395043 6741 3439 ERCC8 CSA CsA 4 0.0 The results suggest that CsA enhances SODV148G-induced cell death by inhibiting cyclophilin rotamase activity and 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280328 10077670 395044 6741 3439 ERCC8 CSA CsA 15 0.0 that does not bind to cyclophilin and treatment with dansylated CsA which has relatively poor binding to cyclophilins at the 1 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280329 10077670 395045 14373 7808 NGF NGF NGF 25 1.2 811 and PSC 833 protected PC12 cells from death after NGF withdrawal (Fig Fig 3 B 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280330 10077670 395045 6741 3439 ERCC8 CSA CsA 8 0.0 In contrast to the above results both immunosuppressants (CsA, CsA CsG and FK506 and nonimmunosuppressants (PKF PKF 211_amp_#x02013 811 and 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280331 10077670 395046 14373 7808 NGF NGF NGF 14 1.2 dansylated CsA had relatively little effect on cell death after NGF withdrawal (Fig Fig 3 B 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280332 10077670 395046 6741 3439 ERCC8 CSA CsA 5 0.0 As expected CsH and dansylated CsA had relatively little effect on cell death after NGF withdrawal 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280333 10077670 395049 20996 11179 SOD1 SOD SOD-induced 9 2.4 Both CsA and PKF 211_amp_#x02013 811 significantly enhanced the mutant SOD-induced death of hippocampal neurons (Fig Fig 4 A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280334 10077670 395049 6741 3439 ERCC8 CSA CsA 1 0.0 Both CsA and PKF 211_amp_#x02013 811 significantly enhanced the mutant SOD-induced death 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280335 10077670 395050 6741 3439 ERCC8 CSA CsA 3 0.0 In contrast both CsA and PKF211_amp_#x02013 811 protected hippocampal neurons from NMDA-induced death (Fig 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280336 10077670 395052 6741 3439 ERCC8 CSA CsA 2 0.0 Effect of CsA on Rotamase Activity Levels 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280337 10077670 395053 20996 11179 SOD1 SOD SOD 12 3.2 studies suggested that CsA and its immunosuppressive analogs might enhance SOD mutant-induced cell death through its interference with rotamase activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280338 10077670 395053 6741 3439 ERCC8 CSA CsA 5 0.0 The above studies suggested that CsA and its immunosuppressive analogs might enhance SOD mutant-induced cell death 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280339 10077670 395054 6741 3439 ERCC8 CSA CsA 31 0.0 and mock cells making the former cells more sensitive to CsA 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280340 10077670 395055 20996 11179 SOD1 SOD SOD-expressing 10 2.4 Therefore we measured rotamase activity in mock WT and mutant SOD-expressing cells before and after CsA treatment 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 280341 10077670 395055 6741 3439 ERCC8 CSA CsA 15 0.0 in mock WT and mutant SOD-expressing cells before and after CsA treatment 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280342 10077670 395056 6741 3439 ERCC8 CSA CsA 14 0.0 all cells had a similar amount of rotamase activity before CsA treatment and that CsA decreased rotamase activity to a similar 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280343 10077670 395056 6741 3439 ERCC8 CSA CsA 18 0.0 similar amount of rotamase activity before CsA treatment and that CsA decreased rotamase activity to a similar level in all three 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280344 10077670 395056 6741 3439 ERCC8 CSA CsA-treated 46 0.0 differences in this inhibition in the SODV148G-expressing cells vs other CsA-treated groups 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280345 10077670 395058 20996 11179 SOD1 SOD SOD-expressing 5 2.4 These results suggested that mutant SOD-expressing cells might be more sensitive to effects of decreased rotamase 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 280346 10077670 395059 20996 11179 SOD1 SOD SOD 6 3.2 Table 1 shows that the baseline SOD activity was similar in mock SODWT- and SODV148G-expressing cells CsA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280347 10077670 395059 20996 11179 SOD1 SOD SOD 21 3.2 mock SODWT- and SODV148G-expressing cells CsA caused a decrease in SOD activity that was significantly (albeit albeit slightly more in SODWT-expressing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280348 10077670 395059 20996 11179 SOD1 SOD SOD-expressing 40 2.4 SODWT-expressing cells than in mock uninfected cells and the mutant SOD-expressing cells had a slightly greater decrease in SOD activity than 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 280349 10077670 395059 20996 11179 SOD1 SOD SOD 48 3.2 the mutant SOD-expressing cells had a slightly greater decrease in SOD activity than SODWT-expressing cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280350 10077670 395059 6741 3439 ERCC8 CSA CsA 16 0.0 SOD activity was similar in mock SODWT- and SODV148G-expressing cells CsA caused a decrease in SOD activity that was significantly (albeit 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280351 10077670 395060 20996 11179 SOD1 SOD SOD 8 3.2 Our interpretation of these studies is that human SOD/rodent SOD rodent SOD heterodimers that are formed in the transiently expressing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280352 10077670 395060 20996 11179 SOD1 SOD SOD 9 3.2 interpretation of these studies is that human SOD/rodent SOD rodent SOD heterodimers that are formed in the transiently expressing cells may 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280353 10077670 395061 20996 11179 SOD1 SOD SOD 5 3.2 In addition the mutant human SOD/rodent SOD rodent SOD heterodimers may be more sensitive to changes in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280354 10077670 395061 20996 11179 SOD1 SOD SOD 6 3.2 In addition the mutant human SOD/rodent SOD rodent SOD heterodimers may be more sensitive to changes in conformation than 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280355 10077670 395061 20996 11179 SOD1 SOD SOD 20 3.2 sensitive to changes in conformation than the WT human SOD/rodent SOD rodent SOD heterodimers 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280356 10077670 395061 20996 11179 SOD1 SOD SOD 21 3.2 changes in conformation than the WT human SOD/rodent SOD rodent SOD heterodimers 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280357 10077670 395062 20996 11179 SOD1 SOD SOD 7 3.2 Effect of Overexpression of Cyclophilin A in SOD Mutant-Induced Cell Death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280358 10077670 395063 20996 11179 SOD1 SOD SOD-induced 11 2.4 further examine the role of cyclophilin rotamase activity on mutant SOD-induced cell death we transfected NGF-differentiated PC12 cells with wild-type CyPA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280359 10077670 395063 14373 7808 NGF NGF NGF-differentiated 16 1.2 cyclophilin rotamase activity on mutant SOD-induced cell death we transfected NGF-differentiated PC12 cells with wild-type CyPA (CyPAWT) CyPAWT cDNA or CyPA(R55A) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280360 10077670 395063 17055 9253 PPIA CYPA CyPA 21 1.3 SOD-induced cell death we transfected NGF-differentiated PC12 cells with wild-type CyPA (CyPAWT) CyPAWT cDNA or CyPA(R55A) CyPA R55A cDNA that contains 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280361 10077670 395063 17055 9253 PPIA CYPA CyPA 25 1.3 PC12 cells with wild-type CyPA (CyPAWT) CyPAWT cDNA or CyPA(R55A) CyPA R55A cDNA that contains a point mutation in the putative 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280362 10077670 395064 17055 9253 PPIA CYPA CyPA 0 1.3 CyPA immunohistochemical staining showed transfection efficiencies of 68 _amp_#x000b1 2_amp_#x00025 ( 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280363 10077670 395065 17055 9253 PPIA CYPA CyPA 10 1.3 cells that overexpressed CyPAWT but not PC12 cells overexpressing CyPA(R55A), CyPA R55A exhibited reduced cell death after SODV148G expression (Fig Fig 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280364 10077670 395066 20996 11179 SOD1 SOD SOD-expression 15 2.4 CyPAWT produced _amp_#x0003e 50_amp_#x00025 protection from cell death after mutant SOD-expression compared with that seen with transfection of a control cDNA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280365 10077670 395066 17055 9253 PPIA CYPA CyPA 29 1.3 transfection of a control cDNA (CD8); CD8 transfection of CyPA(R55A) CyPA R55A was not protective 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280366 10077670 395066 3870 1706 CD8A CD8 CD8 26 0.0 with that seen with transfection of a control cDNA (CD8); CD8 transfection of CyPA(R55A) CyPA R55A was not protective 1 JUMiner_v2.2 1 1 cd8; 0 0 0 0 0 0 0 0 280367 10077670 395067 17055 9253 PPIA CYPA CyPA 8 1.3 These results suggest that the rotamase function of CyPA protects cells from death induced by SODV148G 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280368 10077670 395068 17055 9253 PPIA CYPA CyPA 6 1.3 In contrast overexpression of CyPAWT or CyPA(R55A) CyPA R55A in cells infected with AdSODWT or in mock-infected cells 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280369 10077670 395069 17055 9253 PPIA CYPA CyPA 6 1.3 Furthermore overexpression of either CyPAWT or CyPA(R55A) CyPA R55A did not significantly protect cells from death induced by 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280370 10077670 395069 14373 7808 NGF NGF NGF 16 1.2 R55A did not significantly protect cells from death induced by NGF withdrawal (Fig Fig 5 B indicating that the apoptotic pathway 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280371 10077670 395069 20996 11179 SOD1 SOD SOD 30 3.2 5 B indicating that the apoptotic pathway induced by mutant SOD differs from that after growth factor removal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280372 10077670 395071 17055 9253 PPIA CYPA CyPA 8 1.3 To further investigate these issues we tested whether CyPA rescue of mutant SOD-induced cell death would be decreased with 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280373 10077670 395071 20996 11179 SOD1 SOD SOD-induced 12 2.4 investigate these issues we tested whether CyPA rescue of mutant SOD-induced cell death would be decreased with CsA treatment 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280374 10077670 395071 6741 3439 ERCC8 CSA CsA 19 0.0 rescue of mutant SOD-induced cell death would be decreased with CsA treatment 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280375 10077670 395072 17055 9253 PPIA CYPA CyPA 6 1.3 Table 2 shows that overexpression of CyPA (but but not CD8 _amp_#x0201c control_amp_#x0201d overexpression significantly reduced SODV148G-induced 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280376 10077670 395072 17055 9253 PPIA CYPA CyPA 24 1.3 cell death (from from 49.1 to 21.9_amp_#x00025 and that the CyPA rescue was decreased by CsA (changing changing cell death from 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280377 10077670 395072 3870 1706 CD8A CD8 CD8 9 0.0 Table 2 shows that overexpression of CyPA (but but not CD8 _amp_#x0201c control_amp_#x0201d overexpression significantly reduced SODV148G-induced cell death (from from 1 JUMiner_v2.2 1 1 cd8; 0 0 0 0 0 0 0 0 280378 10077670 395072 6741 3439 ERCC8 CSA CsA 29 0.0 to 21.9_amp_#x00025 and that the CyPA rescue was decreased by CsA (changing changing cell death from 21.9_amp_#x00025 back to 54.6_amp_#x00025 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280379 10077670 395073 20996 11179 SOD1 SOD SOD-expressing 15 2.4 the rotamase activity is vital for the survival of mutant SOD-expressing cells 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 280380 10077670 395076 20996 11179 SOD1 SOD SOD 2 3.2 FALS-associated mutant SOD is believed to kill neurons through a gain of adverse 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280381 10077670 395077 20996 11179 SOD1 SOD SOD 7 3.2 We recently demonstrated that overexpression of mutant SOD leads to altered superoxide content and induces the death of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280382 10077670 395079 20996 11179 SOD1 SOD SOD 5 3.2 ( 16 that WT SOD prevents calcineurin from inactivation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280383 10077670 395080 20996 11179 SOD1 SOD SOD 7 3.2 This finding suggested to us that mutant SOD might induce cell death because it fails to protect calcineurin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280384 10077670 395081 14373 7808 NGF NGF NGF-differentiated 13 1.2 adenovirus as a vector to express SODWT or SODV148G in NGF-differentiated PC12 cells and hippocampal neurons to test whether calcineurin was 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280385 10077670 395081 20996 11179 SOD1 SOD SOD-induced 35 2.4 in this death and to elucidate the mechanism underlying mutant SOD-induced cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280386 10077670 395083 20996 11179 SOD1 SOD SOD-induced 5 2.4 For the latter reason mutant SOD-induced cell death appeared unrelated to an effect on calcineurin activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280387 10077670 395084 20996 11179 SOD1 SOD SOD-induced 10 2.4 To further investigate a role for calcineurin inactivation in mutant SOD-induced cell death we tested the effect of CsA a calcineurin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280388 10077670 395084 6741 3439 ERCC8 CSA CsA 18 0.0 in mutant SOD-induced cell death we tested the effect of CsA a calcineurin inhibitor on cell viability 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280389 10077670 395085 6741 3439 ERCC8 CSA CsA 0 0.0 CsA enhanced death of cells expressing SODV148G but not mock-infected cells 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280390 10077670 395085 6741 3439 ERCC8 CSA CsA 13 0.0 of cells expressing SODV148G but not mock-infected cells even though CsA treatment caused a greater decrease in calcineurin activity in mock-infected 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280391 10077670 395086 20996 11179 SOD1 SOD SOD-induced 13 2.4 demonstrate a lack of correlation between calcineurin activity and mutant SOD-induced cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280392 10077670 395087 6741 3439 ERCC8 CSA CsA 3 0.0 We questioned whether CsA also might influence cell death by its ability to block 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280393 10077670 395089 14373 7808 NGF NGF NGF-withdrawal 1 1.2 Both NGF-withdrawal and expression of SOD mutations have been associated with the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280394 10077670 395089 20996 11179 SOD1 SOD SOD 5 3.2 Both NGF-withdrawal and expression of SOD mutations have been associated with the generation of O 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280395 10077670 395090 14373 7808 NGF NGF NGF 1 1.2 For NGF withdrawal and NMDA toxicity the ability of CsA and its 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280396 10077670 395090 6741 3439 ERCC8 CSA CsA 9 0.0 For NGF withdrawal and NMDA toxicity the ability of CsA and its analogs to block the MPTP and their ability 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280397 10077670 395091 20996 11179 SOD1 SOD SOD 13 3.2 hand CsA and its analogs enhanced death induced by mutant SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280398 10077670 395091 6741 3439 ERCC8 CSA CsA 4 0.0 On the other hand CsA and its analogs enhanced death induced by mutant SOD 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280399 10077670 395093 6741 3439 ERCC8 CSA CsA 9 0.0 In addition to inhibiting calcineurin and blocking the MPTP CsA blocks peptidyl prolyl isomerase (rotamase) rotamase activity of cyclophilins 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280400 10077670 395095 6741 3439 ERCC8 CSA CsA 3 0.0 To test whether CsA enhanced SODV148G toxicity through rotamase inhibition we examined the effect 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280401 10077670 395095 6741 3439 ERCC8 CSA CsA 16 0.0 through rotamase inhibition we examined the effect of immunosuppressants (CsA CsA CsG and FK506 as well as nonimmunosuppressants (PKF PKF 211_amp_#x02013 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280402 10077670 395097 20996 11179 SOD1 SOD SOD 11 3.2 found that both drug classes enhanced apoptosis induced by mutant SOD indicating that the action of CsA may be related to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280403 10077670 395097 6741 3439 ERCC8 CSA CsA 17 0.0 apoptosis induced by mutant SOD indicating that the action of CsA may be related to rotamase inhibition and not to calcineurin 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280404 10077670 395098 20996 11179 SOD1 SOD SOD 6 3.2 A role for rotamase in mutant SOD toxicity was supported by experiments comparing mutant SOD-induced cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280405 10077670 395098 20996 11179 SOD1 SOD SOD-induced 14 2.4 in mutant SOD toxicity was supported by experiments comparing mutant SOD-induced cell death after expression of CyPAWT vs an isomerase activity-deficient 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280406 10077670 395098 17055 9253 PPIA CYPA CyPA 26 1.3 after expression of CyPAWT vs an isomerase activity-deficient mutant CyPA(R55A) CyPA R55A 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280407 10077670 395099 17055 9253 PPIA CYPA CyPA 6 1.3 The WT but not the mutant CyPA protected cells from death induced by mutant SOD expression 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280408 10077670 395099 20996 11179 SOD1 SOD SOD 14 3.2 the mutant CyPA protected cells from death induced by mutant SOD expression 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280409 10077670 395100 17055 9253 PPIA CYPA CyPA 6 1.3 Although a recent report concluded that CyPA(R55A) CyPA R55A may have more rotamase activity than previously suspected ( 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280410 10077670 395101 20996 11179 SOD1 SOD SOD 14 3.2 importance of rotamase activity in modifying the effect of mutant SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280411 10077670 395102 20996 11179 SOD1 SOD SOD-induced 9 2.4 The findings that rotamase activity protects cells from mutant SOD-induced cell death and that there is roughly similar rotamase activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280412 10077670 395102 20996 11179 SOD1 SOD SOD-expressing 27 2.4 similar rotamase activity after CsA treatment in WT- and mutant SOD-expressing cells suggests that cells expressing mutant SOD have a greater 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 280413 10077670 395102 20996 11179 SOD1 SOD SOD 34 3.2 WT- and mutant SOD-expressing cells suggests that cells expressing mutant SOD have a greater reliance on rotamase activity and has implications 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280414 10077670 395102 6741 3439 ERCC8 CSA CsA 21 0.0 death and that there is roughly similar rotamase activity after CsA treatment in WT- and mutant SOD-expressing cells suggests that cells 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280415 10077670 395104 20996 11179 SOD1 SOD SOD 1 3.2 Mutant SOD may increase the oxidative modification of proteins ( 30 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280416 10077670 395107 20996 11179 SOD1 SOD SOD 14 3.2 especially sensitive to the free radical damage induced by mutant SOD because of their high oxidative activity at least partly resulting 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280417 10077670 395109 17055 9253 PPIA CYPA CyPA 2 1.3 In fact CyPA has been shown to be transported by slow axonal transport 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280418 10077670 395110 20996 11179 SOD1 SOD SOD 11 3.2 also may have a role in the normal folding of SOD itself to help stabilize the enzyme or its dimers 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280419 10077670 395111 20996 11179 SOD1 SOD SOD 10 3.2 This activity may be especially critical for abnormal FALS-associated mutant SOD function because SOD mutations may destabilize SOD or the dimer 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280420 10077670 395111 20996 11179 SOD1 SOD SOD 13 3.2 be especially critical for abnormal FALS-associated mutant SOD function because SOD mutations may destabilize SOD or the dimer ( 3 37 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280421 10077670 395111 20996 11179 SOD1 SOD SOD 17 3.2 abnormal FALS-associated mutant SOD function because SOD mutations may destabilize SOD or the dimer ( 3 37 and may lead to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280422 10077670 395113 20996 11179 SOD1 SOD SOD 3 3.2 We found that SOD activity decreased slightly more after mutant SOD expression than after 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280423 10077670 395113 20996 11179 SOD1 SOD SOD 10 3.2 We found that SOD activity decreased slightly more after mutant SOD expression than after SODWT expression suggesting that the mutant enzyme 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280424 10077670 395113 20996 11179 SOD1 SOD SOD 35 3.2 WT to the effects of CsA perhaps because the mutant SOD was more sensitive to a decline in rotamase activity and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280425 10077670 395113 6741 3439 ERCC8 CSA CsA 30 0.0 enzyme was more sensitive than WT to the effects of CsA perhaps because the mutant SOD was more sensitive to a 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280426 10077670 395114 20996 11179 SOD1 SOD SOD 12 3.2 may be that other proteins perhaps ones that interact with SOD are more sensitive to decreased rotamase activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280427 10077670 395118 20996 11179 SOD1 SOD SOD 18 3.2 death seen after CsA treatment of PC12 cells expressing mutant SOD is related to its proapoptotic effect on these cells because 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280428 10077670 395118 6741 3439 ERCC8 CSA CsA 11 0.0 do not believe that the enhancement of death seen after CsA treatment of PC12 cells expressing mutant SOD is related to 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280429 10077670 395119 14373 7808 NGF NGF NGF 11 1.2 addition CsA actually decreased cell death in PC12 cells after NGF withdrawal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280430 10077670 395119 6741 3439 ERCC8 CSA CsA 2 0.0 In addition CsA actually decreased cell death in PC12 cells after NGF withdrawal 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280431 10077670 395129 20996 11179 SOD1 SOD SOD 9 3.2 Figure 1 ( A Western blot analysis of SOD from PC12 cells 3 days after mock infection (lane lane 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280432 10077670 395130 19573 10691 SDS SDS SDS 5 0.0 Cell lysates were subjected to SDS/PAGE, SDS PAGE were blotted (more more ... 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000342255913797283<>ScoreDetail__19440|SBDS|0.000342255913797283__10691|SDS|7.38606987222099e-05__ 0 0 0 0 0 280433 10077670 395131 6741 3439 ERCC8 CSA CsA 4 0.0 Figure 2 Assessment of CsA influence on calcineurin activity and immunoblot analysis of calcineurin at 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280434 10077670 395132 14373 7808 NGF NGF NGF 16 1.2 assayed 3 days after AdV infection or 1 day after NGF withdrawal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280435 10077670 395134 14373 7808 NGF NGF NGF 34 1.2 PC12 cells ( A and show a protective effect after NGF removal ( B 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280436 10077670 395134 6741 3439 ERCC8 CSA CsA 2 0.0 Figure 3 CsA and its immunosuppressant and nonimmunosuppressant analogs potentiate cell death induced 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280437 10077670 395136 6741 3439 ERCC8 CSA CsA 7 0.0 Figure 4 The effect of the immunosuppressant CsA or its nonimmunosuppressive analog PKF211_amp_#x02013 811 on cell survival of 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280438 10077670 395138 17055 9253 PPIA CYPA CyPA 10 1.3 5 Effect of overexpression of WTCyPA or an isomerase-deficient CyPA(R55A) CyPA R55A on PC12 cell death induced by SODV148G expression ( 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280439 10077670 395138 14373 7808 NGF NGF NGF 24 1.2 cell death induced by SODV148G expression ( A or after NGF withdrawal ( B 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280440 10077670 395139 3870 1706 CD8A CD8 CD8 7 0.0 As a control cells were transfected with CD8 cDNA 1 JUMiner_v2.2 1 1 cd8; 0 0 0 0 0 0 0 0 280441 10077670 395141 20996 11179 SOD1 SOD SOD 5 3.2 Table 1 Mean rotamase and SOD activity _amp_#x0005b percent of control (mock-infected) mock-infected PC12 Cells_amp_#x0005d 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280442 10077670 395142 17055 9253 PPIA CYPA CyPA 2 1.3 Table 2 CyPA overexpression rescues PC12 cells from SODV148G-induced death as well as 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280443 10077670 395142 6741 3439 ERCC8 CSA CsA 21 0.0 well as from the enhanced death seen in combination with CsA 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280444 10077670 395143 20996 11179 SOD1 ALS ALS 0 2.4 ALS amyotrophic lateral sclerosis SOD Cu/Zn Cu Zn superoxide dismutase-1 FALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00116678687263326<>ScoreDetail__5468|IGFALS|0.00044478157989652__11179|SOD1|0.00116678687263326__ 0 0 0 0 0 280445 10077670 395143 20996 11179 SOD1 SOD SOD 4 3.2 ALS amyotrophic lateral sclerosis SOD Cu/Zn Cu Zn superoxide dismutase-1 FALS familial ALS CyP cyclophilin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280446 10077670 395143 20996 11179 SOD1 ALS ALS 10 2.4 lateral sclerosis SOD Cu/Zn Cu Zn superoxide dismutase-1 FALS familial ALS CyP cyclophilin WT wild-type NGF nerve growth factor AdV adenovirus 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00116678687263326<>ScoreDetail__5468|IGFALS|0.00044478157989652__11179|SOD1|0.00116678687263326__ 0 0 0 0 0 280447 10077670 395143 14373 7808 NGF NGF NGF 15 1.2 Zn superoxide dismutase-1 FALS familial ALS CyP cyclophilin WT wild-type NGF nerve growth factor AdV adenovirus CsA cyclosporin A NMDA N 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280448 10077670 395143 5344 2595 CYP1A1 CYP CyP 11 0.2 sclerosis SOD Cu/Zn Cu Zn superoxide dismutase-1 FALS familial ALS CyP cyclophilin WT wild-type NGF nerve growth factor AdV adenovirus CsA 5 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 280449 10077670 395143 6741 3439 ERCC8 CSA CsA 21 0.0 CyP cyclophilin WT wild-type NGF nerve growth factor AdV adenovirus CsA cyclosporin A NMDA N -methyl-d -aspartate MPTP mitochondrial permeability transition 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280450 10077670 395144 20996 11179 SOD1 ALS ALS 3 2.4 Amyotrophic lateral sclerosis (ALS) ALS is a fatal progressive neurodegenerative disease that targets motor neurons 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00116678687263326<>ScoreDetail__5468|IGFALS|0.00044478157989652__11179|SOD1|0.00116678687263326__ 0 0 0 0 0 280451 10077670 395145 20996 11179 SOD1 ALS ALS 3 2.4 Approximately 10_amp_#x02013 15_amp_#x00025 of ALS cases are familial and manifest an autosomal dominant inheritance pattern 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00116678687263326<>ScoreDetail__5468|IGFALS|0.00044478157989652__11179|SOD1|0.00116678687263326__ 0 0 0 0 0 280452 10077670 395146 20996 11179 SOD1 SOD SOD 7 3.2 In 1993 mutations in Cu/Zn Cu Zn superoxide dismutase-1 (SOD) SOD were found to be associated with 20_amp_#x00025 of cases of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280453 10077670 395146 20996 11179 SOD1 ALS ALS 19 2.4 found to be associated with 20_amp_#x00025 of cases of familial ALS (FALS) FALS ( 1 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00116678687263326<>ScoreDetail__5468|IGFALS|0.00044478157989652__11179|SOD1|0.00116678687263326__ 0 0 0 0 0 280454 10077670 395147 20996 11179 SOD1 SOD SOD-induced 15 2.4 investigations into the molecular mechanisms underlying the pathogenesis of mutant SOD-induced FALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280455 10077670 395148 20996 11179 SOD1 SOD SOD 0 3.2 SOD is a ubiquitously expressed homodimeric cytosolic enzyme that dismutates superoxide 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280456 10077670 395149 20996 11179 SOD1 SOD SOD 1 3.2 Mutant SOD has been hypothesized to cause FALS not through a loss 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280457 10077670 395149 20996 11179 SOD1 SOD SOD 32 3.2 or an augmentation of a normally present nondismutase activity of SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280458 10077670 395150 20996 11179 SOD1 SOD SOD 26 3.2 transgenic mice ( 4 5 that suggest cells expressing mutant SOD do not necessarily have decreased dismutase function 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280459 10077670 395151 20996 11179 SOD1 SOD SOD 3 3.2 In addition a SOD knockout mouse has normal motor neuron development ( 6 demonstrating 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280460 10077670 395152 20996 11179 SOD1 SOD SOD 4 3.2 The toxicity of mutant SOD has been proposed to involve one or more of the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280461 10077670 395153 20996 11179 SOD1 SOD SOD 11 3.2 recently has been reported that the expression of FALS-associated mutant SOD in nerve growth factor (NGF)-differentiated NGF -differentiated PC12 cells primary 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280462 10077670 395153 14373 7808 NGF NGF NGF 16 1.2 expression of FALS-associated mutant SOD in nerve growth factor (NGF)-differentiated NGF -differentiated PC12 cells primary sympathetic neurons and hippocampal neurons leads 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280463 10077670 395154 20996 11179 SOD1 SOD SOD-induced 8 2.4 The present study explores the relationship of mutant SOD-induced death to calcineurin a calcium/calmodulin-dependent calcium calmodulin-dependent phosphatase and characterizes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280464 10077670 395154 6741 3439 ERCC8 CSA CsA 30 0.0 of calcineurin such as the immunosuppressant compounds cyclosporin A (CsA), CsA CsG and FK506 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280465 10077670 395155 5344 2595 CYP1A1 CYP CyP 8 0.0 Immunosuppressants bind immunophilins _amp_#x0005b the drug receptor e.g. cyclophilins (CyP) CyP or FK binding protein_amp_#x0005d and the drug-immunophilin complex inhibits calcineurin 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280466 10077670 395156 20996 11179 SOD1 SOD SOD 23 3.2 proline residues aids normal folding and assembly of proteins including SOD and has other cellular functions ( 15 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280467 10077670 395157 20996 11179 SOD1 SOD SOD 5 3.2 A recent report demonstrated that SOD normally protects calcineurin from inactivation ( 16 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280468 10077670 395158 20996 11179 SOD1 SOD SOD-expressing 10 2.4 We asked whether the increase in O 2 in mutant SOD-expressing cells leads to calcineurin inactivation and contributes to FALS-related cell 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 280469 10077670 395159 20996 11179 SOD1 SOD SOD 10 3.2 The present investigation demonstrates that the proapoptotic activity of mutant SOD is not related to calcineurin inhibition 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280470 10077670 395160 20996 11179 SOD1 SOD SOD 17 3.2 CsA CsG and FK506 enhance cell death induced by mutant SOD and that this enhancement depends on rotamase inhibition 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 280471 10077670 395160 6741 3439 ERCC8 CSA CsA 7 0.0 Most importantly we show that immunosuppressant drugs (CsA, CsA CsG and FK506 enhance cell death induced by mutant SOD 14 JUMiner_v2.2 1 0 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000747197048186507<>ScoreDetail__3439|ERCC8|0.000425891670957366__5244|HSPA9|0.000747197048186507__2440|CSH1|0.000657473878740493__ 0 0 0 0 0 280472 10077670 395161 20996 11179 SOD1 SOD SOD 5 3.2 These findings suggest that mutant SOD may lead to increased protein damage or turnover and a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 281642 10190145 396301 18723 10261 ROS1 ROS ROS 6 0.0 In the CNS reactive oxygen species (ROS) ROS have been implicated in a wide range of degenerative processes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 281643 10190145 396302 18723 10261 ROS1 ROS ROS 15 0.0 unknown and there is little information on possible roles of ROS in cell injury and the process on recovery of astrocytes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 281644 10190145 396306 24185 29175 WDTC1 ADP ADP-ribose 3 0.0 Caffeine ryanodine cyclic ADP-ribose (endogenous endogenous ryanodine receptor agonist and beta-NAD (precursor precursor of 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 281645 10190145 396306 24185 29175 WDTC1 ADP ADP-ribose 13 0.0 endogenous ryanodine receptor agonist and beta-NAD (precursor precursor of cyclic ADP-ribose suppressed partially the stimulatory effect of H2O2 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 281646 10190145 396308 24185 29175 WDTC1 ADP ADP-ribose 16 0.0 on H2O2-induced thymidine incorporation was suppressed by caffeine ryanodine cyclic ADP-ribose and beta-NAD 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 276496 10229967 388848 20996 11179 SOD1 ALS ALS 17 0.0 AD Parkinson's disease (PD) PD and amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000790083845281272<>ScoreDetail__5468|IGFALS|0.00044089550776466__11179|SOD1|0.000790083845281272__ 0 0 0 0 0 276497 10229967 388850 21472 19420 STOML3 SRO SRO 12 0.0 presented here suggests that the species reactive to oxygen (SRO) SRO play a direct part in the aetiology and/or and or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277401 10385054 390302 20996 11179 SOD1 SOD SODs 2 2.7 Superoxide dismutases (SODs) SODs are enzymes that can influence free radical processes in irradiated 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277402 10385054 390302 20996 11179 SOD1 SOD SODs 22 2.7 irradiated cells and there is some evidence that manipulation of SODs can affect survival of cells after radiation treatments 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277403 10385054 390303 20996 11179 SOD1 SOD1 SOD-1 0 10.2 SOD-1 associated FALS mutants may have an altered radiation response due 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277404 10385054 390304 20996 11179 SOD1 SOD1 SOD-1 14 10.2 ability of the lymphoblastoid cell lines from FALS patients with SOD-1 gene mutations patients with sporadic ALS and controls to handle 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277405 10385054 390304 20996 11179 SOD1 ALS ALS 20 2.7 from FALS patients with SOD-1 gene mutations patients with sporadic ALS and controls to handle oxidative stress induced by ionising radiation 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00104157303092804<>ScoreDetail__5468|IGFALS|0.00103269415823691__11179|SOD1|0.00104157303092804__ 0 0 0 0 0 277406 10385054 390305 20996 11179 SOD1 ALS ALS 22 2.7 fluorescence of a radical-reactive fluorochrome in the cells from familial ALS patients with SOD-1 gene mutations (2.14_amp_#xb1;1.06 2.14_amp_#xb1 1.06 Gy _amp_#x2212 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00104157303092804<>ScoreDetail__5468|IGFALS|0.00103269415823691__11179|SOD1|0.00104157303092804__ 0 0 0 0 0 277407 10385054 390305 20996 11179 SOD1 SOD1 SOD-1 25 10.2 radical-reactive fluorochrome in the cells from familial ALS patients with SOD-1 gene mutations (2.14_amp_#xb1;1.06 2.14_amp_#xb1 1.06 Gy _amp_#x2212 1 and patients 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277408 10385054 390305 20996 11179 SOD1 ALS ALS 36 2.7 (2.14_amp_#xb1;1.06 2.14_amp_#xb1 1.06 Gy _amp_#x2212 1 and patients with sporadic ALS (1.38_amp_#xb1;0.21 1.38_amp_#xb1 0.21 Gy _amp_#x2212 1 were not significantly different 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00104157303092804<>ScoreDetail__5468|IGFALS|0.00103269415823691__11179|SOD1|0.00104157303092804__ 0 0 0 0 0 277409 10385054 390307 20996 11179 SOD1 SOD1 SOD-1 9 10.2 The ability of lymphoblastoid cells from FALS patients with SOD-1 gene mutations to scavenge radiation-induced free radicals is not compromised 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277410 10385054 390310 18723 10261 ROS1 ROS ROS 12 0.3 much interest in the role of reactive oxygen species (ROS) ROS in the pathogenesis of neurodegenerative disease 1 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 277411 10385054 390311 20996 11179 SOD1 SOD1 SOD-1 31 10.2 and defects in the Cu/Zn Cu Zn superoxide dismutase (SOD-1) SOD-1 gene 2 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277412 10385054 390312 20996 11179 SOD1 SOD1 SOD-1 1 10.2 The SOD-1 gene encodes the cytosolic SOD-1 protein which catalyses the dismutation 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277413 10385054 390312 20996 11179 SOD1 SOD1 SOD-1 6 10.2 The SOD-1 gene encodes the cytosolic SOD-1 protein which catalyses the dismutation of superoxide anions (O O 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277414 10385054 390313 20996 11179 SOD1 SOD1 SOD-1 1 10.2 However SOD-1 can also generate free radicals 3 and SOD-1 associated FALS 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277415 10385054 390313 20996 11179 SOD1 SOD1 SOD-1 11 10.2 However SOD-1 can also generate free radicals 3 and SOD-1 associated FALS mutants have been shown to enhance the production 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277416 10385054 390313 20996 11179 SOD1 SOD SOD 55 2.7 radicals 6 and it has been demonstrated that manipulation of SOD activity can influence the cellular radiation response 7 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277417 10385054 390313 18723 10261 ROS1 ROS ROS-mediated 37 0.0 ( OH 4 and 5 lonising radiation results in increased ROS-mediated cell damage particularly by hydroxyl radicals 6 and it has 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277418 10385054 390314 20996 11179 SOD1 SOD1 SOD-1 8 10.2 Cells from FALS patients with mutations in the SOD-1 gene might therefore have a reduced tolerance of ROS and 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277419 10385054 390314 18723 10261 ROS1 ROS ROS 17 0.3 the SOD-1 gene might therefore have a reduced tolerance of ROS and in particular OH thus leading to the DNA damage 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 277420 10385054 390315 18723 10261 ROS1 ROS ROS 8 0.3 Here we have used ionising radiation to generate ROS in lymphoblastoid cell-lines from FALS patients with mutations in the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 277421 10385054 390315 20996 11179 SOD1 SOD1 SOD-1 19 10.2 in lymphoblastoid cell-lines from FALS patients with mutations in the SOD-1 gene and to examine the ability of FALS cells to 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277422 10385054 390318 20996 11179 SOD1 SOD1 SOD-1 26 10.2 ( n =2 and Gly 37 Arg ( n =1 SOD-1 gene mutations 8 and a known UK FALS patient with 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277423 10385054 390318 20996 11179 SOD1 SOD1 SOD-1 46 10.2 FALS patient with a Ile 149 Thr mutation in the SOD-1 gene 9 patients with sporadic ALS and matched spouse-controls were 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277424 10385054 390318 20996 11179 SOD1 ALS ALS 54 2.7 Thr mutation in the SOD-1 gene 9 patients with sporadic ALS and matched spouse-controls were studied 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00104157303092804<>ScoreDetail__5468|IGFALS|0.00103269415823691__11179|SOD1|0.00104157303092804__ 0 0 0 0 0 277425 10385054 390318 117 77 ABL2 ARG Arg 22 0.0 with Ala 4 Val ( n =2 and Gly 37 Arg ( n =1 SOD-1 gene mutations 8 and a known 2 JUMiner_v2.2 1 0 0 2 77 TotalCon:2<>77|ABL2|27|Complete__9965|RERE|473|Complete__<>AvaiableGeneRif=2<>BEST:77|ABL2|0.000803001766603887<>ScoreDetail__77|ABL2|0.000803001766603887__9965|RERE|0__ 0 0 0 0 0 277426 10385054 390319 1759 1102 BRD1 BRL BRL 10 0.3 lines were maintained in Iscove-modified essential medium (IMEM, IMEM Gibco BRL supplemented with 10% (v/v) v v fetal bovine serum 2 1 JUMiner_v2.2 1 2 gibco brl 0 0 0 0 0 0 0 0 277427 10385054 390322 18723 10261 ROS1 ROS ROS 12 0.3 of fluorescence after the production of a standard level of ROS (here here produced by treatment with ionising radiation is related 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 277428 10385054 390322 18723 10261 ROS1 ROS ROS 30 0.3 is related to the level of cellular species that neutralize ROS before they can react with DCFH thus providing a good 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 277429 10385054 390322 18723 10261 ROS1 ROS ROS 50 0.3 good indicator of the ability of the cell to scavenge ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 277430 10385054 390341 20996 11179 SOD1 SOD1 SOD-1 14 10.2 1 in the lymhpoblastoid cell lines from FALS patients with SOD-1 gene mutations were 1.50 and 1.26 ( Ala 4 Val 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277431 10385054 390341 117 77 ABL2 ARG Arg 30 0.0 1.26 ( Ala 4 Val mutation 0.97 ( Gly 37 Arg mutation and 1.43 ( Ile 149 Thr mutation whereas FAR 2 JUMiner_v2.2 1 0 0 2 77 TotalCon:2<>77|ABL2|27|Complete__9965|RERE|473|Complete__<>AvaiableGeneRif=2<>BEST:77|ABL2|0.000803001766603887<>ScoreDetail__77|ABL2|0.000803001766603887__9965|RERE|0__ 0 0 0 0 0 277432 10385054 390345 20996 11179 SOD1 ALS ALS 6 2.7 The mechanism of the neurodegeneration in ALS is unknown but may involve free radical induced damage which 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00104157303092804<>ScoreDetail__5468|IGFALS|0.00103269415823691__11179|SOD1|0.00104157303092804__ 0 0 0 0 0 277433 10385054 390347 20996 11179 SOD1 SOD1 SOD-1 26 10.2 DNA damage might be expected in lymphoblastoid cell lines with SOD-1 gene mutations 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277434 10385054 390348 20996 11179 SOD1 SOD1 SOD-1 16 10.2 reduced ability of lymphobiastoid cells from either FALS patients with SOD-1 gene mutations or from patients with sporadic ALS to cope 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277435 10385054 390348 20996 11179 SOD1 ALS ALS 24 2.7 patients with SOD-1 gene mutations or from patients with sporadic ALS to cope with radiation-induced oxidative stress 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00104157303092804<>ScoreDetail__5468|IGFALS|0.00103269415823691__11179|SOD1|0.00104157303092804__ 0 0 0 0 0 277436 10385054 390350 20996 11179 SOD1 SOD1 SOD-1 20 10.2 production of hydroperoxides and double-strand DNA breaks is equivalent in SOD-1 associated FALS SALS and control lymphoblastoid cell lines 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277437 10385054 390351 18723 10261 ROS1 ROS ROS 9 0.3 However these findings do not exclude a role for ROS in the pathogenesis of ALS as the results relate to 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 277438 10385054 390351 20996 11179 SOD1 ALS ALS 14 2.7 not exclude a role for ROS in the pathogenesis of ALS as the results relate to ROS produced by ionising radiation 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00104157303092804<>ScoreDetail__5468|IGFALS|0.00103269415823691__11179|SOD1|0.00104157303092804__ 0 0 0 0 0 277439 10385054 390351 18723 10261 ROS1 ROS ROS 20 0.3 in the pathogenesis of ALS as the results relate to ROS produced by ionising radiation and other ROS may be involved 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 277440 10385054 390351 18723 10261 ROS1 ROS ROS 27 0.3 results relate to ROS produced by ionising radiation and other ROS may be involved in ALS in response to other stresses 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 277441 10385054 390351 20996 11179 SOD1 ALS ALS 32 2.7 by ionising radiation and other ROS may be involved in ALS in response to other stresses 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00104157303092804<>ScoreDetail__5468|IGFALS|0.00103269415823691__11179|SOD1|0.00104157303092804__ 0 0 0 0 0 277442 10385054 390352 20996 11179 SOD1 SOD SOD 12 2.7 lines used in this study demonstrate a wide range of SOD activity regardless of the presence of the SOD-1 gene mutation 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277443 10385054 390352 20996 11179 SOD1 SOD1 SOD-1 20 10.2 range of SOD activity regardless of the presence of the SOD-1 gene mutation (data data not shown 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277444 10385054 390354 18723 10261 ROS1 ROS ROS 12 0.3 that lymphoblastoid cells maintain their capacity to deal with radiation-induced ROS supports the hypothesis that a gain of an adverse function 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 277445 10385054 390354 20996 11179 SOD1 SOD1 SOD-1 24 10.2 the hypothesis that a gain of an adverse function of SOD-1 rather than a loss of function may lead to motor 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277446 10385054 390355 20996 11179 SOD1 SOD1 SOD-1 7 10.2 An abnormal gain of function could enable SOD-1 to catalyse other reactions that are normally unfavorable e.g nitration 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277447 10385054 390356 18723 10261 ROS1 ROS ROS 22 0.3 differently from neuronal cells in their capacity to deal with ROS and further experiments in neuronal cell lines and primary cultures 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 277448 10385054 390358 18723 10261 ROS1 ROS ROS 3 0.3 Intracellular levels of ROS shown as relative fluorescence of DCFH (RF, RF see text 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 277449 10385054 390361 20996 11179 SOD1 SOD1 SOD-1 14 10.2 1 in the lymphoblastoid cell lines of FALS patients with SOD-1 gene mutations (FALS), FALS patients with sporadic ALS (SALS) SALS 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277450 10385054 390361 20996 11179 SOD1 ALS ALS 21 2.7 patients with SOD-1 gene mutations (FALS), FALS patients with sporadic ALS (SALS) SALS and matched controls 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00104157303092804<>ScoreDetail__5468|IGFALS|0.00103269415823691__11179|SOD1|0.00104157303092804__ 0 0 0 0 0 277451 10385054 390367 20996 11179 SOD1 SOD1 SOD-1 13 10.2 1 in the lymphoblastoid cell lines of FALS patients with SOD-1 gene mutations (FALS), FALS patients with sporadic ALS (SALS) SALS 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 277452 10385054 390367 20996 11179 SOD1 ALS ALS 20 2.7 patients with SOD-1 gene mutations (FALS), FALS patients with sporadic ALS (SALS) SALS and matched controls 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00104157303092804<>ScoreDetail__5468|IGFALS|0.00103269415823691__11179|SOD1|0.00104157303092804__ 0 0 0 0 0 274167 10448978 383978 20996 11179 SOD1 ALS ALS 8 0.0 Biological markers in the diagnosis and treatment of ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000601610416092762<>ScoreDetail__5468|IGFALS|0.000480610375176474__11179|SOD1|0.000601610416092762__ 0 0 0 0 0 274168 10448978 383979 20996 11179 SOD1 ALS ALS 8 0.0 The care of patients with amyotrophic lateral sclerosis (ALS), ALS which has classically focused on treatment of symptomatology has now 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000601610416092762<>ScoreDetail__5468|IGFALS|0.000480610375176474__11179|SOD1|0.000601610416092762__ 0 0 0 0 0 274169 10448978 383985 20996 11179 SOD1 ALS ALS 0 0.0 ALS patients were found to experience a significant increase in the 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000601610416092762<>ScoreDetail__5468|IGFALS|0.000480610375176474__11179|SOD1|0.000601610416092762__ 0 0 0 0 0 274170 10448978 383987 20996 11179 SOD1 ALS ALS 31 0.0 which to screen the efficacy of potential therapeutic agents for ALS and Hospital McGill University Canada 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000601610416092762<>ScoreDetail__5468|IGFALS|0.000480610375176474__11179|SOD1|0.000601610416092762__ 0 0 0 0 0 272908 10593879 381898 20996 11179 SOD1 ALS ALS 17 2.2 a role in the pathogenesis of amyotrophic lateral sclerosis (ALS), ALS a unique microdialysis or microcannula sampling technique was used in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272909 10593879 381898 20996 11179 SOD1 SOD1 SOD1 35 6.2 in mice transfected with a mutant Cu Zn-superoxide dismutase (SOD1) SOD1 gene from humans with familial ALS mice transfected with the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272910 10593879 381898 20996 11179 SOD1 ALS ALS 41 2.2 Cu Zn-superoxide dismutase (SOD1) SOD1 gene from humans with familial ALS mice transfected with the normal human SOD1 gene and normal 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272911 10593879 381898 20996 11179 SOD1 SOD1 SOD1 48 6.2 humans with familial ALS mice transfected with the normal human SOD1 gene and normal mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272912 10593879 381898 18723 10261 ROS1 ROS ROS 6 0.0 To explore whether reactive oxygen species (ROS) ROS play a role in the pathogenesis of amyotrophic lateral sclerosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272913 10593879 381899 20996 11179 SOD1 ALS ALS 40 2.2 the superoxide anion (O O 2 is significantly lower in ALS mutant mice than in controls supporting by in vivo evidence 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272914 10593879 381900 18723 10261 ROS1 ROS ROS 8 0.0 This removes doubts regarding the relevance of elevated ROS in FALS raised by in vitro experiments 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272915 10593879 381904 20996 11179 SOD1 SOD1 SOD1 20 6.2 impairment of its detoxification pathways perhaps by changed interactions between SOD1 and H 2 O 2 detoxification enzymes._amp_#151 Liu D. Wen 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272916 10593879 381906 20996 11179 SOD1 ALS ALS 3 2.2 AMYOTROPHIC LATERAL SCLEROSIS (ALS) ALS is an untreatable age-related fatal motor neuron degenerative disease whose 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272917 10593879 381907 20996 11179 SOD1 SOD1 SOD1 10 6.2 of a single-site mutation in the Cu Zn-superoxide dismutase (SOD1) SOD1 gene in familial ALS (FALS) FALS patients (2 2 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272918 10593879 381907 20996 11179 SOD1 ALS ALS 14 2.2 in the Cu Zn-superoxide dismutase (SOD1) SOD1 gene in familial ALS (FALS) FALS patients (2 2 3 linked this disease to 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272919 10593879 381908 20996 11179 SOD1 ALS ALS 43 2.2 radical ( OH play a role in neuronal degeneration in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272920 10593879 381908 18723 10261 ROS1 ROS ROS 17 0.0 with sound in vivo experiments whether reactive oxygen species (ROS), ROS including superoxide anion (O O 2 hydrogen peroxide (H H 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272921 10593879 381909 20996 11179 SOD1 SOD1 SOD1 4 6.2 To explore how mutant SOD1 (mSOD1) mSOD1 causes ALS Gurney and colleagues (5) 5 produced 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272922 10593879 381909 20996 11179 SOD1 SOD1 mSOD1 5 3.0 To explore how mutant SOD1 (mSOD1) mSOD1 causes ALS Gurney and colleagues (5) 5 produced a transgenic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272923 10593879 381909 20996 11179 SOD1 ALS ALS 7 2.2 To explore how mutant SOD1 (mSOD1) mSOD1 causes ALS Gurney and colleagues (5) 5 produced a transgenic mouse model 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272924 10593879 381909 20996 11179 SOD1 ALS ALS 22 2.2 a transgenic mouse model by introducing a human (with with ALS disease mutant SOD1 (mSOD1) mSOD1 gene (Gly Gly 93 Ala 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272925 10593879 381909 20996 11179 SOD1 SOD1 SOD1 25 6.2 model by introducing a human (with with ALS disease mutant SOD1 (mSOD1) mSOD1 gene (Gly Gly 93 Ala G93A into mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272926 10593879 381909 20996 11179 SOD1 SOD1 mSOD1 26 3.0 introducing a human (with with ALS disease mutant SOD1 (mSOD1) mSOD1 gene (Gly Gly 93 Ala G93A into mice these transfected 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272927 10593879 381909 20996 11179 SOD1 ALS ALS 41 2.2 G93A into mice these transfected mice developed symptoms resembling human ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272928 10593879 381910 20996 11179 SOD1 SOD1 SOD1 5 6.2 Since then over 50 different SOD1 mutants have been identified in FALS families (6) 6 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272929 10593879 381911 20996 11179 SOD1 ALS ALS 26 2.2 whether free radicals play a role in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272930 10593879 381912 20996 11179 SOD1 SOD1 SOD1 2 6.2 Screening revealed SOD1 mutations with reduced SOD1 activity in 16 of 73 (22%) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272931 10593879 381912 20996 11179 SOD1 SOD1 SOD1 6 6.2 Screening revealed SOD1 mutations with reduced SOD1 activity in 16 of 73 (22%) 22% ALS families (7) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272932 10593879 381912 20996 11179 SOD1 ALS ALS 13 2.2 with reduced SOD1 activity in 16 of 73 (22%) 22% ALS families (7) 7 suggesting that a loss of SOD1 function 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272933 10593879 381912 20996 11179 SOD1 SOD1 SOD1 22 6.2 22% ALS families (7) 7 suggesting that a loss of SOD1 function sometimes occurs in ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272934 10593879 381912 20996 11179 SOD1 ALS ALS 27 2.2 suggesting that a loss of SOD1 function sometimes occurs in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272935 10593879 381913 20996 11179 SOD1 SOD1 SOD1 3 6.2 Mutations of the SOD1 gene reduce superoxide dismutase activity (2 2 3 8 9 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272936 10593879 381915 20996 11179 SOD1 SOD1 SOD1 17 6.2 found that transgenic mice expressing high levels of mutant human SOD1 protein became paralyzed even though the animal's own normal SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272937 10593879 381915 20996 11179 SOD1 SOD1 SOD1 27 6.2 SOD1 protein became paralyzed even though the animal's own normal SOD1 gene remained intact while similar overexpression of normal human SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272938 10593879 381915 20996 11179 SOD1 SOD1 SOD1 37 6.2 SOD1 gene remained intact while similar overexpression of normal human SOD1 did not produce ALS (5) 5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272939 10593879 381915 20996 11179 SOD1 ALS ALS 41 2.2 while similar overexpression of normal human SOD1 did not produce ALS (5) 5 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272940 10593879 381917 20996 11179 SOD1 SOD1 SOD1 8 6.2 This result and the significantly increased expression of SOD1 mRNA in spinal cord motor neurons in sporadic ALS (13) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272941 10593879 381917 20996 11179 SOD1 ALS ALS 17 2.2 of SOD1 mRNA in spinal cord motor neurons in sporadic ALS (13) 13 suggest that the mSOD1 protein gains a new 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272942 10593879 381917 20996 11179 SOD1 SOD1 mSOD1 22 3.0 motor neurons in sporadic ALS (13) 13 suggest that the mSOD1 protein gains a new function that damages motor neurons (5) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272943 10593879 381918 20996 11179 SOD1 SOD1 SOD1 7 6.2 It has been demonstrated in vitro that SOD1 can catalyze dissociation of H 2 O 2 to OH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272944 10593879 381918 20996 11179 SOD1 SOD1 mSOD1 27 3.0 OH (14 14 15 and that the OH-generating function of mSOD1 (G93A G93A and A4V is enhanced relative to that of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272945 10593879 381918 20996 11179 SOD1 SOD1 SOD1 39 6.2 and A4V is enhanced relative to that of the normal SOD1 enzyme (16 16 17 18 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272946 10593879 381919 20996 11179 SOD1 SOD1 mSOD1 10 3.0 X-ray crystallographic studies show that the active channel of the mSOD1 containing copper and zinc is slightly larger than that of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272947 10593879 381919 20996 11179 SOD1 SOD1 SOD1 23 6.2 and zinc is slightly larger than that of the normal SOD1 enzyme (3) 3 thus the metal atoms are more accessible 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272948 10593879 381920 20996 11179 SOD1 SOD1 SOD1 2 6.2 The mutant SOD1 might catalyze more OH formation because its Cu is more 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272949 10593879 381921 20996 11179 SOD1 SOD1 SOD1 11 6.2 there is strong disagreement regarding the possibility that the mutant SOD1 gains a new function to catalyze OH formation from H 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272950 10593879 381923 20996 11179 SOD1 SOD1 SOD1 15 6.2 OH levels are not significantly different between mutant (G37R) G37R SOD1 transgenic mice and controls (20) 20 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272951 10593879 381924 20996 11179 SOD1 SOD1 SOD1 25 6.2 (CSF) CSF in G93A transgenic mice than in normal and SOD1 transgenic mice (21) 21 and an elevated level of OH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272952 10593879 381924 11629 6493 LAMC2 CSF CSF 16 0.0 of OH is significantly higher in the cerebrospinal fluid (CSF) CSF in G93A transgenic mice than in normal and SOD1 transgenic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272953 10593879 381925 20996 11179 SOD1 SOD1 SOD1 17 6.2 is no difference in catalytic capability in vitro between mutant SOD1 and normal SOD1 in producing OH from H 2 O 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272954 10593879 381925 20996 11179 SOD1 SOD1 SOD1 20 6.2 in catalytic capability in vitro between mutant SOD1 and normal SOD1 in producing OH from H 2 O 2 questioning the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272955 10593879 381926 20996 11179 SOD1 SOD1 SOD1 18 6.2 examined in vivo the in vitro finding that on mutation SOD1 gains a new function catalyzing OH formation from H 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272956 10593879 381927 20996 11179 SOD1 SOD1 mSOD1 11 3.0 the levels of ROS in the G93A transgenic mice (mSOD1 mSOD1 mice normal SOD1 transgenic mice (SOD1 SOD1 mice and normal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272957 10593879 381927 20996 11179 SOD1 SOD1 SOD1 14 6.2 ROS in the G93A transgenic mice (mSOD1 mSOD1 mice normal SOD1 transgenic mice (SOD1 SOD1 mice and normal mice (or or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272958 10593879 381927 20996 11179 SOD1 SOD1 SOD1 17 6.2 transgenic mice (mSOD1 mSOD1 mice normal SOD1 transgenic mice (SOD1 SOD1 mice and normal mice (or or the littermates of G93A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272959 10593879 381927 18723 10261 ROS1 ROS ROS 5 0.0 We determined the levels of ROS in the G93A transgenic mice (mSOD1 mSOD1 mice normal SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272960 10593879 381928 20996 11179 SOD1 SOD1 mSOD1 12 3.0 indicate that the in vitro finding of OH formation by mSOD1 using H 2 O 2 as a substrate reported previously 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272961 10593879 381928 20996 11179 SOD1 ALS ALS 41 2.2 realistic pathway in vivo demonstrating a role of ROS in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272962 10593879 381928 18723 10261 ROS1 ROS ROS 39 0.1 is a realistic pathway in vivo demonstrating a role of ROS in ALS 6 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 272963 10593879 381931 20996 11179 SOD1 ALS ALS 16 2.2 concerning the role of oxidative stress in the pathogenesis of ALS (19 19 29 and the experimental results are contradictory 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272964 10593879 381932 20996 11179 SOD1 ALS ALS 21 2.2 increased in the spinal cord sections of FALS and sporadic ALS (SALS) SALS patients compared to control patients (30) 30 in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272965 10593879 381932 20996 11179 SOD1 SOD1 SOD1 45 6.2 in the spinal cord (32) 32 in mutant (G93A) G93A SOD1 transgenic mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272966 10593879 381933 20996 11179 SOD1 ALS ALS 10 2.2 The antioxidants vitamin E and selenium delay the appearance of ALS symptoms in these mice (33) 33 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272967 10593879 381935 20996 11179 SOD1 ALS ALS 36 2.2 was also 10-fold higher in the spinal cord tissue in ALS patients than in controls (34) 34 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272968 10593879 381936 20996 11179 SOD1 ALS ALS 15 2.2 oxidation_amp_#151 was elevated by 85% in postmortem brain tissue from ALS patients (8) 8 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272969 10593879 381939 20996 11179 SOD1 SOD1 SOD1 7 6.2 Our results support that the mutation of SOD1 indeed induces oxidative stress and correlate SOD1 mutation to elevated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272970 10593879 381939 20996 11179 SOD1 SOD1 SOD1 14 6.2 the mutation of SOD1 indeed induces oxidative stress and correlate SOD1 mutation to elevated H 2 O 2 OH and oxidative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272971 10593879 381942 20996 11179 SOD1 SOD1 SOD1 16 6.2 the Jackson laboratory were used mice transfected with the mutant SOD1 gene (G93A) G93A from humans with FALS-B6SJL-TgN(SOD1-G93A)1Gur,mice FALS-B6SJL-TgN SOD1-G93A 1Gur 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272972 10593879 381942 20996 11179 SOD1 SOD1 SOD1 27 6.2 with FALS-B6SJL-TgN(SOD1-G93A)1Gur,mice FALS-B6SJL-TgN SOD1-G93A 1Gur mice transfected with normal human SOD1 gene B6SJL-TgN(SOD1)2Gur, B6SJL-TgN SOD1 2Gur and normal control mice (B6SJLF1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272973 10593879 381942 20996 11179 SOD1 SOD1 SOD1 29 6.2 1Gur mice transfected with normal human SOD1 gene B6SJL-TgN(SOD1)2Gur, B6SJL-TgN SOD1 2Gur and normal control mice (B6SJLF1 B6SJLF1 or littermates of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272974 10593879 381942 20996 11179 SOD1 SOD1 mSOD1 38 3.0 2Gur and normal control mice (B6SJLF1 B6SJLF1 or littermates of mSOD1 and SOD1 mice without gene transfection 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272975 10593879 381942 20996 11179 SOD1 SOD1 SOD1 38 6.2 2Gur and normal control mice (B6SJLF1 B6SJLF1 or littermates of mSOD1 and SOD1 mice without gene transfection 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272976 10593879 381942 20996 11179 SOD1 SOD1 SOD1 40 6.2 normal control mice (B6SJLF1 B6SJLF1 or littermates of mSOD1 and SOD1 mice without gene transfection 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272977 10593879 381943 20996 11179 SOD1 ALS ALS 18 2.2 protein carbonyl content 8-OHdG and MDA the onset of the ALS symptoms in the mSOD1 mice we used was delayed due 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 272978 10593879 381943 20996 11179 SOD1 SOD1 mSOD1 22 3.0 and MDA the onset of the ALS symptoms in the mSOD1 mice we used was delayed due to a small transgenic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272979 10593879 381944 20996 11179 SOD1 SOD1 mSOD1 1 3.0 Therefore mSOD1 SOD1 and Nc mice were used at 6-6.5 months of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272980 10593879 381944 20996 11179 SOD1 SOD1 SOD1 2 6.2 Therefore mSOD1 SOD1 and Nc mice were used at 6-6.5 months of age 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272981 10593879 381945 20996 11179 SOD1 SOD1 mSOD1 1 3.0 The mSOD1 mice used for the measurement of O 2 and H 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272982 10593879 381945 20996 11179 SOD1 SOD1 mSOD1 36 3.0 by 4-5 months for those mutants therefore 2.5- to 3-month-old mSOD1 mice and matching age SOD1 and Nc mice were used 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272983 10593879 381945 20996 11179 SOD1 SOD1 SOD1 41 6.2 mutants therefore 2.5- to 3-month-old mSOD1 mice and matching age SOD1 and Nc mice were used while paralysis was developing in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272984 10593879 381946 20996 11179 SOD1 SOD1 mSOD1 14 3.0 levels of O 2 were different among the littermates of mSOD1 mice littermates of SOD1 mice and the normal control mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272985 10593879 381946 20996 11179 SOD1 SOD1 SOD1 18 6.2 were different among the littermates of mSOD1 mice littermates of SOD1 mice and the normal control mice (B6SJLF1); B6SJLF1 no difference 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272986 10593879 381947 20996 11179 SOD1 SOD1 mSOD1 11 3.0 the B6SJLF1 normal control mice are a valid control for mSOD1 mice our definition of normal control (Nc) Nc mice includes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272987 10593879 381947 20996 11179 SOD1 SOD1 mSOD1 26 3.0 control (Nc) Nc mice includes B6SJLF1 mice and littermates of mSOD1 and SOD mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272988 10593879 381947 20996 11179 SOD1 SOD SOD 28 1.9 Nc mice includes B6SJLF1 mice and littermates of mSOD1 and SOD mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272989 10593879 381948 11629 6493 LAMC2 CSF CSF 20 0.0 cistern in the intrathecal space of the mouse spinal cord CSF was sampled from there so as to avoid damage to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272990 10593879 381949 11629 6493 LAMC2 CSF CSF 10 0.0 The cauda equina in the terminal cistern is surrounded by CSF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272991 10593879 381952 20996 11179 SOD1 SOD1 SOD1 3 6.2 The mutation of SOD1 significantly increases the levels of OH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272992 10593879 381953 11629 6493 LAMC2 CSF CSF 15 0.0 2,3- and 2 5-DHBA measured in the dialysates sampled from CSF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272993 10593879 381954 20996 11179 SOD1 SOD1 mSOD1 14 3.0 5-DHBA (mean_amp_#177; mean_amp_#177 SD is 980 _amp_#177 240 nM in mSOD1 mice ( n =8 300 _amp_#177 120 nM in SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272994 10593879 381954 20996 11179 SOD1 SOD1 SOD1 24 6.2 mSOD1 mice ( n =8 300 _amp_#177 120 nM in SOD1 mice ( n =5 and 400 _amp_#177 190 nM in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272995 10593879 381954 20996 11179 SOD1 SOD1 mSOD1 43 3.0 nM in Nc mice ( n =6 ~3.3-fold higher in mSOD1 mice than in SOD1 mice ( P =0.0001 and 2.5-fold 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272996 10593879 381954 20996 11179 SOD1 SOD1 SOD1 47 6.2 ( n =6 ~3.3-fold higher in mSOD1 mice than in SOD1 mice ( P =0.0001 and 2.5-fold higher than in Nc 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272997 10593879 381955 20996 11179 SOD1 SOD1 mSOD1 14 3.0 3-DHBA (mean_amp_#177; mean_amp_#177 SD is 650 _amp_#177 130 nM in mSOD1 mice 330 _amp_#177 90 nM in SOD1 mice and 350 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272998 10593879 381955 20996 11179 SOD1 SOD1 SOD1 21 6.2 130 nM in mSOD1 mice 330 _amp_#177 90 nM in SOD1 mice and 350 _amp_#177 190 nM in Nc mice ~2.0-fold 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 272999 10593879 381955 20996 11179 SOD1 SOD1 mSOD1 34 3.0 350 _amp_#177 190 nM in Nc mice ~2.0-fold higher in mSOD1 mice than in SOD1 mice ( P =0.0006 and 1.9-fold 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273000 10593879 381955 20996 11179 SOD1 SOD1 SOD1 38 6.2 in Nc mice ~2.0-fold higher in mSOD1 mice than in SOD1 mice ( P =0.0006 and 1.9-fold higher than in Nc 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273001 10593879 381956 20996 11179 SOD1 SOD1 mSOD1 9 3.0 Both 2,5- and 2 3-DHBA levels are significantly higher in mSOD1 mice than in SOD1 and Nc mice but there is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273002 10593879 381956 20996 11179 SOD1 SOD1 SOD1 13 6.2 3-DHBA levels are significantly higher in mSOD1 mice than in SOD1 and Nc mice but there is no significant difference between 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273003 10593879 381956 20996 11179 SOD1 SOD1 SOD1 25 6.2 Nc mice but there is no significant difference between the SOD1 and Nc mice ( P =0.3 for 2 5-DHBA and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273004 10593879 381956 20996 11179 SOD1 SOD1 SOD1 43 6.2 and 0.8 for 2 3-DHBA direct in vivo evidence that SOD1 mutation elevates the levels of OH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273005 10593879 381957 20996 11179 SOD1 SOD1 SOD1 15 6.2 the first time using G93A transgenic mice that mutation of SOD1 elevates levels of both H 2 O 2 and OH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273006 10593879 381958 20996 11179 SOD1 SOD1 SOD1 15 6.2 H 2 O 2 level is increased in the mutant SOD1 transgenic mice but not in the mice overexpressing normal human 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273007 10593879 381958 20996 11179 SOD1 SOD1 SOD1 26 6.2 transgenic mice but not in the mice overexpressing normal human SOD1 is particularly important with significant implications about the pathogenesis of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273008 10593879 381958 20996 11179 SOD1 ALS ALS 37 2.2 is particularly important with significant implications about the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 273009 10593879 381959 20996 11179 SOD1 SOD1 mSOD1 16 3.0 hypothesis and indicate that the new function gained by the mSOD1 includes both catalyzing H 2 O 2 conversion to OH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273010 10593879 381960 20996 11179 SOD1 SOD1 mSOD1 13 3.0 20 appeared to rule out elevation of OH production in mSOD1 transgenic mice and reports (18 18 23 as to whether 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273011 10593879 381960 20996 11179 SOD1 SOD1 SOD1 25 6.2 mice and reports (18 18 23 as to whether mutant SOD1 catalyzes increased production of OH from H 2 O 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273012 10593879 381961 20996 11179 SOD1 SOD1 SOD1 8 6.2 However in our in vivo results mutation of SOD1 clearly raised H 2 O 2 levels and induced more 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273013 10593879 381962 20996 11179 SOD1 SOD1 mSOD1 19 3.0 greater ratio of OH]/[H OH H 2 O 2 in mSOD1 mice (0.23) 0.23 than in SOD1 and Nc mice (0.17 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273014 10593879 381962 20996 11179 SOD1 SOD1 SOD1 24 6.2 2 O 2 in mSOD1 mice (0.23) 0.23 than in SOD1 and Nc mice (0.17 0.17 and 0.16 respectively supports the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273015 10593879 381962 20996 11179 SOD1 SOD1 mSOD1 36 3.0 mice (0.17 0.17 and 0.16 respectively supports the notion that mSOD1 mice have a higher capability of converting H 2 O 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273016 10593879 381962 20996 11179 SOD1 SOD1 SOD1 51 6.2 capability of converting H 2 O 2 to OH than SOD1 and Nc mice do 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273017 10593879 381964 20996 11179 SOD1 ALS ALS 18 2.2 2 and OH should contribute to neuronal death in the ALS mice and possibly in human with FALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 273018 10593879 381966 20996 11179 SOD1 SOD1 SOD1 0 6.2 SOD1 mice contain both the SOD1 enzyme from the transfected normal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273019 10593879 381966 20996 11179 SOD1 SOD1 SOD1 5 6.2 SOD1 mice contain both the SOD1 enzyme from the transfected normal human SOD1 (hSOD1) hSOD1 gene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273020 10593879 381966 20996 11179 SOD1 SOD1 SOD1 12 6.2 contain both the SOD1 enzyme from the transfected normal human SOD1 (hSOD1) hSOD1 gene and the mouse's own SOD1 (endogenous endogenous 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273021 10593879 381966 20996 11179 SOD1 SOD1 hSOD1 13 1.9 the SOD1 enzyme from the transfected normal human SOD1 (hSOD1) hSOD1 gene and the mouse's own SOD1 (endogenous endogenous SOD1 eSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273022 10593879 381966 20996 11179 SOD1 SOD1 SOD1 19 6.2 normal human SOD1 (hSOD1) hSOD1 gene and the mouse's own SOD1 (endogenous endogenous SOD1 eSOD1 mSOD1 mice contain the G93A mutant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273023 10593879 381966 20996 11179 SOD1 SOD1 SOD1 21 6.2 (hSOD1) hSOD1 gene and the mouse's own SOD1 (endogenous endogenous SOD1 eSOD1 mSOD1 mice contain the G93A mutant SOD1 and eSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273024 10593879 381966 20996 11179 SOD1 SOD1 mSOD1 23 3.0 gene and the mouse's own SOD1 (endogenous endogenous SOD1 eSOD1 mSOD1 mice contain the G93A mutant SOD1 and eSOD1 whereas Nc 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273025 10593879 381966 20996 11179 SOD1 SOD1 SOD1 29 6.2 (endogenous endogenous SOD1 eSOD1 mSOD1 mice contain the G93A mutant SOD1 and eSOD1 whereas Nc mice contain only eSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273026 10593879 381967 20996 11179 SOD1 SOD1 SOD1 26 6.2 thereby reduce the level of O 2 has the order SOD1 mice > mSOD1 mice > Nc mice and the opposite 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273027 10593879 381967 20996 11179 SOD1 SOD1 mSOD1 29 3.0 level of O 2 has the order SOD1 mice > mSOD1 mice > Nc mice and the opposite order for the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273028 10593879 381967 20996 11179 SOD1 SOD1 mSOD1 48 3.0 order for the level of O 2 Nc mice > mSOD1 mice > SOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273029 10593879 381967 20996 11179 SOD1 SOD1 SOD1 51 6.2 level of O 2 Nc mice > mSOD1 mice > SOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273030 10593879 381969 20996 11179 SOD1 SOD1 SOD1 9 6.2 All together our results demonstrate that the mutation of SOD1 induced more OH formation from elevated H 2 O 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273031 10593879 381969 20996 11179 SOD1 ALS ALS 39 2.2 OH evidence that ROS are involved in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 273032 10593879 381969 18723 10261 ROS1 ROS ROS 32 0.0 sequence O 2 H 2 O 2 OH evidence that ROS are involved in the pathogenesis of ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273033 10593879 381970 20996 11179 SOD1 SOD1 SOD1 42 6.2 H 2 O 2 may be converted to OH by SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273034 10593879 381971 20996 11179 SOD1 SOD1 SOD1 16 6.2 ability more H 2 O 2 should be produced in SOD1 mice however no accumulation of H 2 O 2 was 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273035 10593879 381971 20996 11179 SOD1 SOD1 SOD1 29 6.2 no accumulation of H 2 O 2 was observed in SOD1 mice compared to Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273036 10593879 381972 20996 11179 SOD1 SOD1 mSOD1 21 3.0 which is the normal catalytic function of GSH-Px and catalase mSOD1 mice had significantly higher levels of H 2 O 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273037 10593879 381972 20996 11179 SOD1 SOD1 SOD1 37 6.2 of H 2 O 2 and OH than did the SOD1 and Nc mice and significantly lower levels of O 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273038 10593879 381973 20996 11179 SOD1 SOD1 mSOD1 3 3.0 This suggests that mSOD1 gains a new function blocking H 2 O 2 conversion 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273039 10593879 381974 20996 11179 SOD1 SOD1 SOD1 43 6.2 O 2 caused by increasing or decreasing levels of wild-type SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273040 10593879 381977 20996 11179 SOD1 SOD1 hSOD1 4 1.9 Because overexpression of hSOD1 or knocking out eSOD1 did not change the onset and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273041 10593879 381977 20996 11179 SOD1 ALS ALS 33 2.2 the hypothesis that ROS are involved in the pathogenesis of ALS (19) 19 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 273042 10593879 381977 18723 10261 ROS1 ROS ROS 26 0.0 of the disease they strongly disagreed with the hypothesis that ROS are involved in the pathogenesis of ALS (19) 19 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273043 10593879 381978 20996 11179 SOD1 SOD1 SOD1 17 6.2 of mice show that although addition of mutant and normal SOD1 both decrease O 2 concentrations concentrations of H 2 O 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273044 10593879 381978 20996 11179 SOD1 SOD1 SOD1 38 6.2 2 increase with the presence of mutated but not normal SOD1 contrary to their assumption 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273045 10593879 381979 20996 11179 SOD1 SOD1 hSOD1 14 1.9 results that H 2 O 2 formed by overexpression of hSOD1 is efficiently destroyed whereas more of that produced by the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273046 10593879 381979 20996 11179 SOD1 SOD1 SOD1 26 6.2 efficiently destroyed whereas more of that produced by the mutant SOD1 escapes into the tissue where it may produce damaging OH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273047 10593879 381980 20996 11179 SOD1 SOD1 SOD1 22 6.2 O 2 detoxification pathway a crucial change whereby mutation of SOD1 leads to ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273048 10593879 381980 20996 11179 SOD1 ALS ALS 25 2.2 pathway a crucial change whereby mutation of SOD1 leads to ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 273049 10593879 381981 20996 11179 SOD1 ALS ALS 36 2.2 evidence against aberrant O 2 destruction being a cause of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 273050 10593879 381982 20996 11179 SOD1 SOD1 mSOD1 13 3.0 possible to discover this problem in vitro by using purified mSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273051 10593879 381983 20996 11179 SOD1 SOD1 SOD1 2 6.2 The deleterious SOD1 mutations typically are in the interaction regions crucial to subunit 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273052 10593879 381983 20996 11179 SOD1 SOD1 SOD1 23 6.2 folding and dimer contact (3) 3 explaining why there is SOD1 aggregation only in the G93A and G85R transgenic mice but 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273053 10593879 381983 20996 11179 SOD1 SOD1 SOD1 39 6.2 and G85R transgenic mice but not in the mice overexpressing SOD1 (19) 19 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273054 10593879 381984 20996 11179 SOD1 SOD1 SOD1 1 6.2 The SOD1 dimer may act in tandem as a superoxide dismutase and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273055 10593879 381986 20996 11179 SOD1 SOD1 mSOD1 28 3.0 evidenced by the accumulation of H 2 O 2 in mSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273056 10593879 381988 20996 11179 SOD1 SOD1 SOD1 17 6.2 radicals their work supports a relationship between free radicals and SOD1 mutation in FALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273057 10593879 381989 20996 11179 SOD1 SOD1 SOD1 18 6.2 2 O 2 of fibroblasts from FALS patients with an SOD1 mutation is higher than for controls suggests that the mechanism 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273058 10593879 381992 20996 11179 SOD1 SOD1 mSOD1 15 3.0 O 2 levels in the dialysates are also elevated in mSOD1 mice is consistent with this explanation since H 2 O 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273059 10593879 381993 20996 11179 SOD1 SOD1 mSOD1 27 3.0 level of H 2 O 2 in the cells in mSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273060 10593879 381993 11629 6493 LAMC2 CSF CSF 11 0.0 the higher level of H 2 O 2 measured in CSF may also indicate a higher level of H 2 O 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273061 10593879 381996 20996 11179 SOD1 SOD1 mSOD1 9 3.0 The elevated level of H 2 O 2 in mSOD1 mice supports the notion that the increased levels of OH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273062 10593879 381996 20996 11179 SOD1 SOD1 SOD1 35 6.2 partly formed from H 2 O 2 by the mutant SOD1 however a contribution of peroxynitrate cannot be ruled out since 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273063 10593879 381996 20996 11179 SOD1 SOD1 mSOD1 56 3.0 we have found that the level of nitric oxide in mSOD1 mice is also significantly higher than in SOD1 and Nc 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273064 10593879 381996 20996 11179 SOD1 SOD1 SOD1 64 6.2 oxide in mSOD1 mice is also significantly higher than in SOD1 and Nc mice (65) 65 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273065 10593879 381997 20996 11179 SOD1 SOD1 hSOD1 7 1.9 Based on the observations that overexpression of hSOD1 did not change the onset and progress of the disease 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273066 10593879 381997 20996 11179 SOD1 ALS ALS 34 2.2 any possible effect of oxidative stress on the pathogenesis of ALS (19) 19 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 273067 10593879 381998 20996 11179 SOD1 SOD1 SOD1 10 6.2 It has been suggested that the deleterious effect of mutant SOD1 on motor neurons in ALS is not related to increased 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273068 10593879 381998 20996 11179 SOD1 ALS ALS 15 2.2 the deleterious effect of mutant SOD1 on motor neurons in ALS is not related to increased oxidant stress caused by increased 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 273069 10593879 381999 20996 11179 SOD1 SOD1 mSOD1 18 3.0 of protein DNA and membrane lipids are significantly higher in mSOD1 mice than in SOD1 and Nc mice but not between 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273070 10593879 381999 20996 11179 SOD1 SOD1 SOD1 22 6.2 membrane lipids are significantly higher in mSOD1 mice than in SOD1 and Nc mice but not between SOD1 and Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273071 10593879 381999 20996 11179 SOD1 SOD1 SOD1 29 6.2 mice than in SOD1 and Nc mice but not between SOD1 and Nc mice is consistent with some other reports (8 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273072 10593879 382000 20996 11179 SOD1 SOD1 mSOD1 16 3.0 membrane lipid oxidation together with elevated level of OH in mSOD1 mice support the hypothesis that OH-triggered oxidation of major cell 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273073 10593879 382001 20996 11179 SOD1 SOD1 SOD1 25 6.2 been revealed the finding that there are higher levels of SOD1 in motoneurons relative to other neurons (66) 66 implicates a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273074 10593879 382001 20996 11179 SOD1 ALS ALS 46 2.2 of free radicals in the selective degeneration of motoneurons in ALS because higher levels of mSOD1 are probably present in those 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 273075 10593879 382001 20996 11179 SOD1 SOD1 mSOD1 51 3.0 selective degeneration of motoneurons in ALS because higher levels of mSOD1 are probably present in those neurons relative to others when 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273076 10593879 382019 20996 11179 SOD1 SOD1 mSOD1 23 3.0 EC detection in the three groups of mice (8 8 mSOD1 5 SOD1 and 6 Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273077 10593879 382019 20996 11179 SOD1 SOD1 SOD1 25 6.2 in the three groups of mice (8 8 mSOD1 5 SOD1 and 6 Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273078 10593879 382024 20996 11179 SOD1 SOD1 mSOD1 9 3.0 b Chromatogram of 10 microl dialysate obtained from a mSOD1 mouse 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273079 10593879 382026 20996 11179 SOD1 SOD1 SOD1 9 6.2 c Chromatogram of 10 microl dialysate obtained from a SOD1 mouse 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273080 10593879 382049 20996 11179 SOD1 SOD1 mSOD1 13 3.0 of reduced cytochrome c measured in the perfusates collected from mSOD1 ( n =6 SOD1 ( n =3 and Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273081 10593879 382049 20996 11179 SOD1 SOD1 SOD1 17 6.2 measured in the perfusates collected from mSOD1 ( n =6 SOD1 ( n =3 and Nc mice ( n =6 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273082 10593879 382051 20996 11179 SOD1 SOD1 mSOD1 13 3.0 of reduced cytochrome c measured in spinal cord tissue in mSOD1 ( n =3 SOD1 ( n =3 and Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273083 10593879 382051 20996 11179 SOD1 SOD1 SOD1 17 6.2 measured in spinal cord tissue in mSOD1 ( n =3 SOD1 ( n =3 and Nc mice ( n =4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273084 10593879 382056 20996 11179 SOD1 SOD1 mSOD1 12 3.0 in microdialysates was measured by HPLC and fluorescence detection in mSOD1 ( n =8 SOD1 ( n =7 and Nc ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273085 10593879 382056 20996 11179 SOD1 SOD1 SOD1 16 6.2 by HPLC and fluorescence detection in mSOD1 ( n =8 SOD1 ( n =7 and Nc ( n =9 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273086 10593879 382061 20996 11179 SOD1 SOD1 mSOD1 10 3.0 Protein carbonyl content in the mouse spinal cord tissue of mSOD1 SOD1 and Nc mice was measured spectrophotometrically after labeling with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273087 10593879 382061 20996 11179 SOD1 SOD1 SOD1 11 6.2 carbonyl content in the mouse spinal cord tissue of mSOD1 SOD1 and Nc mice was measured spectrophotometrically after labeling with DNPH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273088 10593879 382076 8255 4236 GFER HPO HPO 28 0.0 0.9 Mg 1.3 Ca 132 Cl 21.0 HCO 3 2.5 HPO 4 and 3.5 glucose 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273089 10593879 382087 6335 17029 ECD ECD ECD 47 0.0 by high-performance liquid chromatography (HPLC HPLC with electrochemical detection (ECD) ECD 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>17029|ECD|11319|No_GeneRif__10845|SHFM1|7979|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 273090 10593879 382088 7625 3758 FLOT2 ESA ESA 36 0.0 column were used to separate these two isomers and an ESA Coulochem II ECD was used for detection 1 JUMiner_v2.2 1 0 0 2 9204 TotalCon:2<>3758|FLOT2|2319|Complete__9204|PON1|5444|Complete__<>AvaiableGeneRif=2<>BEST:9204|PON1|0.000460111132972805<>ScoreDetail__9204|PON1|0.000460111132972805__3758|FLOT2|0.000428948557840402__ 0 0 0 0 0 273091 10593879 382088 6335 17029 ECD ECD ECD 39 0.0 to separate these two isomers and an ESA Coulochem II ECD was used for detection 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>17029|ECD|11319|No_GeneRif__10845|SHFM1|7979|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 273092 10593879 382111 11629 6493 LAMC2 CSF CSF 11 0.0 MDA concentration was measured in the microdialysates sampled from the CSF in the terminal cistern of the mouse intrathecal space by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273093 10593879 382136 7625 3758 FLOT2 ESA ESA 12 0.0 for HPLC analysis was according to the standard method of ESA Inc 1 JUMiner_v2.2 1 0 0 2 9204 TotalCon:2<>3758|FLOT2|2319|Complete__9204|PON1|5444|Complete__<>AvaiableGeneRif=2<>BEST:9204|PON1|0.000460111132972805<>ScoreDetail__9204|PON1|0.000460111132972805__3758|FLOT2|0.000428948557840402__ 0 0 0 0 0 273094 10593879 382137 7625 3758 FLOT2 ESA ESA 10 0.0 A Shimadzu HPLC with a Waters ODS2 column and an ESA ECD was used 1 JUMiner_v2.2 1 0 0 2 9204 TotalCon:2<>3758|FLOT2|2319|Complete__9204|PON1|5444|Complete__<>AvaiableGeneRif=2<>BEST:9204|PON1|0.000460111132972805<>ScoreDetail__9204|PON1|0.000460111132972805__3758|FLOT2|0.000428948557840402__ 0 0 0 0 0 273095 10593879 382137 6335 17029 ECD ECD ECD 11 0.0 Shimadzu HPLC with a Waters ODS2 column and an ESA ECD was used 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>17029|ECD|11319|No_GeneRif__10845|SHFM1|7979|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 273096 10593879 382139 7625 3758 FLOT2 ESA ESA 31 0.0 4 at a 1 ml/min ml min flow rate (ESA, ESA Inc. standard method 1 JUMiner_v2.2 1 0 0 2 9204 TotalCon:2<>3758|FLOT2|2319|Complete__9204|PON1|5444|Complete__<>AvaiableGeneRif=2<>BEST:9204|PON1|0.000460111132972805<>ScoreDetail__9204|PON1|0.000460111132972805__3758|FLOT2|0.000428948557840402__ 0 0 0 0 0 273097 10593879 382141 20996 11179 SOD1 SOD1 mSOD1 20 3.0 all measurements to determine whether the mean results obtained from mSOD1 SOD1 and Nc mice were significantly different 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273098 10593879 382141 20996 11179 SOD1 SOD1 SOD1 21 6.2 measurements to determine whether the mean results obtained from mSOD1 SOD1 and Nc mice were significantly different 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273099 10593879 382142 20996 11179 SOD1 SOD1 SOD1 3 6.2 The mutation of SOD1 significantly increases the levels of H 2 O 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273100 10593879 382144 20996 11179 SOD1 SOD1 mSOD1 17 3.0 2 (mean_amp_#177; mean_amp_#177 SD is 2.8 _amp_#177 0.3 microM in mSOD1 mice ( n =4 1.9 _amp_#177 0.2 microM in SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273101 10593879 382144 20996 11179 SOD1 SOD1 SOD1 27 6.2 mSOD1 mice ( n =4 1.9 _amp_#177 0.2 microM in SOD1 mice ( n =3 and 2.1 _amp_#177 0.4 microM in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273102 10593879 382145 20996 11179 SOD1 SOD1 mSOD1 11 3.0 levels of H 2 O 2 are significantly higher in mSOD1 mice than in SOD1 ( P =0.005 and Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273103 10593879 382145 20996 11179 SOD1 SOD1 SOD1 15 6.2 O 2 are significantly higher in mSOD1 mice than in SOD1 ( P =0.005 and Nc mice ( P =0.007 but 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273104 10593879 382145 20996 11179 SOD1 SOD1 SOD1 33 6.2 P =0.007 but there is no significant difference between the SOD1 and Nc mice ( P =0.6 indicating that mutant SOD1in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273105 10593879 382145 20996 11179 SOD1 SOD1 mSOD1 45 3.0 Nc mice ( P =0.6 indicating that mutant SOD1in the mSOD1 mice also elevates H 2 O 2 levels 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273106 10593879 382147 20996 11179 SOD1 SOD1 mSOD1 14 3.0 levels of O 2 in the perfusates collected from the mSOD1 SOD1 and Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273107 10593879 382147 20996 11179 SOD1 SOD1 SOD1 15 6.2 of O 2 in the perfusates collected from the mSOD1 SOD1 and Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273108 10593879 382148 20996 11179 SOD1 SOD1 mSOD1 15 3.0 cytochrome c (mean_amp_#177; mean_amp_#177 SD is 0.060 _amp_#177 0.011 in mSOD1 mice ( n =6 0.037 _amp_#177 0.004 in SOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273109 10593879 382148 20996 11179 SOD1 SOD1 SOD1 24 6.2 in mSOD1 mice ( n =6 0.037 _amp_#177 0.004 in SOD1 mice ( n =3 and 0.130 _amp_#177 0.030 in Nc 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273110 10593879 382149 20996 11179 SOD1 SOD1 mSOD1 26 3.0 2 are significantly higher in normal control mice than in mSOD1 ( P =0.0007 and SOD1 mice ( P =0.002 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273111 10593879 382149 20996 11179 SOD1 SOD1 SOD1 31 6.2 normal control mice than in mSOD1 ( P =0.0007 and SOD1 mice ( P =0.002 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273112 10593879 382150 20996 11179 SOD1 SOD1 mSOD1 10 3.0 The level of O 2 is also significantly higher in mSOD1 than in SOD1 mice ( P =0.01 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273113 10593879 382150 20996 11179 SOD1 SOD1 SOD1 13 6.2 O 2 is also significantly higher in mSOD1 than in SOD1 mice ( P =0.01 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273114 10593879 382151 20996 11179 SOD1 SOD1 mSOD1 16 3.0 of O 2 in the spinal cord tissue of the mSOD1 SOD1 and Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273115 10593879 382151 20996 11179 SOD1 SOD1 SOD1 17 6.2 O 2 in the spinal cord tissue of the mSOD1 SOD1 and Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273116 10593879 382152 20996 11179 SOD1 SOD1 mSOD1 19 3.0 absorbance g wet weight tissue is 158 _amp_#177 10 in mSOD1 mice ( n =3 138 _amp_#177 10 in SOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273117 10593879 382152 20996 11179 SOD1 SOD1 SOD1 28 6.2 in mSOD1 mice ( n =3 138 _amp_#177 10 in SOD1 mice ( n =3 and 186 _amp_#177 12 in Nc 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273118 10593879 382153 20996 11179 SOD1 SOD1 mSOD1 26 3.0 tissue of normal control mice is significantly higher than in mSOD1 ( P =0.02 and SOD1 mice ( P =0.003 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273119 10593879 382153 20996 11179 SOD1 SOD1 SOD1 31 6.2 is significantly higher than in mSOD1 ( P =0.02 and SOD1 mice ( P =0.003 and is also higher in mSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273120 10593879 382153 20996 11179 SOD1 SOD1 mSOD1 41 3.0 SOD1 mice ( P =0.003 and is also higher in mSOD1 than in SOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273121 10593879 382153 20996 11179 SOD1 SOD1 SOD1 44 6.2 P =0.003 and is also higher in mSOD1 than in SOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273122 10593879 382154 11629 6493 LAMC2 CSF CSF 15 0.0 vivo measurement of the levels of O 2 in the CSF and spinal cord 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273123 10593879 382155 20996 11179 SOD1 SOD1 SOD1 2 6.2 Mutation of SOD1 significantly increases membrane peroxidation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273124 10593879 382156 20996 11179 SOD1 SOD1 mSOD1 15 3.0 of MDA in the dialysates collected from the CSF in mSOD1 SOD1 and Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273125 10593879 382156 20996 11179 SOD1 SOD1 SOD1 16 6.2 MDA in the dialysates collected from the CSF in mSOD1 SOD1 and Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273126 10593879 382156 11629 6493 LAMC2 CSF CSF 13 0.1 the concentrations of MDA in the dialysates collected from the CSF in mSOD1 SOD1 and Nc mice 6 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 273127 10593879 382157 20996 11179 SOD1 SOD1 mSOD1 14 3.0 MDA (mean_amp_#177; mean_amp_#177 SD is 70 _amp_#177 15 nM in mSOD1 mice ( n =8 40 _amp_#177 5 nM in SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273128 10593879 382157 20996 11179 SOD1 SOD1 SOD1 24 6.2 mSOD1 mice ( n =8 40 _amp_#177 5 nM in SOD1 mice ( n =7 and 30 _amp_#177 10 nM in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273129 10593879 382158 20996 11179 SOD1 SOD1 mSOD1 6 3.0 The MDA level in dialysates in mSOD1 mice is 1.8-fold that in SOD1 mice ( P =0.0005 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273130 10593879 382158 20996 11179 SOD1 SOD1 SOD1 12 6.2 level in dialysates in mSOD1 mice is 1.8-fold that in SOD1 mice ( P =0.0005 and 2.3-fold higher than in Nc 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273131 10593879 382159 20996 11179 SOD1 SOD1 SOD1 6 6.2 There was no significant difference between SOD1 and Nc mice ( P =0.1 suggesting that overexpression of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273132 10593879 382159 20996 11179 SOD1 SOD1 SOD1 18 6.2 Nc mice ( P =0.1 suggesting that overexpression of normal SOD1 does not increase peroxidation of membrane lipids 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273133 10593879 382160 20996 11179 SOD1 SOD1 mSOD1 7 3.0 The significantly higher levels of MDA in mSOD1 mice than in SOD1 and Nc mice demonstrate that oxidative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273134 10593879 382160 20996 11179 SOD1 SOD1 SOD1 11 6.2 significantly higher levels of MDA in mSOD1 mice than in SOD1 and Nc mice demonstrate that oxidative damage to membrane phospholipids 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273135 10593879 382160 20996 11179 SOD1 SOD1 SOD1 30 6.2 membrane phospholipids indeed occurs after the induction of the mutant SOD1 gene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273136 10593879 382161 20996 11179 SOD1 SOD1 SOD1 3 6.2 The mutation of SOD1 significantly increases protein oxidation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273137 10593879 382163 20996 11179 SOD1 SOD1 mSOD1 15 3.0 SD is 2.31 _amp_#177 0.16 nmol/mg nmol mg protein in mSOD1 mice 1.95 _amp_#177 0.09 nmol/mg nmol mg protein in SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273138 10593879 382163 20996 11179 SOD1 SOD1 SOD1 23 6.2 mSOD1 mice 1.95 _amp_#177 0.09 nmol/mg nmol mg protein in SOD1 mice and 1.94 _amp_#177 0.13 nmol/mg nmol mg in Nc 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273139 10593879 382164 20996 11179 SOD1 SOD1 mSOD1 12 3.0 carbonyl content in spinal cord tissue is 1.2-fold higher in mSOD1 mice than in SOD1 ( P =0.0002 and Nc ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273140 10593879 382164 20996 11179 SOD1 SOD1 SOD1 16 6.2 cord tissue is 1.2-fold higher in mSOD1 mice than in SOD1 ( P =0.0002 and Nc ( P =0.0004 mice_amp_#151 a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273141 10593879 382164 20996 11179 SOD1 SOD1 SOD1 44 6.2 two controls ( P =0.9 indicating that overexpression of normal SOD1 does not induce protein oxidation and only mutant SOD1 in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273142 10593879 382164 20996 11179 SOD1 SOD1 SOD1 53 6.2 normal SOD1 does not induce protein oxidation and only mutant SOD1 in mSOD1 mice causes significantly more protein oxidation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273143 10593879 382164 20996 11179 SOD1 SOD1 mSOD1 55 3.0 does not induce protein oxidation and only mutant SOD1 in mSOD1 mice causes significantly more protein oxidation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273144 10593879 382165 20996 11179 SOD1 SOD1 SOD1 3 6.2 The mutation of SOD1 significantly increases DNA oxidation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273145 10593879 382168 20996 11179 SOD1 SOD1 mSOD1 9 3.0 The average concentration (from from three samples of 8-OHdG in mSOD1 mice is 0.27 _amp_#177 0.06 fmol/mg fmol mg wet tissue 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273146 10593879 382168 20996 11179 SOD1 SOD1 mSOD1 28 3.0 _amp_#177 0.12 fmol/microg fmol microg DNA (mean_amp_#177; mean_amp_#177 SD 10 mSOD1 mouse spinal cords were measured as three samples 8-OHdG was 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273147 10593879 382168 20996 11179 SOD1 SOD1 SOD1 47 6.2 8-OHdG was undetectable in the same amount of tissue from SOD1 or Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273148 10593879 382169 20996 11179 SOD1 SOD1 mSOD1 5 3.0 Thus DNA oxidation occurs in mSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273149 10593879 382170 20996 11179 SOD1 SOD1 SOD1 39 6.2 and reduction of O 2 in the presence of mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273150 10593879 382171 20996 11179 SOD1 SOD1 SOD1 12 6.2 by in vivo experiments the in vitro discovery that mutant SOD1 gains a new function catalyzing more OH production from H 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273151 10593879 382173 20996 11179 SOD1 SOD1 SOD1 13 6.2 also indicate that the new function gained by the mutant SOD1 enzyme is not only catalyzing more OH formation but also 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 273152 10593879 382174 20996 11179 SOD1 ALS ALS 17 2.2 constituents supports that ROS-initiated processes lead to motoneuron degeneration in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00184180076460148<>ScoreDetail__5468|IGFALS|0.000606445861920314__11179|SOD1|0.00184180076460148__ 0 0 0 0 0 273153 10593879 382174 18723 10261 ROS1 ROS ROS-initiated 10 0.0 Our verification of increased oxidation of cellular constituents supports that ROS-initiated processes lead to motoneuron degeneration in ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 266724 10621940 369909 13412 7214 MPHOSPH6 MPP MPP 2 0.0 Methylphenylpyridium ion (MPP+) MPP selectively enhances glutamate and NO cytotoxicity against dopaminergic neurons of 1 JUMiner_v2.2 1 0 0 2 7214 TotalCon:2<>7214|MPHOSPH6|10200|Complete__7225|MPZ|4359|Complete__<>AvaiableGeneRif=2<>BEST:7214|MPHOSPH6|0.000518134715025907<>ScoreDetail__7214|MPHOSPH6|0.000518134715025907__7225|MPZ|0.000307464556169219__ 0 0 0 0 0 267112 10627601 370968 20996 11179 SOD1 ALS ALS 13 0.3 selective vulnerability of motor neurons in amyotrophic lateral sclerosis (ALS) ALS is primarily unknown 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000782634140781008<>ScoreDetail__5468|IGFALS|0.00029671829565011__11179|SOD1|0.000782634140781008__ 0 0 0 0 0 267113 10627601 370970 20996 11179 SOD1 ALS ALS 23 0.3 large numbers of these channels but do not degenerate in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000782634140781008<>ScoreDetail__5468|IGFALS|0.00029671829565011__11179|SOD1|0.000782634140781008__ 0 0 0 0 0 267114 10627601 370976 18723 10261 ROS1 ROS ROS 18 0.0 depolarization assessed using tetramethylrhodamine ethylester and reactive oxygen species (ROS) ROS generation assessed using hydroethidine in motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267115 10627601 370978 18723 10261 ROS1 ROS ROS 30 0.0 neuron injury suggesting that the mitochondrial Ca uptake and consequent ROS generation are central to the injury process 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267116 10627601 370979 20996 11179 SOD1 ALS ALS 9 0.3 Key words glutamate kainate hydroethidine oxidative stress mitochondria GABA ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000782634140781008<>ScoreDetail__5468|IGFALS|0.00029671829565011__11179|SOD1|0.000782634140781008__ 0 0 0 0 0 267117 10627601 370980 20996 11179 SOD1 ALS ALS 3 0.3 Amyotrophic lateral sclerosis (ALS) ALS is a neurodegenerative disease characterized by the progressive loss of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000782634140781008<>ScoreDetail__5468|IGFALS|0.00029671829565011__11179|SOD1|0.000782634140781008__ 0 0 0 0 0 267118 10627601 370984 17319 9413 PRKDC HYRC Hyrc 31 1.0 injury (Hartley Hartley et al. 1993 Lu et al. 1996 Hyrc et al. 1997 2 JUMiner_v2.2 1 2 34 0 0 0 0 0 0 0 0 267119 10627601 370985 18723 10261 ROS1 ROS ROS 45 0.0 at the expense of triggering injurious reactive oxygen species (ROS) ROS production (Lafon-Cazal Lafon-Cazal et al. 1993 Dugan et al. 1995 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267120 10627601 370988 18723 10261 ROS1 ROS ROS 29 0.0 kainate exposures trigger high Ca i elevations and subsequent mitochondrial ROS production in GABAergic cortical neurons (Carriedo Carriedo et al. 1998 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267121 10627601 370990 20996 11179 SOD1 ALS ALS 28 0.3 injury (Yin Yin et al. 1994 do not degenerate in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000782634140781008<>ScoreDetail__5468|IGFALS|0.00029671829565011__11179|SOD1|0.000782634140781008__ 0 0 0 0 0 267122 10627601 370992 18723 10261 ROS1 ROS ROS 23 0.0 focused on assessments of mitochondrial Ca buffering mitochondrial depolarization and ROS generation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267123 10627601 371017 8046 4092 GAD1 GAD GAD 9 0.6 GABAergic cortical neurons were labeled using glutamic acid decarboxylase (GAD; GAD Developmental Studies Hybridoma Bank at the University of Iowa Iowa 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267124 10627601 371020 8046 4092 GAD1 GAD GAD 13 0.6 solution at 1 6000 for SMI-32 and 1 500 for GAD were performed for 48-72 hr at 4degreeC 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267125 10627601 371023 8255 4236 GFER HSS HSS 15 0.6 performed in room air using a HEPES-buffered salt solution (HSS) HSS with the following composition (in in m M Na 130 1 JUMiner_v2.2 1 2 UserEdit 0 2 10818 TotalCon:4<>4236|GFER|2671|Complete__15894|PANK2|80025|Complete__10818|SGSH|6448|Complete__14524|SPAG9|9043|Complete__<>AvaiableGeneRif=4<>BEST:10818|SGSH|0.000133654103180968<>ScoreDetail__4236|GFER|8.03793907242183e-05__14524|SPAG9|0__10818|SGSH|0.000133654103180968__15894|PANK2|1.87202815530346e-05__ 1 1 0 0 0 267126 10627601 371032 8255 4236 GFER HSS HSS 10 0.6 agonist exposures were performed at room temperature (25degreeC) 25degreeC in HSS either constantly perfused or in a 1.5 ml static bath 1 JUMiner_v2.2 1 2 UserEdit 0 2 10818 TotalCon:4<>4236|GFER|2671|Complete__15894|PANK2|80025|Complete__10818|SGSH|6448|Complete__14524|SPAG9|9043|Complete__<>AvaiableGeneRif=4<>BEST:10818|SGSH|0.000133654103180968<>ScoreDetail__4236|GFER|8.03793907242183e-05__14524|SPAG9|0__10818|SGSH|0.000133654103180968__15894|PANK2|1.87202815530346e-05__ 1 1 0 0 0 267127 10627601 371033 19254 10472 RUNX2 CCD CCD 38 0.0 and the emitted fluorescence was collected using a Hamamatsu intensified CCD camera 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267128 10627601 371036 8255 4236 GFER HSS HSS 21 0.6 in the dark with 5 micro M Fura-2FF AM in HSS containing 0.2% pluronic acid and 1.5% dimethylsulfoxide (DMSO) DMSO for 1 JUMiner_v2.2 1 2 UserEdit 0 2 10818 TotalCon:4<>4236|GFER|2671|Complete__15894|PANK2|80025|Complete__10818|SGSH|6448|Complete__14524|SPAG9|9043|Complete__<>AvaiableGeneRif=4<>BEST:10818|SGSH|0.000133654103180968<>ScoreDetail__4236|GFER|8.03793907242183e-05__14524|SPAG9|0__10818|SGSH|0.000133654103180968__15894|PANK2|1.87202815530346e-05__ 1 1 0 0 0 267129 10627601 371037 8255 4236 GFER HSS HSS 5 0.6 Cultures were then washed in HSS (three three times and kept in the dark for an 1 JUMiner_v2.2 1 2 UserEdit 0 2 10818 TotalCon:4<>4236|GFER|2671|Complete__15894|PANK2|80025|Complete__10818|SGSH|6448|Complete__14524|SPAG9|9043|Complete__<>AvaiableGeneRif=4<>BEST:10818|SGSH|0.000133654103180968<>ScoreDetail__4236|GFER|8.03793907242183e-05__14524|SPAG9|0__10818|SGSH|0.000133654103180968__15894|PANK2|1.87202815530346e-05__ 1 1 0 0 0 267130 10627601 371045 17497 9543 PSMB6 Delta Delta 8 1.0 ROS production and changes in mitochondrial polarization ( Delta Psi m were monitored using the oxidation-sensitive dye HEt (Bindokas 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 267131 10627601 371045 17497 9543 PSMB6 Delta Delta 23 1.0 using the oxidation-sensitive dye HEt (Bindokas Bindokas et al. 1996 Delta Psi m -sensitive dye TMRE (Farkas Farkas et al. 1989 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 267132 10627601 371045 18723 10261 ROS1 ROS ROS 0 0.0 ROS production and changes in mitochondrial polarization ( Delta Psi m 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267133 10627601 371046 18723 10261 ROS1 ROS ROS 41 0.0 intercalation of ethidium within nuclear DNA (increasing increasing sensitivity for ROS detection 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267134 10627601 371047 8255 4236 GFER HSS HSS 12 0.6 loaded in the dark with 5 micro M HEt in HSS (45 45 min 25degreeC or 0.5 micro M TMRE in 1 JUMiner_v2.2 1 2 UserEdit 0 2 10818 TotalCon:4<>4236|GFER|2671|Complete__15894|PANK2|80025|Complete__10818|SGSH|6448|Complete__14524|SPAG9|9043|Complete__<>AvaiableGeneRif=4<>BEST:10818|SGSH|0.000133654103180968<>ScoreDetail__4236|GFER|8.03793907242183e-05__14524|SPAG9|0__10818|SGSH|0.000133654103180968__15894|PANK2|1.87202815530346e-05__ 1 1 0 0 0 267135 10627601 371048 8255 4236 GFER HSS HSS 12 0.6 were washed (four four times into a static bath of HSS containing either probe 1 JUMiner_v2.2 1 2 UserEdit 0 2 10818 TotalCon:4<>4236|GFER|2671|Complete__15894|PANK2|80025|Complete__10818|SGSH|6448|Complete__14524|SPAG9|9043|Complete__<>AvaiableGeneRif=4<>BEST:10818|SGSH|0.000133654103180968<>ScoreDetail__4236|GFER|8.03793907242183e-05__14524|SPAG9|0__10818|SGSH|0.000133654103180968__15894|PANK2|1.87202815530346e-05__ 1 1 0 0 0 267136 10627601 371054 18723 10261 ROS1 ROS ROS 3 0.0 In HEt experiments ROS production causes an increase in somatic and nuclear fluorescence 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267137 10627601 371055 18723 10261 ROS1 ROS ROS 8 0.0 Because HEt fluorescence is cumulative the rate of ROS generation was assessed as the rate of increase (or or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267138 10627601 371055 18723 10261 ROS1 ROS ROS 31 0.0 F x / F 0 curves over time and net ROS production was assessed as the increase in F x / 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267139 10627601 371056 8046 4092 GAD1 GAD GAD 20 0.6 for either SMI-32 (for for identifying spinal motor neurons or GAD (for for identifying GABAergic cortical neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267140 10627601 371074 20996 11179 SOD1 ALS ALS 15 0.3 by motor neurons likely contributes to their high vulnerability in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000782634140781008<>ScoreDetail__5468|IGFALS|0.00029671829565011__11179|SOD1|0.000782634140781008__ 0 0 0 0 0 267141 10627601 371080 18723 10261 ROS1 ROS ROS 15 0.0 to either AMPA or kainate triggered abrupt mitochondrial depolarization and ROS generation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267142 10627601 371082 18723 10261 ROS1 ROS ROS 11 0.0 that both mitochondrial poisons (which which prevent Ca uptake and ROS scavengers are protective suggest that the mitochondrial Ca uptake and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267143 10627601 371082 18723 10261 ROS1 ROS ROS 23 0.0 are protective suggest that the mitochondrial Ca uptake and consequent ROS generation contribute directly to AMPA/kainate AMPA kainate receptor-mediated motor neuron 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267144 10627601 371087 8790 4572 GRIA2 GLUR2 GluR2 43 1.9 Yin et al. 1994 may express low levels of the GluR2 AMPA subunit (which which confers Ca impermeability to heteromeric AMPA 14 JUMiner_v2.2 1 0 0 2 4572 TotalCon:2<>4572|GRIA2|2891|Complete__4594|GRM2|2912|Complete__<>AvaiableGeneRif=2<>BEST:4572|GRIA2|0.00109155541817198<>ScoreDetail__4594|GRM2|0.000364598856902915__4572|GRIA2|0.00109155541817198__ 0 0 0 0 0 267145 10627601 371087 8790 4572 GRIA2 GLUR2 GluR2 78 1.9 both of these populations are comprised of AMPA subunits lacking GluR2 14 JUMiner_v2.2 1 0 0 2 4572 TotalCon:2<>4572|GRIA2|2891|Complete__4594|GRM2|2912|Complete__<>AvaiableGeneRif=2<>BEST:4572|GRIA2|0.00109155541817198<>ScoreDetail__4594|GRM2|0.000364598856902915__4572|GRIA2|0.00109155541817198__ 0 0 0 0 0 267146 10627601 371091 18723 10261 ROS1 ROS ROS 6 0.0 Thus the substantial mitochondrial depolarization and ROS generation seen with kainate but not AMPA exposures in GABAergic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267147 10627601 371098 4918 2348 CREBBP CBP CBPs 28 0.3 i elevations is the presence of Ca -binding proteins (CBPs) CBPs 13 JUMiner_v2.2 1 2 UserEdit 0 2 3287 TotalCon:4<>9936|OPN1LW|5956|Complete__2348|CREBBP|1387|Complete__30043|PAG1|55824|Complete__3287|EIF4E|1977|Complete__<>AvaiableGeneRif=4<>BEST:3287|EIF4E|0.000328082258978219<>ScoreDetail__9936|OPN1LW|0.000141278151749356__30043|PAG1|0.000161835653706693__3287|EIF4E|0.000328082258978219__2348|CREBBP|0.000273162608013667__ 1 1 0 0 0 267148 10627601 371099 4918 2348 CREBBP CBP CBPs 10 0.3 Indeed GABAergic interneurons are characterized by the strong expression of CBPs including parvalbumin (Celio, Celio 1986 calretinin (Rogers, Rogers 1992 and 13 JUMiner_v2.2 1 2 UserEdit 0 2 3287 TotalCon:4<>9936|OPN1LW|5956|Complete__2348|CREBBP|1387|Complete__30043|PAG1|55824|Complete__3287|EIF4E|1977|Complete__<>AvaiableGeneRif=4<>BEST:3287|EIF4E|0.000328082258978219<>ScoreDetail__9936|OPN1LW|0.000141278151749356__30043|PAG1|0.000161835653706693__3287|EIF4E|0.000328082258978219__2348|CREBBP|0.000273162608013667__ 1 1 0 0 0 267149 10627601 371100 4918 2348 CREBBP CBP CBPs 4 0.3 Recent studies suggest that CBPs may serve important roles in protecting neurons from intracellular Ca 13 JUMiner_v2.2 1 2 UserEdit 0 2 3287 TotalCon:4<>9936|OPN1LW|5956|Complete__2348|CREBBP|1387|Complete__30043|PAG1|55824|Complete__3287|EIF4E|1977|Complete__<>AvaiableGeneRif=4<>BEST:3287|EIF4E|0.000328082258978219<>ScoreDetail__9936|OPN1LW|0.000141278151749356__30043|PAG1|0.000161835653706693__3287|EIF4E|0.000328082258978219__2348|CREBBP|0.000273162608013667__ 1 1 0 0 0 267150 10627601 371101 20996 11179 SOD1 ALS ALS 10 0.3 Motor neuron subpopulations that are relatively resistant to degeneration in ALS express high levels of CBPs suggesting that the expression of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000782634140781008<>ScoreDetail__5468|IGFALS|0.00029671829565011__11179|SOD1|0.000782634140781008__ 0 0 0 0 0 267151 10627601 371101 4918 2348 CREBBP CBP CBPs 15 0.3 relatively resistant to degeneration in ALS express high levels of CBPs suggesting that the expression of CBPs may modulate motor neuron 13 JUMiner_v2.2 1 2 UserEdit 0 2 3287 TotalCon:4<>9936|OPN1LW|5956|Complete__2348|CREBBP|1387|Complete__30043|PAG1|55824|Complete__3287|EIF4E|1977|Complete__<>AvaiableGeneRif=4<>BEST:3287|EIF4E|0.000328082258978219<>ScoreDetail__9936|OPN1LW|0.000141278151749356__30043|PAG1|0.000161835653706693__3287|EIF4E|0.000328082258978219__2348|CREBBP|0.000273162608013667__ 1 1 0 0 0 267152 10627601 371101 4918 2348 CREBBP CBP CBPs 21 0.3 express high levels of CBPs suggesting that the expression of CBPs may modulate motor neuron vulnerability (Alexianu Alexianu et al. 1994 13 JUMiner_v2.2 1 2 UserEdit 0 2 3287 TotalCon:4<>9936|OPN1LW|5956|Complete__2348|CREBBP|1387|Complete__30043|PAG1|55824|Complete__3287|EIF4E|1977|Complete__<>AvaiableGeneRif=4<>BEST:3287|EIF4E|0.000328082258978219<>ScoreDetail__9936|OPN1LW|0.000141278151749356__30043|PAG1|0.000161835653706693__3287|EIF4E|0.000328082258978219__2348|CREBBP|0.000273162608013667__ 1 1 0 0 0 267153 10627601 371102 4918 2348 CREBBP CBP CBPs 4 0.3 Thus a lack of CBPs in most motor neurons may compel them to resort to 13 JUMiner_v2.2 1 2 UserEdit 0 2 3287 TotalCon:4<>9936|OPN1LW|5956|Complete__2348|CREBBP|1387|Complete__30043|PAG1|55824|Complete__3287|EIF4E|1977|Complete__<>AvaiableGeneRif=4<>BEST:3287|EIF4E|0.000328082258978219<>ScoreDetail__9936|OPN1LW|0.000141278151749356__30043|PAG1|0.000161835653706693__3287|EIF4E|0.000328082258978219__2348|CREBBP|0.000273162608013667__ 1 1 0 0 0 267154 10627601 371104 17497 9543 PSMB6 Delta Delta 23 1.0 activity to mitochondrial energy production (McCormack McCormack and Denton 1990 Delta Psi m with the consequent cessation of ATP production (Beatrice 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 267155 10627601 371105 18723 10261 ROS1 ROS ROS 40 0.0 K channels (Carriedo Carriedo et al. 1998 can trigger mitochondrial ROS production 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267156 10627601 371107 18723 10261 ROS1 ROS ROS 12 0.0 present finding that either inhibitors of mitochondrial Ca uptake or ROS scavengers can protect motor neurons against injury resulting from Ca 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267157 10627601 371108 20996 11179 SOD1 ALS ALS 7 0.3 Are the present findings of relevance to ALS pathogenesis 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000782634140781008<>ScoreDetail__5468|IGFALS|0.00029671829565011__11179|SOD1|0.000782634140781008__ 0 0 0 0 0 267158 10627601 371109 20996 11179 SOD1 ALS ALS 12 0.3 implicates a role for excitotoxicity in the pathogenesis of sporadic ALS (Leigh Leigh and Meldrum 1996 Rothstein 1996 Shaw and Ince 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000782634140781008<>ScoreDetail__5468|IGFALS|0.00029671829565011__11179|SOD1|0.000782634140781008__ 0 0 0 0 0 267159 10627601 371111 20996 11179 SOD1 ALS ALS 16 0.3 receptor-mediated injury contributes to the loss of motor neurons in ALS the present findings may well pertain to their high susceptibility 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000782634140781008<>ScoreDetail__5468|IGFALS|0.00029671829565011__11179|SOD1|0.000782634140781008__ 0 0 0 0 0 267160 10627601 371113 20996 11179 SOD1 ALS ALS 24 0.3 induction of cumulative motor neuron injury that may occur in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000782634140781008<>ScoreDetail__5468|IGFALS|0.00029671829565011__11179|SOD1|0.000782634140781008__ 0 0 0 0 0 267161 10627601 371117 20996 11179 SOD1 ALS ALS 79 0.3 Volterra et al. 1994 Trotti et al. 1999 seen in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000782634140781008<>ScoreDetail__5468|IGFALS|0.00029671829565011__11179|SOD1|0.000782634140781008__ 0 0 0 0 0 267162 10627601 371117 18723 10261 ROS1 ROS ROS 8 0.0 In addition repeated mitochondrial Ca loading and consequent ROS generation could be relevant to the findings of mitochondrial dysfunction 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267163 10627601 371122 8046 4092 GAD1 GAD GAD 20 0.6 for SMI-32 GABAergic cortical neurons were identified by staining for GAD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267164 10627601 371170 18723 10261 ROS1 ROS ROS 4 0.0 Kainate exposure triggers preferential ROS generation in motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267165 10627601 371172 18723 10261 ROS1 ROS ROS 7 0.0 To assess involvement of mitochondria in the ROS generation in some cultures we added the electron transport chain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267166 10627601 371177 18723 10261 ROS1 ROS ROS 5 0.0 AMPA/kainate AMPA kainate receptor activation causes greater ROS generation in motor neurons than in GABAergic cortical neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267167 10627601 371197 17319 9413 PRKDC HYRC Hyrc 55 1.0 like fura-2 may markedly underestimate true Ca i levels (Hyrc Hyrc et al. 1997 Carriedo et al. 1998 Khodorov et al. 2 JUMiner_v2.2 1 2 34 0 0 0 0 0 0 0 0 267168 10627601 371214 18723 10261 ROS1 ROS ROS 7 0.0 AMPA exposure causes strong mitochondrial depolarization and ROS generation in motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267169 10627601 371216 17497 9543 PSMB6 Delta Delta 12 1.0 AMPA kainate receptor-mediated changes in the mitochondrial membrane potential ( Delta Psi m that might occur in response to mitochondrial Ca 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 267170 10627601 371216 17497 9543 PSMB6 Delta Delta 58 1.0 cellular domains rich in mitochondria is indicative of loss of Delta Psi m (Farkas Farkas et al. 1989 Delta Psi m 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 267171 10627601 371216 17497 9543 PSMB6 Delta Delta 65 1.0 loss of Delta Psi m (Farkas Farkas et al. 1989 Delta Psi m in GABAergic cortical neurons reflecting the rapid Ca 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 267172 10627601 371220 17497 9543 PSMB6 Delta Delta 38 1.0 more rapid fluorescence decreases resulting from Ca -dependent loss of Delta Psi m 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 267173 10627601 371221 17497 9543 PSMB6 Delta Delta 30 1.0 control indicating that the signal is caused by loss of Delta Psi m because kainate induces Na -dependent neuronal depolarization in 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 267174 10627601 371223 18723 10261 ROS1 ROS ROS 23 0.0 responses to AMPA/kainate AMPA kainate receptor activation we examined kainate-induced ROS production using the oxidation-sensitive dye HEt that readily permeates living 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267175 10627601 371227 18723 10261 ROS1 ROS ROS 1 0.0 Basal ROS production was minimal as evidenced by the stable but small 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267176 10627601 371230 18723 10261 ROS1 ROS ROS 19 0.0 was used to examine the role of mitochondria in kainate-triggered ROS production 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267177 10627601 371232 18723 10261 ROS1 ROS ROS 25 0.0 kainate receptor activation we used HEt to compare directly the ROS generation triggered by identical 10 min AMPA or kainate exposures 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267178 10627601 371236 17497 9543 PSMB6 Delta Delta 1 1.0 (1997) 1997 Delta Psi m might cause a voltage-dependent release of oxidized ethidium 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 267179 10627601 371236 18723 10261 ROS1 ROS ROS 32 0.0 examine the degree to which observed kainate-triggered HEt signals reflect ROS production 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267180 10627601 371238 17497 9543 PSMB6 Delta Delta 1 1.0 (1997) 1997 Delta Psi m (Carriedo Carriedo et al. 1998 Delta Psi m 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 267181 10627601 371238 17497 9543 PSMB6 Delta Delta 8 1.0 (1997) 1997 Delta Psi m (Carriedo Carriedo et al. 1998 Delta Psi m assessed using the Delta Psi m -sensitive dye 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 267182 10627601 371238 17497 9543 PSMB6 Delta Delta 14 1.0 Carriedo et al. 1998 Delta Psi m assessed using the Delta Psi m -sensitive dye TMRE (Carriedo Carriedo et al. 1998 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 267183 10627601 371238 17497 9543 PSMB6 Delta Delta 24 1.0 Psi m -sensitive dye TMRE (Carriedo Carriedo et al. 1998 Delta Psi m and most likely reflects ROS production 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 267184 10627601 371238 18723 10261 ROS1 ROS ROS 31 0.0 et al. 1998 Delta Psi m and most likely reflects ROS production 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267185 10627601 371239 18723 10261 ROS1 ROS ROS 13 0.0 to motor neurons is dependent on mitochondrial Ca loading and ROS generation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267186 10627601 371240 18723 10261 ROS1 ROS ROS 13 0.0 the hypothesis that Ca accumulation within the mitochondria and consequent ROS generation contribute directly to AMPA/kainate AMPA kainate receptor-mediated motor neuron 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267187 10627601 371246 18723 10261 ROS1 ROS ROS 5 0.0 To test the role of ROS in AMPA/kainate AMPA kainate receptor-mediated motor neuron injury we performed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267188 10627601 371251 20996 11179 SOD1 ALS ALS 21 0.3 (J.H.W.) J.H.W. and AG00919 (S.L.S.), S.L.S. a grant from the ALS Association (J.H.W.), J.H.W. and the National Research Service Award Predoctoral 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000782634140781008<>ScoreDetail__5468|IGFALS|0.00029671829565011__11179|SOD1|0.000782634140781008__ 0 0 0 0 0 267189 10627601 371252 832 549 AOC2 RAO Rao 12 0.0 Simin Amindari for her assistance in cell culture and Shyam Rao and Jade Jeng for their thoughtful comments on this manuscript 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267876 10643818 372625 14352 7794 NFKB1 NF-kB NF-kB 24 1.3 cGMP followed by activation of cGMP-dependent kinase and phosphorylation of NF-kB proteins and possibly CREB 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267877 10643818 372625 4911 2345 CREB1 CREB CREB 28 1.3 of cGMP-dependent kinase and phosphorylation of NF-kB proteins and possibly CREB 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267878 10643818 372642 4911 2345 CREB1 CREB CREB 3 1.3 The transcription factor CREB is a likely substrate for cGMP-dependent kinase that has been 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267879 10643818 372654 7333 11920 FAS FAS Fas 47 0.6 TNF-receptor-dependent signaling 9 10 and 11 and engagement of the Fas antigen 12 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000708498551406617<>ScoreDetail__11920|FAS|0.000708498551406617__3594|FASN|0.000615254271478426__ 0 0 0 0 0 267880 10643818 372655 14352 7794 NFKB1 NF-kB NF-kB 18 1.3 nervous system expression of heme oxygenase-1 and nuclear localization of NF-kB p50 13 are intimately associated with the outlined pathway because 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267881 10643818 372655 3889 11919 CD40 p50 p50 19 1.1 system expression of heme oxygenase-1 and nuclear localization of NF-kB p50 13 are intimately associated with the outlined pathway because heme 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267882 10643818 372655 14352 7794 NFKB1 NF-kB NF-kB 42 1.3 because heme oxygenase-1 may activate cGMP kinase 7 while the NF-kB proteins p50 and p49 are substrates for this enzyme (Weber, 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267883 10643818 372655 3889 11919 CD40 p50 p50 44 1.1 oxygenase-1 may activate cGMP kinase 7 while the NF-kB proteins p50 and p49 are substrates for this enzyme (Weber, Weber unpublished 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267884 10643818 372655 21252 26333 SRFBP1 p49 p49 46 0.6 activate cGMP kinase 7 while the NF-kB proteins p50 and p49 are substrates for this enzyme (Weber, Weber unpublished results 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>26333|SRFBP1|153443|Complete__9369|PRIM1|5557|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 267885 10643818 372656 4911 2345 CREB1 CREB CREB 13 1.3 also induces expression of c-Fos possibly via activation of SRE CREB or FAP 14 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267886 10643818 372656 4169 1848 CEL FAP FAP 15 1.0 expression of c-Fos possibly via activation of SRE CREB or FAP 14 1 JUMiner_v2.2 1 0 0 2 3590 TotalCon:4<>3590|FAP|2191|Complete__1848|CEL|1056|Complete__14373|GLMN|11146|Complete__583|APC|324|Complete__<>AvaiableGeneRif=4<>BEST:3590|FAP|0.00088164479274856<>ScoreDetail__14373|GLMN|0.000374531835205993__1848|CEL|0.000447105478014074__3590|FAP|0.00088164479274856__583|APC|0.000521687179385948__ 0 0 0 0 0 267887 10643818 372656 14714 8022 NT5C2 GMP GMP-dependent 1 0.0 Cyclic GMP-dependent kinase also induces expression of c-Fos possibly via activation of 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267888 10643818 372664 926 620 APP amyloid amyloid 13 1.8 factors for familial Alzheimer's disease have been localized to the amyloid precursor protein apolipoprotein E presenilin 1 and presenilin 2 genes 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267889 10643818 372665 926 620 APP amyloid amyloid 11 1.8 mechanisms of action of these diverse molecules include regulation of amyloid production and of the metabolism of reactive oxygen intermediates so 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267890 10643818 372665 926 620 APP amyloid amyloid 32 1.8 that malfunctioning of these gene products causes elevated generation of amyloid _amp_#x3b2 protein and of reactive oxygen species ( Table 1 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267891 10643818 372666 926 620 APP amyloid amyloid 13 1.8 stress may sensitize neurons to the apoptotic signals induced by amyloid (see see later creating a double burden 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267892 10643818 372667 17461 9508 PSEN1 PS1 PS1 1 0.9 Presenilins (PS1 PS1 and PS2 contribute to the regulation of apoptosis with the 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>9508|PSEN1|5663|Complete__20640|TAS2R62P|338399|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 267893 10643818 372667 17462 9509 PSEN2 PS2 PS2 1 2.4 Presenilins (PS1 PS1 and PS2 contribute to the regulation of apoptosis with the 15 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>9509|PSEN2|5664|Complete__20642|TAS2R64P|338412|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 267894 10643818 372667 17462 9509 PSEN2 PS2 PS2 3 2.4 Presenilins (PS1 PS1 and PS2 contribute to the regulation of apoptosis with the wild-type of 15 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>9509|PSEN2|5664|Complete__20642|TAS2R64P|338412|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 267895 10643818 372667 17462 9509 PSEN2 STM2 STM2 16 3.2 the regulation of apoptosis with the wild-type of Alzheimer's gene STM2 (PS2) PS2 exerting anti-apoptotic effects 16 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267896 10643818 372667 17462 9509 PSEN2 PS2 PS2 17 2.4 of apoptosis with the wild-type of Alzheimer's gene STM2 (PS2) PS2 exerting anti-apoptotic effects 16 15 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>9509|PSEN2|5664|Complete__20642|TAS2R64P|338412|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 267897 10643818 372670 926 620 APP amyloid amyloid 17 1.8 -catenin can activate _amp_#x3b3 -secretase the enzyme that releases the amyloid fragment A_amp_#x3b2;(1-42), A_amp_#x3b2 1-42 with a consequent increase in the 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267898 10643818 372670 926 620 APP amyloid amyloid 27 1.8 A_amp_#x3b2;(1-42), A_amp_#x3b2 1-42 with a consequent increase in the excreted amyloid _amp_#x3b2 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267899 10643818 372671 912 613 APOE APOE ApoE 2 1.3 Apolipoprotein E (ApoE) ApoE protects neurons from hydrogen peroxide toxicity and binds specific metal 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267900 10643818 372673 926 620 APP amyloid amyloid 6 1.8 Apolipoprotein E may also protect from _amp_#x3b2 -amyloid peptide toxicity by binding to amyloid _amp_#x3b2 and under certain 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267901 10643818 372673 926 620 APP amyloid amyloid 12 1.8 also protect from _amp_#x3b2 -amyloid peptide toxicity by binding to amyloid _amp_#x3b2 and under certain circumstances acting as kinetic inhibitor of 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267902 10643818 372673 926 620 APP amyloid amyloid 23 1.8 _amp_#x3b2 and under certain circumstances acting as kinetic inhibitor of amyloid formation 18 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267903 10643818 372674 926 620 APP amyloid amyloid 7 1.8 The major proteinaceous component of plaques is _amp_#x3b2 -amyloid the abnormal cleavage product of the amyloid precursor protein (APP) 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267904 10643818 372674 926 620 APP amyloid amyloid 14 1.8 plaques is _amp_#x3b2 -amyloid the abnormal cleavage product of the amyloid precursor protein (APP) APP 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267905 10643818 372674 926 620 APP APP APP 17 0.3 the abnormal cleavage product of the amyloid precursor protein (APP) APP 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267906 10643818 372675 926 620 APP amyloid amyloid 5 1.8 Various metals can bind to amyloid precursor protein and influence its conformation stability and homophilic interactions 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267907 10643818 372676 926 620 APP APP APP 0 0.3 APP may bind copper and catalyze a redox reaction that reduces 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267908 10643818 372676 926 620 APP amyloid amyloid 22 1.8 Cu I and gives rise to cystine formation in the amyloid precursor protein 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267909 10643818 372678 926 620 APP amyloid amyloid 15 1.8 the binding of zinc which can lead to precipitation of amyloid protein 20 may also be associated with changes in the 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267910 10643818 372679 926 620 APP amyloid amyloid 4 1.8 While the function of amyloid precursor protein as a free radical generator may contribute to 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267911 10643818 372679 926 620 APP amyloid amyloid 21 1.8 generator may contribute to affecting neuron viability the concentrations of amyloid _amp_#x3b2 required to generate free radicals are in general moderately 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267912 10643818 372680 926 620 APP amyloid amyloid 7 1.8 Furthermore the accumulation of intercellular masses of amyloid in contrast to the soluble molecules is not suitable to 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267913 10643818 372681 926 620 APP amyloid amyloid 5 1.8 An alternative mechanism by which amyloid _amp_#x3b2 may cause oxidative stress in neurons as well as 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267914 10643818 372683 14352 7794 NFKB1 NF-kB NF-kB 13 1.3 RAGE may increase lipid peroxidation as well as activation of NF-kB p50 22 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267915 10643818 372683 3889 11919 CD40 p50 p50 14 1.1 may increase lipid peroxidation as well as activation of NF-kB p50 22 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267916 10643818 372684 926 620 APP amyloid amyloid 18 1.8 -acetylcysteine 23 and inhibition of lipoxygenase protects hippocampal neurons from amyloid _amp_#x3b2 toxicity 24 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267917 10643818 372686 926 620 APP amyloid amyloid 10 1.8 The oxidative stress generated via production of free radicals by amyloid or via amyloid-dependent signaling can be increased by the common 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267918 10643818 372686 926 620 APP amyloid amyloid-dependent 13 1.0 generated via production of free radicals by amyloid or via amyloid-dependent signaling can be increased by the common risk factors through 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267919 10643818 372690 14714 8022 NT5C2 GMP GMP 23 0.0 the generation of reactive oxygen species nitric oxide and cyclic GMP 25 and 26 even though the two signal transduction pathways 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267920 10643818 372740 16745 9065 PLCG1 PLC PLC 7 0.6 PLA 2 phopholipase A 2 PLC phospholipase C DAG diacyl glycerol AA arachidonic acid PKC protein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267921 10643818 372740 14533 7872 NOS1 NOS NOS 23 0.9 AA arachidonic acid PKC protein kinase C GPX glutathione peroxidase NOS NO synthetase LTP long-term potentiation 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000583435278444126<>ScoreDetail__7873|NOS2A|0.000554595872352032__7872|NOS1|0.000583435278444126__ 0 0 0 0 0 267922 10643818 372740 5438 2666 DAG1 DAG DAG 10 0.0 PLA 2 phopholipase A 2 PLC phospholipase C DAG diacyl glycerol AA arachidonic acid PKC protein kinase C GPX 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 267923 10643818 372745 926 620 APP amyloid amyloid 12 1.8 affected in Alzheimer's disease share two common mechanisms control of amyloid _amp_#x3b2 secretion and of oxidative stress leading to apoptosis 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267924 10643818 372746 926 620 APP amyloid amyloid 6 1.8 The mechanism of apoptosis induction by amyloid _amp_#x3b2 converges with the signal transduction cascade that mediates long-term 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 267925 10643818 372751 5135 2528 CTSC HMS HMS 10 0.0 the involvement of glutathione in the hexose monophosphate shunt (HMS) HMS is pointed out and the relationships of glutamate with the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268171 10671549 373491 22671 11998 TP53 p53 p53 3 5.8 Tumor suppressor protein p53 and cell cycle inhibitor p21 accumulate as an early sign 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268172 10671549 373491 4059 1784 CDKN1A p21 p21 8 1.4 Tumor suppressor protein p53 and cell cycle inhibitor p21 accumulate as an early sign of S -nitrosoglutathione-mediated toxicity 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268173 10671549 373495 1576 990 BCL2 Bcl-2 Bcl-2 13 4.3 susceptibility of the WT cells to higher and more stable Bcl-2 and decreased reactive oxygen species 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268174 10671549 373497 1576 990 BCL2 Bcl-2 Bcl-2 8 4.3 Furthermore G93A cells showed a significant decrease of Bcl-2 expression and as target of NO-derived radicals showed lower cytochrome 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268175 10671549 373511 1576 990 BCL2 Bcl-2 Bcl-2 4 4.3 Constitutive expression of high Bcl-2 protein levels by transfection experiments has proven that Bcl-2 or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268176 10671549 373511 1576 990 BCL2 Bcl-2 Bcl-2 13 4.3 high Bcl-2 protein levels by transfection experiments has proven that Bcl-2 or related family members can protect from NO-mediated apoptosis ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268177 10671549 373512 22671 11998 TP53 p53 p53 5 5.8 The tumor suppressor gene product p53 is able to modulate apoptosis in DNA-damaged cell ( 17 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268178 10671549 373518 20996 11179 SOD1 SOD SOD 4 2.4 The enzyme superoxide dismutase (SOD) SOD may play a fundamental role in modulating NO toxicity since 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268179 10671549 373519 20996 11179 SOD1 SOD SOD 10 2.4 As matter of fact cells producing an increased amount of SOD were resistant to NO-mediated toxicity ( 24 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268180 10671549 373521 20996 11179 SOD1 SOD SOD 28 2.4 sclerosis (FALS FALS are pro-apoptotic agents although they retain enzymatic SOD activity ( 26 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268181 10671549 373524 1576 990 BCL2 Bcl-2 Bcl-2 19 4.3 cells is associated with a canonical sequence of events including Bcl-2 p53 and p21 modulation cytochrome c release in the cytosol 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268182 10671549 373524 22671 11998 TP53 p53 p53 20 5.8 is associated with a canonical sequence of events including Bcl-2 p53 and p21 modulation cytochrome c release in the cytosol and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268183 10671549 373524 4059 1784 CDKN1A p21 p21 22 1.4 with a canonical sequence of events including Bcl-2 p53 and p21 modulation cytochrome c release in the cytosol and caspase 3 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268184 10671549 373525 20996 11179 SOD1 SOD SOD 4 2.4 Cells carrying wild type SOD are protected from NO-mediated apoptosis whereas cells transfected with the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268185 10671549 373525 20996 11179 SOD1 SOD SOD 16 2.4 protected from NO-mediated apoptosis whereas cells transfected with the mutant SOD are more susceptible 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268186 10671549 373530 14532 7871 NONO NONO NONO 12 0.6 3 inhibitor I (Ac-DEVD-CHO Ac-DEVD-CHO Hoechst 33342 diethylamine NONOate (NONO NONO and 3-[(_amp_#177;)-( 3- _amp_#177 - E )-ethyl-2'-[( -ethyl-2'- E -hydroxyimino 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 268187 10671549 373540 6895 3530 F12 F12 F12 18 0.0 of Cell Culture and grown in Dulbecco's modified Eagle's/F12 Eagle's F12 medium supplemented with 15% fetal calf serum at 37 degreeC 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268188 10671549 373541 20996 11179 SOD1 SOD SOD 18 2.4 type Cu Zn-SOD (named named WT or with a mutated SOD G93A (named named G93A were obtained as described previously ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268189 10671549 373542 20997 11180 SOD2 Mn-SOD Mn-SOD 10 1.9 Transfected cells had the same antioxidant pattern such as of Mn-SOD as SH-SY5Y cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268190 10671549 373555 14532 7871 NONO NONO NONO 2 0.6 Diethylamine NONOate (NONO NONO and NOR-4 were used at concentration of 0.5 m M 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 268191 10671549 373555 14532 7871 NONO NONO NONO 26 0.6 the rapid half-life of these compounds (16 16 min for NONO and 60 min for NOR-4 we treated the cells for 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 268192 10671549 373560 18723 10261 ROS1 ROS ROS 4 0.3 For detection of intracellular ROS cells were incubated with 50 micro M DCF-DA (dissolved dissolved 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 268193 10671549 373563 18723 10261 ROS1 ROS ROS 12 0.3 of 2' 7'-dichlorofluorescein formed by the reaction of DCF-DA with ROS of more than 10 000 viable cells from each sample 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 268194 10671549 373564 22000 11730 TERT TERT tert 19 0.0 the sample for gating out dead cells 100 micro M tert -butylhydroperoxide treatment was used as a positive control 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268195 10671549 373577 19573 10691 SDS SDS SDS-polyacrylamide 42 0.3 protein extracts were loaded onto each lane of a 12% SDS-polyacrylamide gel separated and then blotted to nitrocellulose membrane (Bio-Rad) Bio-Rad 11 JUMiner_v2.2 1 2 sds 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000368543577206808<>ScoreDetail__19440|SBDS|0.000368543577206808__10691|SDS|4.84566555216359e-05__ 0 0 0 0 0 268196 10671549 373581 22671 11998 TP53 p53 p53 0 5.8 p53 p21 and Bcl-2 Proteins Detection--Cell pellet was resuspended in lysis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268197 10671549 373581 4059 1784 CDKN1A p21 p21 1 1.4 p53 p21 and Bcl-2 Proteins Detection--Cell pellet was resuspended in lysis buffer 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268198 10671549 373581 1576 990 BCL2 Bcl-2 Bcl-2 3 4.3 p53 p21 and Bcl-2 Proteins Detection--Cell pellet was resuspended in lysis buffer containing 10 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268199 10671549 373583 22671 11998 TP53 p53 p53 33 5.8 microg of proteins were loaded on a 10 (for for p53 or 12% (for for p21 and Bcl-2 polyacrylamide gel 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268200 10671549 373583 4059 1784 CDKN1A p21 p21 37 1.4 on a 10 (for for p53 or 12% (for for p21 and Bcl-2 polyacrylamide gel 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268201 10671549 373583 1576 990 BCL2 Bcl-2 Bcl-2 39 4.3 10 (for for p53 or 12% (for for p21 and Bcl-2 polyacrylamide gel 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268202 10671549 373596 20996 11179 SOD1 SOD SOD 4 2.4 Supernatants were used for SOD activity and protein content assay 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268203 10671549 373598 20997 11180 SOD2 Mn-SOD Mn-SOD 6 1.9 Under these conditions the activity of Mn-SOD is almost fully inhibited ( 33 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268204 10671549 373618 14532 7871 NONO NONO NONO 12 0.6 Presentation--All experiments were done with n = 6 those with NONO NOR-4 and bathocuproine were done with n = 4 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 268205 10671549 373631 14532 7871 NONO NONO NONO 19 0.6 of transfected cell lines to pure NO donors such as NONO and NOR-4 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 268206 10671549 373638 20996 11179 SOD1 SOD SOD 5 2.4 However cells transfected with normal SOD were much less protected than against NO-mediated apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268207 10671549 373639 14532 7871 NONO NONO NONO 30 0.6 upon treatment with commercially available pure NO donors such as NONO ( 27 we studied in detail the molecular mechanisms involved 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 268208 10671549 373642 20996 11179 SOD1 SOD SOD 13 2.4 be strengthened by O 2 via formation of peroxynitrite and SOD that catalytically removes O 2 is therefore indicated as a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268209 10671549 373644 20996 11179 SOD1 SOD SOD 5 2.4 However cells transfected with a SOD mutant (G93A G93A as active as the wild type were 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268210 10671549 373645 20996 11179 SOD1 SOD SOD 23 2.4 NO-mediated apoptosis and that additional properties of the G93A mutant SOD potentiate apoptogenic stimuli of NO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268211 10671549 373650 22671 11998 TP53 p53 p53 10 5.8 In our model apoptosis was characterized by an induction of p53 protein which is able to induce either growth arrest or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268212 10671549 373651 22671 11998 TP53 p53 p53 16 5.8 is dependent upon sequence-specific DNA binding and transcriptional activation of p53 target genes such as p21 which is an inhibitor of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268213 10671549 373651 4059 1784 CDKN1A p21 p21 21 1.4 binding and transcriptional activation of p53 target genes such as p21 which is an inhibitor of cyclin-dependent kinases and thereby blocks 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268214 10671549 373651 22671 11998 TP53 p53 p53 38 5.8 cyclin-dependent kinases and thereby blocks cell cycle progression ( 42 p53 increase was an early response to GSNO treatment in fact 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268215 10671549 373651 22671 11998 TP53 p53 p53 66 5.8 entered the apoptotic pathway they showed the same degree of p53 accumulation as the other cell lines tested 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268216 10671549 373652 22671 11998 TP53 p53 p53 1 5.8 Furthermore p53 accumulation and activation leads to p21 increase in all the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268217 10671549 373652 4059 1784 CDKN1A p21 p21 7 1.4 Furthermore p53 accumulation and activation leads to p21 increase in all the three cell types however the cleavage 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268218 10671549 373652 4059 1784 CDKN1A p21 p21 20 1.4 all the three cell types however the cleavage product of p21 was observed only in the G93A and SH-SY5Y cells at 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268219 10671549 373653 4059 1784 CDKN1A p21 p21 5 1.4 It has been demonstrated that p21 cleavage could be reproduced in extracts prepared from irradiated cells 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268220 10671549 373654 4059 1784 CDKN1A p21 p21 7 1.4 From these observations it was suggested that p21 may serve as a critical checkpoint regulator for both cell 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268221 10671549 373654 22671 11998 TP53 p53 p53-mediated 24 0.6 regulator for both cell cycle arrest and apoptosis during the p53-mediated DNA damage response ( 42 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268222 10671549 373666 1576 990 BCL2 Bcl-2 Bcl-2 17 4.3 on Bax and/or and or Bid two members of the Bcl-2 protein family ( 57 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268223 10671549 373668 1576 990 BCL2 Bcl-2 Bcl-2 3 4.3 In our experiments Bcl-2 was down-regulated by the GSNO treatment in SH-SY5Y cells whereas 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268224 10671549 373670 1576 990 BCL2 Bcl-2 Bcl-2 15 4.3 prone to NO-induced apoptosis we propose a causative role for Bcl-2 in the increased susceptibility of G93A cells to apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268225 10671549 373671 1576 990 BCL2 Bcl-2 Bcl-2 9 4.3 It has been suggested that the antiapoptotic effects of Bcl-2 be at least in part due to its antioxidant activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268226 10671549 373672 1576 990 BCL2 Bcl-2 Bcl-2 38 4.3 modulators of physiological signal transduction ( 60 is increased when Bcl-2 is down-regulated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268227 10671549 373677 20996 11179 SOD1 SOD SOD 24 2.4 a factor protecting neurons from NO-induced apoptosis whereas the G93A SOD mutant despite high dismutating activity increased intracellular flux of ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268228 10671549 373677 18723 10261 ROS1 ROS ROS 34 0.3 SOD mutant despite high dismutating activity increased intracellular flux of ROS 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 268229 10671549 373679 18723 10261 ROS1 ROS ROS 12 0.3 molecule has been extensively utilized to demonstrate intracellular production of ROS 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 268230 10671549 373682 18723 10261 ROS1 ROS ROS 20 0.3 for aberrant copper chemistry of the mutant enzyme both in ROS production and in NO-increased apoptosis in G93A cells as already 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 268231 10671549 373687 1576 990 BCL2 Bcl-2 Bcl-2 6 4.3 A vicious circle including down-regulation of Bcl-2 and deviating redox activity of copper in the G93A mutant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268232 10671549 373687 18723 10261 ROS1 ROS ROS 24 0.3 the G93A mutant may be the amplification factor leading to ROS unbalance in G93A cells and may explain how and why 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 268233 10671549 373687 20996 11179 SOD1 ALS ALS 36 1.4 in G93A cells and may explain how and why an ALS mutant cause a pro-apoptotic response 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000800634691463152<>ScoreDetail__5468|IGFALS|0.000370322031614254__11179|SOD1|0.000800634691463152__ 0 0 0 0 0 268234 10671549 373693 14532 7871 NONO NONO NONO 19 0.6 ( B 0.5 m M NOR-4 or 0.5 m M NONO ( C 5 microg/ml microg ml puromycin ( D for 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 268235 10671549 373696 14532 7871 NONO NONO NONO-treated 10 0.6 C lane 1 SH-SY5Y cells lane 2 NOR-4-treated lane 3 NONO-treated lane 4 G93A cells lane 5 NOR-4-treated lane 6 NONO-treated 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 268236 10671549 373696 14532 7871 NONO NONO NONO-treated 20 0.6 NONO-treated lane 4 G93A cells lane 5 NOR-4-treated lane 6 NONO-treated lane 7 WT cells lane 8 NOR-4-treated lane 9 NONO-treated 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 268237 10671549 373696 14532 7871 NONO NONO NONO-treated 30 0.6 NONO-treated lane 7 WT cells lane 8 NOR-4-treated lane 9 NONO-treated 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 268238 10671549 373697 14532 7871 NONO NONO NONO 11 0.6 are expressed as means _amp_#177 S.D. n = 4 for NONO and NOR-4 n = 6 for GSNO and puromycin * 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 268239 10671549 373709 22671 11998 TP53 p53 p53 1 5.8 Immunoreactive p53 protein ( C and immunoreactive p21 protein ( D were 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268240 10671549 373709 4059 1784 CDKN1A p21 p21 8 1.4 Immunoreactive p53 protein ( C and immunoreactive p21 protein ( D were measured by Western blotting using monoclonal 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268241 10671549 373712 1576 990 BCL2 Bcl-2 Bcl-2 0 4.3 Bcl-2 content of SH-SY5Y cells and effects on it by Cu 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268242 10671549 373713 1576 990 BCL2 Bcl-2 Bcl-2 0 4.3 Bcl-2 immunoreactive protein was detected by Western blotting using a monoclonal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268243 10671549 373716 18723 10261 ROS1 ROS ROS 5 0.3 Correlation between intracellular production of ROS and increased cell susceptibility to apoptosis 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 268244 10671549 373720 22000 11730 TERT TERT tert 13 0.0 cells empty GSNO-treated cells Tb cells-treated with 100 micro M tert -butyl-hydroperoxide as a positive control 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268245 10671549 373739 20996 11179 SOD1 SOD SOD 0 2.4 SOD activity (not not shown and protein levels of WT and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268246 10671549 373740 20996 11179 SOD1 SOD SOD 1 2.4 Furthermore SOD activity of the three cell lines was unaffected by GSNO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268247 10671549 373740 20996 11179 SOD1 SOD SOD 19 2.4 by GSNO treatment (not not shown as well as the SOD protein content as assessed by Western blot analysis (Fig Fig 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268248 10671549 373742 22671 11998 TP53 p53 p53 7 5.8 Apoptotic Markers Cytochrome c Release Caspase Activation p53 Accumulation p21 Increase and Bcl2 Down-regulation-- To examine the sequence 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268249 10671549 373742 4059 1784 CDKN1A p21 p21 9 1.4 Apoptotic Markers Cytochrome c Release Caspase Activation p53 Accumulation p21 Increase and Bcl2 Down-regulation-- To examine the sequence of events 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268250 10671549 373742 1576 990 BCL2 Bcl2 Bcl2 12 1.0 Cytochrome c Release Caspase Activation p53 Accumulation p21 Increase and Bcl2 Down-regulation-- To examine the sequence of events occurring upon GSNO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268251 10671549 373749 22671 11998 TP53 p53 p53 4 5.8 The tumor suppressor gene p53 is known to be a member of the DNA damage-response 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268252 10671549 373750 22671 11998 TP53 p53 p53 5 5.8 It has been demonstrated that p53 protein increases in response to NO donors and that it 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268253 10671549 373751 22671 11998 TP53 p53 p53 6 5.8 Fig 3 C shows that the p53 protein was stably expressed in neuroblastoma cells to a varying 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268254 10671549 373751 22671 11998 TP53 p53 p53 25 5.8 a varying extent in particular WT cells showed a lower p53 protein level with respect to SH-SY5Y cells and G93A cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268255 10671549 373752 22671 11998 TP53 p53 p53 3 5.8 Upon GSNO treatment p53 significantly accumulated even in the WT cells reaching comparable values 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268256 10671549 373754 22671 11998 TP53 p53 p53 16 5.8 almost disappeared after GSNO treatment supporting the current opinion that p53 activation involves phosphorylation of the protein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268257 10671549 373755 22671 11998 TP53 p53 p53 6 5.8 In response to DNA damage human p53 is phosphorylated within its transactivation domain at serine 15 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268258 10671549 373756 22671 11998 TP53 p53 p53 8 5.8 In order to confirm further a role for p53 activation in the GSNO-mediated toxicity we analyze the expression of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268259 10671549 373756 4059 1784 CDKN1A p21 p21 19 1.4 activation in the GSNO-mediated toxicity we analyze the expression of p21 which is a potent inhibitor of cell cycle kinases also 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268260 10671549 373757 22671 11998 TP53 p53 p53 8 5.8 It has been demonstrated that ectopic expression of p53 alone could induce p21 expression followed by p21 cleavage and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268261 10671549 373757 4059 1784 CDKN1A p21 p21 12 1.4 been demonstrated that ectopic expression of p53 alone could induce p21 expression followed by p21 cleavage and apoptosis ( 43 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268262 10671549 373757 4059 1784 CDKN1A p21 p21 16 1.4 expression of p53 alone could induce p21 expression followed by p21 cleavage and apoptosis ( 43 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268263 10671549 373758 4059 1784 CDKN1A p21 p21 5 1.4 Fig 3 D shows that p21 is expressed in SH-SY5Y cells and that the protein accumulated 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.00153772593219844<>ScoreDetail__1784|CDKN1A|0.00153772593219844__11616|TCEAL1|0.000796080832823025__ 0 0 0 0 0 268264 10671549 373760 22671 11998 TP53 p53 p53 13 5.8 a 2-fold indication as follows first it is confirmatory of p53 activation and second it indicates that G93A (at at higher 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268265 10671549 373761 1576 990 BCL2 Bcl-2 Bcl-2 0 4.3 Bcl-2 protein modulation is responsible for cell survival or suicide constitutive 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268266 10671549 373761 1576 990 BCL2 Bcl-2 Bcl-2 14 4.3 responsible for cell survival or suicide constitutive expression of high Bcl-2 protein levels by transfection experiments has proven that Bcl-2 or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268267 10671549 373761 1576 990 BCL2 Bcl-2 Bcl-2 23 4.3 high Bcl-2 protein levels by transfection experiments has proven that Bcl-2 or related family members can protect cells from NO-mediated apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268268 10671549 373762 1576 990 BCL2 Bcl-2 Bcl-2 18 4.3 analysis untreated SH-SY5Y and WT cells express high levels of Bcl-2 protein whereas G93A cells show a much lower content (Fig 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268269 10671549 373762 1576 990 BCL2 Bcl-2 Bcl-2 37 4.3 content (Fig Fig 4 48 h of GSNO treatment decreased Bcl-2 expression although to a different extent in particular Bcl-2 content 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268270 10671549 373762 1576 990 BCL2 Bcl-2 Bcl-2 46 4.3 decreased Bcl-2 expression although to a different extent in particular Bcl-2 content of G93A cells was at the limit of detection 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268271 10671549 373763 20996 11179 SOD1 SOD SOD 43 2.4 apoptosis of G93A cells cannot be explained in terms of SOD level 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268272 10671549 373764 18723 10261 ROS1 ROS ROS 8 0.3 However we found evidence for different levels of ROS in the three cell lines used during the GSNO treatment 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 268273 10671549 373768 20996 11179 SOD1 SOD SOD 15 2.4 or hydroxyl radical formation has been demonstrated for fully active SOD mutants associated with FALS ( 47 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268274 10671549 373772 18723 10261 ROS1 ROS ROS 4 0.3 An increased flux of ROS may lead to increased peroxynitrite levels 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 268275 10671549 373775 20996 11179 SOD1 SOD SOD 19 2.4 not significantly affected either by the transfection with the mutant SOD or by the GSNO treatment 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 268276 10671549 373783 14532 7871 NONO NONO NONO 29 0.6 Zn-SOD Cu Zn-SOD copper zinc superoxide dismutase GSNO S -nitrosoglutathione NONO diethylamine NONOate NOR-4 3-[(_amp_#177;)-( 3- _amp_#177 - E )-ethyl-2'-[( -ethyl-2'- 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 268277 10671549 373783 18723 10261 ROS1 ROS ROS 52 0.3 Ac-Asp-Glu-Val-Asp-AMC caspase-3 substrate II fluorogenic Ac-DEVD-CHO Ac-Asp-Glu-Val-Asp-CHO caspase-3 inhibitor I ROS reactive oxygen species FALS familial amyotrophic lateral sclerosis PIPES piperazine-N 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 263998 10742195 364641 2163 1325 C4BPA PrP PrP 30 1.9 a theme echoed in the recent proposal that A_amp_#x3b2 and PrP the proteins respectively involved in Alzheimer_amp_#x2019 s disease and prion 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 263999 10742195 364679 18723 10261 ROS1 ROS ROS 12 0.0 intimately associated with glutathione the chief reactive oxygen species (ROS) ROS scavenger of the cytosol 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264000 10742195 364687 20291 11014 SLC30A3 ZNT3 ZnT3 21 1.0 have cloned and characterized in the past five years is ZnT3 whose protein resides on synaptic vesicle membranes of zinc-containing neurons 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264001 10742195 364688 20291 11014 SLC30A3 ZNT3 ZnT3 3 1.0 The phenotype of ZnT3 knockout mice was recently reported by this group 7 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264002 10742195 364693 3838 1613 CCS CCS CCS 23 0.9 the elaboration of the copper chaperone of superoxide dismutase (CCS) CCS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264003 10742195 364695 3838 1613 CCS CCS CCS 1 0.9 Recently CCS was reported to play an essential role in loading Cu 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264004 10742195 364695 20996 11179 SOD1 SOD SOD 16 1.4 essential role in loading Cu 2 onto superoxide dismutase (SOD)1 SOD 1 under conditions of low cytosolic Cu 2 8 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264005 10742195 364696 20996 11179 SOD1 SOD1 SOD1 16 1.9 it shows that the cell possesses machinery to ensure that SOD1 antioxidant activity (which which depends upon a Cu 2 catalytic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264006 10742195 364697 20996 11179 SOD1 SOD1 SOD1 5 1.9 It is proposed that although SOD1 has a very high affinity (femtomolar) femtomolar Cu 2 -binding 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264007 10742195 364697 3838 1613 CCS CCS CCS 20 0.9 (femtomolar) femtomolar Cu 2 -binding site and does not require CCS to be loaded with Cu 2 when Cu 2 is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264008 10742195 364697 3838 1613 CCS CCS CCS 53 0.9 so low (less less than one atom per cell that CCS facilitates Cu 2 loading onto SOD1 by competing against the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264009 10742195 364697 20996 11179 SOD1 SOD1 SOD1 59 1.9 atom per cell that CCS facilitates Cu 2 loading onto SOD1 by competing against the pool of cytosolic Cu 2 scavengers 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264010 10742195 364698 3838 1613 CCS CCS CCS 4 0.9 The crystal structure of CCS reveals a dimeric protein with one domain resembling the metallochaperone 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264011 10742195 364698 1277 798 ATOX1 ATX1 Atx1 16 2.1 a dimeric protein with one domain resembling the metallochaperone protein Atx1 and a second domain resembling SOD1 itself but lacking its 2 JUMiner_v2.2 1 0 0 2 798 TotalCon:2<>10548|ATXN1|6310|Complete__798|ATOX1|475|Complete__<>AvaiableGeneRif=2<>BEST:798|ATOX1|0.000931343788486646<>ScoreDetail__10548|ATXN1|0.00045331700007959__798|ATOX1|0.000931343788486646__ 0 0 0 0 0 264012 10742195 364698 20996 11179 SOD1 SOD1 SOD1 22 1.9 resembling the metallochaperone protein Atx1 and a second domain resembling SOD1 itself but lacking its metal-binding sites and catalytic-site residues 9 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264013 10742195 364699 3838 1613 CCS CCS CCS 3 0.9 The work on CCS the Cu 2 ATPases and MT underscores the understanding that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264014 10742195 364701 23482 12442 TYR tyrosinase tyrosinase 19 1.0 function of numerous enzymes of interest to neurobiology such as tyrosinase ceruloplasmin cytochrome c oxidase and dopamine _amp_#x3b2 hydroxylase free or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264015 10742195 364704 20996 11179 SOD1 SOD1 SOD1 51 1.9 unlikely to play any role in disease biochemistry outside of SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264016 10742195 364712 20996 11179 SOD1 SOD1 SOD1 4 1.9 Familial amyotrophic lateral sclerosis SOD1 and copper 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264017 10742195 364713 20996 11179 SOD1 SOD SOD 16 1.4 the elucidation of how a mutation of Cu/Zn Cu Zn SOD (SOD1) SOD1 engenders a gain of function that changes this 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264018 10742195 364713 20996 11179 SOD1 SOD1 SOD1 17 1.9 of how a mutation of Cu/Zn Cu Zn SOD (SOD1) SOD1 engenders a gain of function that changes this ubiquitous antioxidant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264019 10742195 364714 20996 11179 SOD1 SOD1 SOD1 13 1.9 abundant literature on the oxidative insult caused by the FALS-linked SOD1 mutation 15 and 16 as well as the formation of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264020 10742195 364714 20996 11179 SOD1 SOD1 SOD1 26 1.9 mutation 15 and 16 as well as the formation of SOD1 aggregates in affected motor neurons and glia 17 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264021 10742195 364717 20996 11179 SOD1 SOD1 SOD1 17 1.9 I believe will become fundamental not only to understanding how SOD1 mutations cause FALS but also how well known toxic proteins 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264022 10742195 364717 2163 1325 C4BPA PrP PrP 32 1.9 also how well known toxic proteins such as A_amp_#x3b2 and PrP could function as antioxidants (see see below 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264023 10742195 364719 20996 11179 SOD1 SOD SOD 4 1.4 Alone it has a SOD activity with a rate constant the same as SOD1 itself 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264024 10742195 364719 20996 11179 SOD1 SOD1 SOD1 13 1.9 a SOD activity with a rate constant the same as SOD1 itself 18 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264025 10742195 364720 20996 11179 SOD1 SOD1 SOD1 4 1.9 The purpose of the SOD1 protein is to harness this activity of Cu 2 without 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264026 10742195 364721 20996 11179 SOD1 SOD1 SOD1 9 1.9 Hence the Cu 2 at the active site of SOD1 has the potential to be abnormally redox reactive generating unwanted 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264027 10742195 364722 20996 11179 SOD1 SOD1 SOD1 21 1.9 19 describing a likely mechanism for the pathogenicity of mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264028 10742195 364723 20996 11179 SOD1 SOD1 SOD1 2 1.9 The pathogenic SOD1 mutations do not cause a loss of function when the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264029 10742195 364724 20996 11179 SOD1 SOD SOD 14 1.4 al 19 observed that altered Cu 2 coordination made Zn-deficient SOD (wild wild type or mutant a more efficient oxidant able 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264030 10742195 364725 20996 11179 SOD1 SOD SOD 5 1.4 The altered reactivity of Zn-deficient SOD enables it to be reduced by cellular reductants (such such 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264031 10742195 364726 20996 11179 SOD1 SOD SOD 0 1.4 SOD then donates an electron to O 2 to generate O 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264032 10742195 364727 20996 11179 SOD1 SOD1 SOD1 2 1.9 Thus if SOD1 loses Zn 2 its catalytic activity is diminished while it 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264033 10742195 364728 20996 11179 SOD1 SOD1 SOD1 7 1.9 The O 2 _amp_#x2212 formed by Zn-deficient SOD1 might not be released as a free intermediate which would 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264034 10742195 364728 20996 11179 SOD1 SOD1 SOD1 21 1.9 released as a free intermediate which would explain why excess SOD1 fails to slow disease progression in FALS/SOD1 FALS SOD1 transgenic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264035 10742195 364728 20996 11179 SOD1 SOD1 SOD1 28 1.9 excess SOD1 fails to slow disease progression in FALS/SOD1 FALS SOD1 transgenic mice 17 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264036 10742195 364729 20996 11179 SOD1 SOD1 SOD1 10 1.9 Intriguingly Estevez et al 19 found that apo SOD1 was not neurotoxic in cell culture whereas Zn-deficient Cu-loaded SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264037 10742195 364729 20996 11179 SOD1 SOD1 SOD1 20 1.9 SOD1 was not neurotoxic in cell culture whereas Zn-deficient Cu-loaded SOD1 was neurotoxic an effect that could be rescued by treatment 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264038 10742195 364729 20996 11179 SOD1 SOD1 SOD1 48 1.9 the treatment efficacy of Cu 2 chelators upon FALS/SOD1 FALS SOD1 transgenic mice 22 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264039 10742195 364733 926 620 APP amyloid amyloid 4 1.0 Familial AD-linked mutations of amyloid precursor protein (APP), APP presenilin-1 and presenilin-2 increase both cerebral 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 264040 10742195 364733 926 620 APP APP APP 7 0.3 Familial AD-linked mutations of amyloid precursor protein (APP), APP presenilin-1 and presenilin-2 increase both cerebral A_amp_#x3b2 burden and A_amp_#x3b2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264041 10742195 364734 12369 6893 MAPT tau tau 26 0.3 many of the other neuropathological features of AD including intraneuronal tau abnormalities and neuronal loss 23 as well as signs of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264042 10742195 364735 926 620 APP amyloid amyloid 29 1.0 minor free soluble species in biological fluids is enriched in amyloid deposits 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 264043 10742195 364741 926 620 APP amyloid amyloid 45 1.0 perhaps explaining why these animals do not form cerebral A_amp_#x3b2 amyloid 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 264044 10742195 364741 117 77 ABL2 ARG Arg 14 0.0 (with with substitutions of Arg_amp_#x2192 Gly Tyr_amp_#x2192 Phe and His_amp_#x2192 Arg at positions 5 10 and 13 respectively is unaffected by 2 JUMiner_v2.2 1 0 0 2 77 TotalCon:2<>77|ABL2|27|Complete__9965|RERE|473|Complete__<>AvaiableGeneRif=2<>BEST:77|ABL2|0.000647132654365927<>ScoreDetail__77|ABL2|0.000647132654365927__9965|RERE|0.0001717858860716__ 0 0 0 0 0 264045 10742195 364742 912 613 APOE APOE apoE 10 1.3 We have also reported 25 that apolipoprotein E (apoE) apoE modulates the precipitation of A_amp_#x3b2 by Cu 2 and Zn 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264046 10742195 364742 912 613 APOE APOE apoE 27 1.3 by Cu 2 and Zn 2 which is important because apoE isoforms segregate with the genetic risk for AD inheritance of 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264047 10742195 364746 926 620 APP amyloid amyloid 4 1.0 Zn 2 in A_amp_#x3b2 amyloid deposits has recently been detected by histological fluorescent techniques in 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 264048 10742195 364753 926 620 APP amyloid amyloid 28 1.0 that we have found on human A_amp_#x3b2 extracted from AD amyloid 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 264049 10742195 364762 20996 11179 SOD1 SOD SOD-like 18 1.4 cell-culture data indicate that Cu/Zn-loaded Cu Zn-loaded A_amp_#x3b2 possesses catalytic SOD-like activity and that A_amp_#x3b2 1-42 has greater activity than A_amp_#x3b2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264050 10742195 364763 20996 11179 SOD1 SOD1 SOD1 18 1.9 be mechanistically related to the oxidative stress induced by mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264051 10742195 364765 17345 9449 PRNP CJD CJD 2 0.8 Creutzfeldt_amp_#x2013 Jakob disease (CJD) CJD and related transmissible spongioform encephalopathies (TSEs), TSEs like AD are 1 JUMiner_v2.2 1 2 creutzfeldt 0 0 0 0 0 0 0 0 264052 10742195 364765 17345 9449 PRNP CJD CJD 19 0.8 like AD are characterized by neuroamyloid formation and dementia but CJD is a far more aggressive disease and is contagious 1 JUMiner_v2.2 1 2 creutzfeldt 0 0 0 0 0 0 0 0 264053 10742195 364766 2163 1325 C4BPA PrP PrP 6 1.9 The infectious particle is a protein PrP Sc that collects in the CJD-affected brain and is a 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264054 10742195 364766 17345 9449 PRNP CJD CJD-affected 13 0.8 particle is a protein PrP Sc that collects in the CJD-affected brain and is a modified and protease-resistant form of a 1 JUMiner_v2.2 1 2 creutzfeldt 0 0 0 0 0 0 0 0 264055 10742195 364766 2163 1325 C4BPA PrP PrP 26 1.9 is a modified and protease-resistant form of a ubiquitous protein PrP c 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264056 10742195 364767 2163 1325 C4BPA PrP PrP 25 1.9 was the publication by David Brown et al 35 that PrP c possesses SOD activity 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264057 10742195 364767 20996 11179 SOD1 SOD SOD 28 1.4 by David Brown et al 35 that PrP c possesses SOD activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264058 10742195 364768 2163 1325 C4BPA PrP PrP 15 1.9 of the earlier work of Brown (and and others characterizing PrP c as a Cu 2 -binding protein exhibiting high-affinity cooperative 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264059 10742195 364769 926 620 APP APP APP 6 0.3 Therefore it is especially intriguing that APP the A_amp_#x3b2 precursor which has second Cu 2 -binding and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264060 10742195 364769 2163 1325 C4BPA PrP PrP 52 1.9 out of cells 40 an activity resembling that proposed for PrP c 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264061 10742195 364770 2163 1325 C4BPA PrP PrP 1 1.9 Unlike PrP c interaction with Cu 2 37 the A_amp_#x3b2 precursor interaction 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264062 10742195 364771 20996 11179 SOD1 SOD SOD 1 1.4 The SOD activity of PrP c is also intriguing because of the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264063 10742195 364771 2163 1325 C4BPA PrP PrP 4 1.9 The SOD activity of PrP c is also intriguing because of the neuropathological similarities between 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264064 10742195 364771 17345 9449 PRNP CJD CJD 15 0.8 is also intriguing because of the neuropathological similarities between CJD/TSE, CJD TSE AD and FALS 1 JUMiner_v2.2 1 2 creutzfeldt 0 0 0 0 0 0 0 0 264065 10742195 364772 2163 1325 C4BPA PrP PrP 2 1.9 Assuming that PrP c and A_amp_#x3b2 are indeed also physiological SOD-type antioxidants then 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264066 10742195 364772 17345 9449 PRNP CJD CJD 14 0.8 and A_amp_#x3b2 are indeed also physiological SOD-type antioxidants then FALS CJD and AD might all share a common cause the corruption 1 JUMiner_v2.2 1 2 creutzfeldt 0 0 0 0 0 0 0 0 264067 10742195 364773 17345 9449 PRNP CJD CJD 11 0.8 far there is only indirect evidence of oxidative neuropathology in CJD and TSE but this evidence probably will emerge with time 1 JUMiner_v2.2 1 2 creutzfeldt 0 0 0 0 0 0 0 0 264068 10742195 364774 20996 11179 SOD1 SOD1 SOD1 2 1.9 Like mutant SOD1 PrP sc might be a modification of PrP that induces 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264069 10742195 364774 2163 1325 C4BPA PrP PrP 3 1.9 Like mutant SOD1 PrP sc might be a modification of PrP that induces a 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264070 10742195 364774 2163 1325 C4BPA PrP PrP 10 1.9 Like mutant SOD1 PrP sc might be a modification of PrP that induces a Cu 2 -related gain of function perhaps 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264071 10742195 364775 2163 1325 C4BPA PrP PrP 13 1.9 supported by recent reports that Cu 2 treatment of denatured PrP Sc restores protease resistance and infectivity 42 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264072 10742195 364776 2163 1325 C4BPA PrP PrP 8 1.9 Also the respective conformations of strain variants of PrP Sc have now been reported to depend upon Cu 2 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264073 10742195 364777 2163 1325 C4BPA PrP PrP 12 1.9 Recently we have reported 44 that the copper-binding domain of PrP c reduces Cu 2 and uses O 2 to produce 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264074 10742195 364778 17345 9449 PRNP CJD CJD 6 0.8 It is intriguing to contemplate that CJD/TSE, CJD TSE FALS and AD may be caused by an abnormality 1 JUMiner_v2.2 1 2 creutzfeldt 0 0 0 0 0 0 0 0 264075 10742195 364779 18723 10261 ROS1 ROS ROS 16 0.0 be expected to be exposed to constitutively high concentrations of ROS O 2 _amp_#x2212 and H 2 O 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264076 10742195 364781 20996 11179 SOD1 SOD1 SOD1 2 1.9 In normal SOD1 Cu A_amp_#x3b2 or PrP c the Cu 2 active site 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264077 10742195 364781 2163 1325 C4BPA PrP PrP 5 1.9 In normal SOD1 Cu A_amp_#x3b2 or PrP c the Cu 2 active site would be shielded from 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.00135577372604021<>ScoreDetail__1325|C4BPA|0.000940860215053763__47|ABCB6|0.0003584229390681__9353|PRDX2|0.00135577372604021__9449|PRNP|0.000841788623648039__ 0 0 0 0 0 264078 10742195 364799 20996 11179 SOD1 SOD SOD 2 1.4 A manganese SOD SOD2 is the mitochondrial equivalent of SOD1 preventing O 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264079 10742195 364799 20997 11180 SOD2 SOD2 SOD2 3 0.9 A manganese SOD SOD2 is the mitochondrial equivalent of SOD1 preventing O 2 _amp_#x2212 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264080 10742195 364799 20996 11179 SOD1 SOD1 SOD1 9 1.9 A manganese SOD SOD2 is the mitochondrial equivalent of SOD1 preventing O 2 _amp_#x2212 from reacting with sensitive substrates such 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264081 10742195 364799 166 118 ACO2 aconitase aconitase 21 1.3 O 2 _amp_#x2212 from reacting with sensitive substrates such as aconitase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264082 10742195 364800 20997 11180 SOD2 SOD2 SOD2 3 0.9 Knockout mice for SOD2 die within the first week of life from heart failure 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264083 10742195 364802 20997 11180 SOD2 SOD2 SOD2 13 0.9 the heart failure and subsequent early neonatal death of the SOD2 knockout mice the ROS produced within the developing brain reach 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264084 10742195 364802 18723 10261 ROS1 ROS ROS 17 0.0 subsequent early neonatal death of the SOD2 knockout mice the ROS produced within the developing brain reach sufficient levels to uncover 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264085 10742195 364803 20997 11180 SOD2 SOD2 SOD2 4 0.9 By two weeks the SOD2 mutant mice develop a profound spongiform encephalopathy accompanied by gliosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264086 10742195 364804 18723 10261 ROS1 ROS ROS 5 0.0 These findings demonstrate that mitochondrial ROS can be deleterious to the brain and can give rise 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 264087 10742195 364806 17345 9449 PRNP CJD CJD 10 0.8 From the study of the abnormal biochemistry of AD FALS CJD and cataracts I propose a triad of features shared by 1 JUMiner_v2.2 1 2 creutzfeldt 0 0 0 0 0 0 0 0 265595 10795881 367404 20996 11179 SOD1 SOD1 SOD1 10 1.4 In one or two percentage of patients mutations in the SOD1 gene are known to underly the disease 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 265596 10795881 367407 20996 11179 SOD1 SOD1 SOD1-related 11 0.9 evidence for oxidative stress is not only found in mutant SOD1-related familial amyotrophic lateral sclerosis but also in sporadic amyotrophic lateral 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 266053 10826922 368226 20996 11179 SOD1 SOD SODs 4 1.4 Eight mutant Cu Zn-superoxide dismutases (SODs) SODs related to familial amyotrophic lateral sclerosis (FALS) FALS were produced 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 266054 10826922 368227 20996 11179 SOD1 SOD SOD 14 1.4 with Chelex 100 resin decreased Cu contents as well as SOD activities in all mutant Cu Zn-SODs indicating that the affinities 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 266055 10826922 368229 20996 11179 SOD1 SOD SOD 1 1.4 Both SOD activities and their reactive oxidant forming correlated well with the 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 266056 10826922 368231 20996 11179 SOD1 SOD1 SOD1 8 1.4 Since hyaline inclusions found in FALS patients with SOD1 mutations contained components which were reactive to anti-Cu Zn-SOD antibody 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 266057 10826922 368231 20996 11179 SOD1 SOD1 SOD1 24 1.4 to anti-Cu Zn-SOD antibody a primary reaction caused by mutant SOD1 may be attributed to their propensity to form aggregates 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 266058 10826922 368232 20996 11179 SOD1 SOD1 SOD1 5 1.4 Aggregated but still active mutant SOD1 would be expected to mediate the formation of reactive oxygen 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 261644 10899935 360033 20996 11179 SOD1 SOD1 SOD1 23 0.9 by overexpression of wild-type antioxidant Cu Zn superoxide dismutase (SOD1) SOD1 that promotes CN activity and protects it from oxidative inactivation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 261645 10899935 360034 20996 11179 SOD1 SOD1 SOD1s 6 0.9 On the contrary overexpression of mutant SOD1s associated with familial amyotrophic lateral sclerosis (FALS) FALS impairs CN 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 261646 10899935 360035 20996 11179 SOD1 SOD1 SOD1-linked 13 0.9 that CN might be a target in the pathogenesis of SOD1-linked FALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262245 10930589 361583 20996 11179 SOD1 ALS ALS 3 2.2 Amyotrophic lateral sclerosis (ALS) ALS is a paralytic disorder characterized by degeneration of large motor 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00235023118796336<>ScoreDetail__5468|IGFALS|0.000716283511835732__11179|SOD1|0.00235023118796336__ 0 0 0 0 0 262246 10930589 361584 20996 11179 SOD1 ALS ALS 3 2.2 A subset of ALS is inherited (familial familial ALS FALS and is associated with 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00235023118796336<>ScoreDetail__5468|IGFALS|0.000716283511835732__11179|SOD1|0.00235023118796336__ 0 0 0 0 0 262247 10930589 361584 20996 11179 SOD1 ALS ALS 7 2.2 A subset of ALS is inherited (familial familial ALS FALS and is associated with more than 70 different mutations 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00235023118796336<>ScoreDetail__5468|IGFALS|0.000716283511835732__11179|SOD1|0.00235023118796336__ 0 0 0 0 0 262248 10930589 361584 20996 11179 SOD1 SOD1 SOD1 20 5.1 is associated with more than 70 different mutations in the SOD1 gene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262249 10930589 361585 20996 11179 SOD1 SOD1 SOD1 16 5.1 lines derived from FALS patients with 16 different mutations in SOD1 gene exhibit significant increase of intracellular reactive oxygen species (ROS) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262250 10930589 361585 18723 10261 ROS1 ROS ROS 26 0.3 gene exhibit significant increase of intracellular reactive oxygen species (ROS) ROS compared with sporadic ALS (SALS) SALS and normal controls (spouses 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262251 10930589 361585 20996 11179 SOD1 ALS ALS 30 2.2 of intracellular reactive oxygen species (ROS) ROS compared with sporadic ALS (SALS) SALS and normal controls (spouses spouses of ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00235023118796336<>ScoreDetail__5468|IGFALS|0.000716283511835732__11179|SOD1|0.00235023118796336__ 0 0 0 0 0 262252 10930589 361585 20996 11179 SOD1 ALS ALS 37 2.2 sporadic ALS (SALS) SALS and normal controls (spouses spouses of ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00235023118796336<>ScoreDetail__5468|IGFALS|0.000716283511835732__11179|SOD1|0.00235023118796336__ 0 0 0 0 0 262253 10930589 361586 18723 10261 ROS1 ROS ROS 1 0.3 The ROS generation did not correlate with SOD1 activity 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262254 10930589 361586 20996 11179 SOD1 SOD1 SOD1 7 5.1 The ROS generation did not correlate with SOD1 activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262255 10930589 361587 18723 10261 ROS1 ROS ROS 13 0.3 with vitamin C catalase or the flavinoid quercetin significantly reduced ROS in all groups 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262256 10930589 361588 18723 10261 ROS1 ROS ROS 10 0.3 inhibitor 3-amino-1 2 4-triazole resulted in a ten-fold increase of ROS in all groups 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262257 10930589 361589 18723 10261 ROS1 ROS ROS 12 0.3 a nitric oxide synthase inhibitor or vitamin E altered the ROS levels 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262258 10930589 361590 18723 10261 ROS1 ROS ROS 15 0.3 hydrogen peroxide (H H 2 O 2 is a major ROS elevated in FALS lymphoblasts and it may contribute to the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262259 10930589 361591 20996 11179 SOD1 SOD1 SOD1 17 5.1 increased H 2 O 2 could be generated by mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262260 10930589 361594 20996 11179 SOD1 ALS ALS 3 2.2 Amyotrophic lateral sclerosis (ALS), ALS also known as Lou Gehrig disease is characterized by degeneration 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00235023118796336<>ScoreDetail__5468|IGFALS|0.000716283511835732__11179|SOD1|0.00235023118796336__ 0 0 0 0 0 262261 10930589 361596 20996 11179 SOD1 ALS ALS 3 2.2 About 2% of ALS cases are associated with missense mutations in the gene for 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00235023118796336<>ScoreDetail__5468|IGFALS|0.000716283511835732__11179|SOD1|0.00235023118796336__ 0 0 0 0 0 262262 10930589 361596 20996 11179 SOD1 SOD1 SOD1 19 5.1 in the gene for cytosolic Cu Zn superoxide dismutase ( SOD1 CuZnSOD 1 and 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262263 10930589 361597 20996 11179 SOD1 SOD1 SOD1 0 5.1 SOD1 functions as a homodimeric enzyme that is widely expressed and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262264 10930589 361598 20996 11179 SOD1 SOD1 SOD1 4 5.1 The mechanisms by which SOD1 mutations cause selective motor neuron degeneration is not clearly understood 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262265 10930589 361599 20996 11179 SOD1 SOD1 SOD1 1 5.1 However SOD1 activity in red blood cells of most SOD1 mutant heterozygotes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262266 10930589 361599 20996 11179 SOD1 SOD1 SOD1 9 5.1 However SOD1 activity in red blood cells of most SOD1 mutant heterozygotes is reduced 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262267 10930589 361600 20996 11179 SOD1 SOD1 SOD1 12 5.1 be less than 50% in some cases suggesting that mutant SOD1 may affect the activity of the wildtype enzyme 2 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262268 10930589 361601 20996 11179 SOD1 SOD1 SOD1 2 5.1 Evidence from SOD1 transgenic mice and SOD1 knockout mice suggests that reduced dismutase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262269 10930589 361601 20996 11179 SOD1 SOD1 SOD1 6 5.1 Evidence from SOD1 transgenic mice and SOD1 knockout mice suggests that reduced dismutase activity is not the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262270 10930589 361602 20996 11179 SOD1 SOD1 SOD1 1 5.1 Decreased SOD1 activity in ALS patients would be expected to lead to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262271 10930589 361602 20996 11179 SOD1 ALS ALS 4 2.2 Decreased SOD1 activity in ALS patients would be expected to lead to an ambient increase 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00235023118796336<>ScoreDetail__5468|IGFALS|0.000716283511835732__11179|SOD1|0.00235023118796336__ 0 0 0 0 0 262272 10930589 361603 20996 11179 SOD1 SOD1 SOD1 1 5.1 Mutant SOD1 was shown to have increased peroxidase activity over wildtype SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262273 10930589 361603 20996 11179 SOD1 SOD1 SOD1 11 5.1 SOD1 was shown to have increased peroxidase activity over wildtype SOD1 in vitro 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262274 10930589 361604 20996 11179 SOD1 SOD1 SOD1 2 5.1 Thus mutant SOD1 may produce more free radicals than wild SOD1 7 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262275 10930589 361604 20996 11179 SOD1 SOD1 SOD1 10 5.1 Thus mutant SOD1 may produce more free radicals than wild SOD1 7 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262276 10930589 361605 20996 11179 SOD1 SOD1 SOD1 15 5.1 show any difference in peroxidase activity of mutant and wildtype SOD1 8 and 9 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262277 10930589 361606 20996 11179 SOD1 SOD1 SOD1 12 5.1 was shown this discrepancy was due to different preparations of SOD1 proteins and experimental conditions 8 and 9 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262278 10930589 361607 18723 10261 ROS1 ROS ROS 8 0.3 We therefore investigated levels of reactive oxygen species (ROS) ROS in lymphoblast cell lines derived from patients with SOD1 linked 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262279 10930589 361607 20996 11179 SOD1 SOD1 SOD1 17 5.1 (ROS) ROS in lymphoblast cell lines derived from patients with SOD1 linked FALS sporadic ALS and normal controls (spouses spouses of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262280 10930589 361607 20996 11179 SOD1 ALS ALS 21 2.2 cell lines derived from patients with SOD1 linked FALS sporadic ALS and normal controls (spouses spouses of FALS patients using two 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00235023118796336<>ScoreDetail__5468|IGFALS|0.000716283511835732__11179|SOD1|0.00235023118796336__ 0 0 0 0 0 262281 10930589 361608 18723 10261 ROS1 ROS ROS 16 0.3 inhibitors of intracellular antioxidant enzymes which influence the metabolism of ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262282 10930589 361609 20996 11179 SOD1 SOD1 SOD1 28 5.1 were similar in all groups despite a 45% decrease in SOD1 activity in FALS mutants 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262283 10930589 361629 7329 16460 FARP2 FRG FRG 27 0.0 Elmer LS-5 luminescence spectrometer (Boden Boden Swerk Perkin-Elmer _amp_#xc5 berlingen FRG using excitation and emission slits of 5 nm bandwidth 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262284 10930589 361631 20996 11179 SOD1 SOD SOD 0 2.2 SOD assay 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262285 10930589 361632 20996 11179 SOD1 SOD SOD 1 2.2 Total SOD activity was determined by its ability to catalyze the disproportionation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262286 10930589 361634 20997 11180 SOD2 MnSOD MnSOD 9 1.9 Cyanide (3 3 mM was used to distinguish between resistant MnSOD and the sensitive CuZnSOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262287 10930589 361640 18723 10261 ROS1 ROS ROS 6 0.3 Intracellular elevation of reactive oxygen species (ROS) ROS in FALS cells 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262288 10930589 361641 18723 10261 ROS1 ROS ROS 13 0.3 lymphoblast cell lines from FALS patients generate increased levels of ROS we used the fluorescent probe C-DCDHF-DA-AM 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262289 10930589 361648 20996 11179 SOD1 SOD1 SOD1 10 5.1 No significant correlation was observed between relative C-DCF fluorescence and SOD1 activity in all groups at resting levels 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262290 10930589 361649 20996 11179 SOD1 SOD1 SOD1 14 5.1 with menadione showed an inverse correlation of C-DCF fluorescence with SOD1 activity ( r =0.6 P _amp_#x3c 0.001 ( Table 1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262291 10930589 361650 18723 10261 ROS1 ROS ROS 12 0.3 to test whether O 2 ._amp_#x2212 caused an increase in ROS we used HE a fluorescent probe specific for O 2 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262292 10930589 361652 20996 11179 SOD1 SOD1 SOD1 17 5.1 is unlikely to be increased in FALS cells despite reduced SOD1 activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262293 10930589 361654 18723 10261 ROS1 ROS ROS 3 0.3 Decreased generation of ROS in cells incubated with diethyldithiocarbamate (DDC) DDC 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262294 10930589 361654 5532 2719 DDC DDC DDC 9 0.0 Decreased generation of ROS in cells incubated with diethyldithiocarbamate (DDC) DDC 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262295 10930589 361655 20996 11179 SOD1 SOD1 SOD1 5 5.1 Previous studies have shown that SOD1 is inhibited by a number of metal chelating agents e.g 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262296 10930589 361655 5532 2719 DDC DDC DDC 21 0.0 of metal chelating agents e.g cyanide azide o -phenanthroline and DDC 19 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262297 10930589 361656 20996 11179 SOD1 SOD1 SOD1 2 5.1 Reaction of SOD1 with DDC requires two molecule of DDC (i) i one 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262298 10930589 361656 20996 11179 SOD1 SOD1 SOD1 19 5.1 (i) i one molecule interacts with the copper center of SOD1 with retention of activity (ii) ii while a second molecule 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262299 10930589 361656 5532 2719 DDC DDC DDC 4 0.1 Reaction of SOD1 with DDC requires two molecule of DDC (i) i one molecule interacts 6 JUMiner_v2.2 1 2 diethyldithiocarbamate 0 0 0 0 0 0 0 0 262300 10930589 361656 5532 2719 DDC DDC DDC 9 0.0 Reaction of SOD1 with DDC requires two molecule of DDC (i) i one molecule interacts with the copper center of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262301 10930589 361657 5532 2719 DDC DDC DDC 3 0.0 To test whether DDC affects free radical generation in cells we examined C-DCF fluorescence 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262302 10930589 361657 5532 2719 DDC DDC DDC 23 0.0 fluorescence in cells preincubated with 0.01 0.05 and 0.1 mM DDC 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262303 10930589 361658 5532 2719 DDC DDC DDC 7 0.0 Fluorescence in the presence of 0.01 mM DDC ( Fig 3A was significantly less inhibited in FALS cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262304 10930589 361660 5532 2719 DDC DDC DDC 9 0.0 Fluorescence was comparable inhibited with 0.05 and 0.1 mM DDC in all three groups 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262305 10930589 361661 5532 2719 DDC DDC DDC 11 0.0 menadione stimulated FALS lymphoblasts were not inhibited by 0.01 mM DDC and significantly less inhibited (38%) 38% than normal control lymphoblasts 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262306 10930589 361661 5532 2719 DDC DDC DDC 29 0.0 60% and SALS lymphoblasts (38_amp_#x2013;57%) 38_amp_#x2013 57% at 0.05 mM DDC ( P _amp_#x3c 0.006 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262307 10930589 361662 20996 11179 SOD1 SOD1 SOD1 8 5.1 This suggests the interaction of DDC with mutant SOD1 may be altered and that wildtype SOD1 contributes approximately 30_amp_#x2013 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262308 10930589 361662 20996 11179 SOD1 SOD1 SOD1 15 5.1 DDC with mutant SOD1 may be altered and that wildtype SOD1 contributes approximately 30_amp_#x2013 50% of C-DCF fluorescence in resting cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262309 10930589 361662 5532 2719 DDC DDC DDC 5 0.0 This suggests the interaction of DDC with mutant SOD1 may be altered and that wildtype SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262310 10930589 361664 18723 10261 ROS1 ROS ROS 8 0.3 Effect of the antioxidants and agents involved in ROS metabolism 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262311 10930589 361665 20996 11179 SOD1 SOD1 SOD1 0 5.1 SOD1 is a major source of H 2 O 2 in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262312 10930589 361674 14533 7872 NOS1 NOS NOS 23 1.2 ascorbic acid -nitroarginine an inhibitor of nitric oxide synthase (NOS) NOS 27 did not affect the C-DCF fluorescence in resting cells 1 JUMiner_v2.2 1 0 0 2 7873 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7873|NOS2A|0.000703463367777734<>ScoreDetail__7873|NOS2A|0.000703463367777734__7872|NOS1|0.000654307898112955__ 0 0 0 0 0 262313 10930589 361675 14533 7872 NOS1 NOS NOS 25 1.2 all groups with -nitroarginine treatment suggesting a protective role of NOS in menadione stressed cells 1 JUMiner_v2.2 1 0 0 2 7873 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7873|NOS2A|0.000703463367777734<>ScoreDetail__7873|NOS2A|0.000703463367777734__7872|NOS1|0.000654307898112955__ 0 0 0 0 0 262314 10930589 361680 20996 11179 SOD1 SOD1 SOD1 3 5.1 Since mutations in SOD1 are associated with FALS and activity of SOD1 is decreased 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262315 10930589 361680 20996 11179 SOD1 SOD1 SOD1 11 5.1 mutations in SOD1 are associated with FALS and activity of SOD1 is decreased (primarily primarily due to decreased half life of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262316 10930589 361680 20996 11179 SOD1 SOD1 SOD1 22 5.1 decreased (primarily primarily due to decreased half life of mutant SOD1 we investigated whether this would lead to increased free radical 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262317 10930589 361683 20996 11179 SOD1 SOD1 SOD1 15 5.1 O 2 ._amp_#x2212 is cleared very quickly from cells by SOD1 28 even when SOD1 is reduced by 50% 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262318 10930589 361683 20996 11179 SOD1 SOD1 SOD1 21 5.1 cleared very quickly from cells by SOD1 28 even when SOD1 is reduced by 50% 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262319 10930589 361686 20996 11179 SOD1 SOD1 SOD1 7 5.1 Our hypothesis is that copper in mutant SOD1 is available to O 2 ._amp_#x2212 only or mostly in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262320 10930589 361687 20996 11179 SOD1 SOD1 SOD1 18 5.1 it is reported to have a greater interaction with mutant SOD1 than with wildtype SOD1 7 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262321 10930589 361687 20996 11179 SOD1 SOD1 SOD1 22 5.1 have a greater interaction with mutant SOD1 than with wildtype SOD1 7 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262322 10930589 361688 20996 11179 SOD1 SOD1 SOD1 16 5.1 hypothesis of increased H 2 O 2 generation by mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262323 10930589 361691 20996 11179 SOD1 SOD1 SOD1 10 5.1 has shown that DDC reacts with Cu(II) Cu II of SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262324 10930589 361691 5532 2719 DDC DDC DDC 5 0.0 Previous study has shown that DDC reacts with Cu(II) Cu II of SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262325 10930589 361692 5532 2719 DDC DDC DDC 1 0.0 Further DDC did not react with apoenzyme and gave no indication of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262326 10930589 361693 20996 11179 SOD1 SOD1 SOD1 5 5.1 The reaction of DDC with SOD1 was shown to occur in two phases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262327 10930589 361693 5532 2719 DDC DDC DDC 3 0.1 The reaction of DDC with SOD1 was shown to occur in two phases 6 JUMiner_v2.2 1 2 diethyldithiocarbamate 0 0 0 0 0 0 0 0 262328 10930589 361694 5532 2719 DDC DDC DDC 10 0.0 Phase 1 is associated with ligation of one molecule of DDC to Cu(II), Cu II leaving Cu(II) Cu II still attached 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262329 10930589 361695 20996 11179 SOD1 SOD1 SOD1 16 5.1 a modest concentration of DDC (0.1_amp_#x2013;1.0 0.1_amp_#x2013 1.0 mM and SOD1 retains its full dismutase activity 19 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262330 10930589 361695 5532 2719 DDC DDC DDC 12 0.0 of the reaction occurs slowly at a modest concentration of DDC (0.1_amp_#x2013;1.0 0.1_amp_#x2013 1.0 mM and SOD1 retains its full dismutase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262331 10930589 361696 20996 11179 SOD1 SOD1 SOD1 7 5.1 Phase 2 involves displacement of Cu(II) Cu II from SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262332 10930589 361697 20996 11179 SOD1 SOD1 SOD1 17 5.1 Cu(II) Cu II polymerize into colloidal particles stabilized by unfolded SOD1 protein subunits 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262333 10930589 361697 5532 2719 DDC DDC DDC 6 0.0 In this phase two molecules of DDC and one Cu(II) Cu II polymerize into colloidal particles stabilized 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262334 10930589 361698 20996 11179 SOD1 SOD1 SOD1 21 5.1 equal to 10 mM and leads to a loss of SOD1 dismutase activity 19 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262335 10930589 361698 5532 2719 DDC DDC DDC 7 0.0 This phase of the reaction requires a DDC concentration greater or equal to 10 mM and leads to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262336 10930589 361699 20996 11179 SOD1 SOD1 SOD1 3 5.1 The contribution of SOD1 to C-DCF fluorescence in our studies was demonstrated by using 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262337 10930589 361699 5532 2719 DDC DDC DDC 14 0.0 to C-DCF fluorescence in our studies was demonstrated by using DDC concentrations of phase 1 reaction 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262338 10930589 361700 20996 11179 SOD1 SOD1 SOD1 14 5.1 Fig 3A and B suggests that hydrogen peroxide generated by SOD1 was indeed involved in the oxidation of C-DCDHF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262339 10930589 361701 20996 11179 SOD1 SOD1 SOD1 22 5.1 cells suggesting either altered interaction or modified stoichiometry between mutant SOD1 and DDC 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262340 10930589 361701 5532 2719 DDC DDC DDC 5 0.0 However the lower concentrations of DDC showed less inhibitory effect in FALS cells suggesting either altered 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262341 10930589 361701 5532 2719 DDC DDC DDC 24 0.1 either altered interaction or modified stoichiometry between mutant SOD1 and DDC 6 JUMiner_v2.2 1 2 diethyldithiocarbamate 0 0 0 0 0 0 0 0 262342 10930589 361702 14533 7872 NOS1 NOS NOS 19 1.2 vitamin C and the flavinoid quercetin but not inhibitor of NOS supports the conclusion that C-DCDHF was oxidized by H 2 1 JUMiner_v2.2 1 0 0 2 7873 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7873|NOS2A|0.000703463367777734<>ScoreDetail__7873|NOS2A|0.000703463367777734__7872|NOS1|0.000654307898112955__ 0 0 0 0 0 262343 10930589 361703 14533 7872 NOS1 NOS NOS 18 1.2 biological membranes against lipid peroxidation and -nitroarginine (inhibitor inhibitor of NOS showed no effect in ROS levels of all groups tested 1 JUMiner_v2.2 1 0 0 2 7873 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7873|NOS2A|0.000703463367777734<>ScoreDetail__7873|NOS2A|0.000703463367777734__7872|NOS1|0.000654307898112955__ 0 0 0 0 0 262344 10930589 361703 18723 10261 ROS1 ROS ROS 23 0.3 and -nitroarginine (inhibitor inhibitor of NOS showed no effect in ROS levels of all groups tested suggesting that lipid peroxides and 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262345 10930589 361707 20996 11179 SOD1 SOD1 SOD1 35 5.1 2 O 2 damage due to increased concentrations of mutant SOD1 in these cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262346 10930589 361708 20996 11179 SOD1 SOD1 SOD1 5 5.1 Such an accumulation of mutant SOD1 has been reported in FALS spinal cords 33 and could 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 262347 10930589 361715 18723 10261 ROS1 ROS ROS 12 0.3 test the role of H 2 O 2 and increased ROS studies are in progress to determine if increased glutathione peroxidase 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262348 10930589 361717 18723 10261 ROS1 ROS ROS 22 0.3 with SALS and normal control cells (B) B Menadione elevated ROS in all three groups with the highest levels recorded in 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262349 10930589 361729 18723 10261 ROS1 ROS ROS 3 0.3 Diethyldithiocarbamate (DDC) DDC inhibited ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 262350 10930589 361729 5532 2719 DDC DDC DDC 1 0.1 Diethyldithiocarbamate (DDC) DDC inhibited ROS generation 6 JUMiner_v2.2 1 2 diethyldithiocarbamate 0 0 0 0 0 0 0 0 262351 10930589 361730 5532 2719 DDC DDC DDC 12 0.0 of fluorescence was calculated relative to samples without addition of DDC 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 255941 11020331 350858 976 662 ARFRP1 ARP ARP 4 0.0 A biotinylated aldehyde-specific reagent ARP has been shown to react specifically with the aldehyde group 1 JUMiner_v2.2 1 2 UserEdit 0 3 9965 TotalCon:4<>662|ARFRP1|10139|Complete__15461|ARMET|7873|No_GeneRif__304|CRISP1|167|No_GeneRif__9965|RERE|473|Complete__<>AvaiableGeneRif=2<>BEST:9965|RERE|0<>ScoreDetail__662|ARFRP1|0__9965|RERE|0__ 1 1 0 0 1 arp; 255942 11020331 350860 976 662 ARFRP1 ARP ARP 1 0.0 The ARP assay is thus a simple rapid and sensitive method for 1 JUMiner_v2.2 1 2 UserEdit 0 3 9965 TotalCon:4<>662|ARFRP1|10139|Complete__15461|ARMET|7873|No_GeneRif__304|CRISP1|167|No_GeneRif__9965|RERE|473|Complete__<>AvaiableGeneRif=2<>BEST:9965|RERE|0<>ScoreDetail__662|ARFRP1|0__9965|RERE|0__ 1 1 0 0 1 arp; 255943 11020331 350861 976 662 ARFRP1 ARP ARP 17 0.0 N-glycosylases generates AP sites that can be measured by the ARP reagent 1 JUMiner_v2.2 1 2 UserEdit 0 3 9965 TotalCon:4<>662|ARFRP1|10139|Complete__15461|ARMET|7873|No_GeneRif__304|CRISP1|167|No_GeneRif__9965|RERE|473|Complete__<>AvaiableGeneRif=2<>BEST:9965|RERE|0<>ScoreDetail__662|ARFRP1|0__9965|RERE|0__ 1 1 0 0 1 arp; 255944 11020331 350862 14921 8125 OGG1 OGG1 OGG1 15 0.6 either endonuclease III from Escherichia coli or 8-oxoguanine N-glycosylase (OGG1) OGG1 from yeast investigators can rapidly determine the amount of oxidative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 255945 11020331 350862 14921 8125 OGG1 OGG1 OGG1-sensitive 34 0.6 pyrimidine damage (endonuclease endonuclease III-sensitive sites or purine damage (OGG1-sensitive OGG1-sensitive sites in cellular DNA respectively 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 255946 11020331 350862 976 662 ARFRP1 ARP ARP 3 0.0 By coupling the ARP assay with either endonuclease III from Escherichia coli or 8-oxoguanine 1 JUMiner_v2.2 1 2 UserEdit 0 3 9965 TotalCon:4<>662|ARFRP1|10139|Complete__15461|ARMET|7873|No_GeneRif__304|CRISP1|167|No_GeneRif__9965|RERE|473|Complete__<>AvaiableGeneRif=2<>BEST:9965|RERE|0<>ScoreDetail__662|ARFRP1|0__9965|RERE|0__ 1 1 0 0 1 arp; 255947 11020331 350864 976 662 ARFRP1 ARP ARP 6 0.0 The sensitivity and simplicity of the ARP assay thus make it a valuable method for investigators who 1 JUMiner_v2.2 1 2 UserEdit 0 3 9965 TotalCon:4<>662|ARFRP1|10139|Complete__15461|ARMET|7873|No_GeneRif__304|CRISP1|167|No_GeneRif__9965|RERE|473|Complete__<>AvaiableGeneRif=2<>BEST:9965|RERE|0<>ScoreDetail__662|ARFRP1|0__9965|RERE|0__ 1 1 0 0 1 arp; 257587 11050436 352943 18723 10261 ROS1 ROS ROS 26 0.3 a new problem _amp_#x2013 that of reactive oxygen species (ROS) ROS produced as a byproduct of normal metabolism 1 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 257588 11050436 352957 20997 11180 SOD2 MnSOD MnSOD-depleted 21 1.9 inhibitors on superoxide production in isolated whole mitochondria compared with MnSOD-depleted submitochondrial particles also suggests that there is a sidedness to 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257589 11050436 352958 20997 11180 SOD2 MnSOD MnSOD 32 1.9 is likewise suggested by the presence of appreciable levels of MnSOD in the mitochondrial matrix and the comparatively low levels of 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257590 11050436 352958 20997 11180 SOD2 MnSOD MnSOD 49 1.9 comparatively low levels of superoxide production by whole mitochondria containing MnSOD ( Ref 23 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257591 11050436 352960 18723 10261 ROS1 ROS ROS 5 0.3 Damage caused by mitochondrially generated ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 257592 11050436 352964 166 118 ACO2 aconitase aconitase 8 1.3 For example damage to the cytosolic isoenzyme of aconitase evident after exposure to superoxide results in the release of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257593 11050436 352965 166 118 ACO2 aconitase aconitase 8 1.3 The damage to other systems such as mitochondrial aconitase complex I and succinate dehydrogenase which also have important functional 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257594 11050436 352965 20997 11180 SOD2 MnSOD MnSOD 25 1.9 also have important functional iron-sulphur centres becomes very pronounced in MnSOD knockout mice where superoxide produced in the mitochondria is not 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257595 11050436 352969 20997 11180 SOD2 MnSOD MnSOD 25 1.9 birth with the severe phenotypic changes evident in mice lacking MnSOD which suggests that either the mitochondria are more susceptible to 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257596 11050436 352972 20997 11180 SOD2 MnSOD MnSOD 27 1.9 from patients with complex I deficiency displayed significant elevations of MnSOD sometimes two- to threefold whereas patients with defects in complex 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257597 11050436 352974 20997 11180 SOD2 MnSOD MnSOD 21 1.9 symptoms (EI EI and CD were less likely to induce MnSOD above the basal levels normally seen in fibroblasts whereas patients 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257598 11050436 352974 20997 11180 SOD2 MnSOD MnSOD 46 1.9 LD FILA which were usually fatal always had elevations of MnSOD ( 20 and 27 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257599 11050436 352975 20997 11180 SOD2 MnSOD MnSOD 17 1.9 increased superoxide production from complex I with no increase in MnSOD ( 26 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257600 11050436 352976 20997 11180 SOD2 MnSOD MnSOD 8 1.9 The correlation of increased levels of expression of MnSOD with a poor prognosis in complex I deficiency suggests that 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257601 11050436 352976 20997 11180 SOD2 MnSOD MnSOD 26 1.9 deficiency suggests that responding to the increased superoxide by inducing MnSOD could itself be detrimental in the long term because of 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257602 11050436 352977 20997 11180 SOD2 MnSOD MnSOD 16 1.9 radical were demonstrated in cell lines with increased induction of MnSOD ( 28 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257603 11050436 352978 20997 11180 SOD2 MnSOD MnSOD 42 1.9 to form increased amounts of superoxide (iv) iv induction of MnSOD (v) v increased formation of hydrogen peroxide from superoxide via 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257604 11050436 352978 20997 11180 SOD2 MnSOD MnSOD 52 1.9 (v) v increased formation of hydrogen peroxide from superoxide via MnSOD or (vi) vi transformation of hydrogen peroxide to hydroxyl radicals 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257605 11050436 352980 20996 11179 SOD1 ALS ALS 19 0.9 when mutations in CuZnSOD predisposing to amyotrophic lateral sclerosis (ALS) ALS are present 29 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000605951449456795<>ScoreDetail__5468|IGFALS|0.000329364523693537__11179|SOD1|0.000605951449456795__ 0 0 0 0 0 257606 11050436 352981 20996 11179 SOD1 ALS ALS 8 0.9 Although only a small proportion of patients with ALS have such mutations their existence has led to a number 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000605951449456795<>ScoreDetail__5468|IGFALS|0.000329364523693537__11179|SOD1|0.000605951449456795__ 0 0 0 0 0 257607 11050436 352982 20996 11179 SOD1 ALS ALS 6 0.9 The mutations seen in CuZnSOD in ALS patients are odd in that they do not destroy superoxide 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000605951449456795<>ScoreDetail__5468|IGFALS|0.000329364523693537__11179|SOD1|0.000605951449456795__ 0 0 0 0 0 257608 11050436 352987 18723 10261 ROS1 ROS ROS-induced 2 0.0 Evidence for ROS-induced mitochondrial damage associated with ageing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257609 11050436 352989 18723 10261 ROS1 ROS ROS 66 0.3 more rapid rates of basal metabolism have faster rates of ROS production and a shorter life span 30 34 and 35 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 257610 11050436 352997 20996 11179 SOD1 ALS ALS 9 0.9 In transgenic mice bearing CuZnSOD mutations known to cause ALS in humans the protective bcl-2 protein when overexpressed transgenically can 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000605951449456795<>ScoreDetail__5468|IGFALS|0.000329364523693537__11179|SOD1|0.000605951449456795__ 0 0 0 0 0 257611 11050436 352997 20996 11179 SOD1 ALS ALS 27 0.9 overexpressed transgenically can protect against neuronal death brought about by ALS mutations in experimental animals 37 and 38 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000605951449456795<>ScoreDetail__5468|IGFALS|0.000329364523693537__11179|SOD1|0.000605951449456795__ 0 0 0 0 0 257612 11050436 352998 18723 10261 ROS1 ROS ROS-generating 8 0.0 One intriguing example of the link between the ROS-generating function of the respiratory chain and life span is that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257613 11050436 353012 20997 11180 SOD2 MnSOD MnSOD 3 1.9 The overexpression of MnSOD in cultured rat glioma cells made those cells more sensitive 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257614 11050436 353012 20997 11180 SOD2 MnSOD MnSOD 26 1.9 to damage by radiation and carcinogens 45 and 46 whereas MnSOD overexpression in mouse heart is protective against adriamycin-induced cardiotoxicity 47 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257615 11050436 353017 18723 10261 ROS1 ROS ROS 4 0.3 Clearly the role of ROS in ageing needs to be put into context with respect 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 257616 11050436 353028 18723 10261 ROS1 ROS ROS 12 0.3 telomere length was reduced significantly by peroxide-induced damage suggesting that ROS actively attack telomeric DNA and cause increased shortening as DNA 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 257617 11050436 353043 166 118 ACO2 aconitase aconitase 11 1.3 alternative scenario superoxide attacks enzymes (usually usually hydrolyases such as aconitase with 4Fe-4S centres releasing ferrous ions 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257618 11050436 353049 14261 7715 NDUFS8 TYKY TYKY 11 1.9 are then passed to two 4Fe-4S centres in the 23-kDa TYKY subunit and a single 4Fe-4S centre in the 20-kDa PSST 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257619 11050436 353049 14260 7714 NDUFS7 PSST PSST 21 1.9 TYKY subunit and a single 4Fe-4S centre in the 20-kDa PSST subunit both of which are associated with the membrane-spanning segment 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257620 11050436 353049 14260 7714 NDUFS7 PSST PSST 77 1.9 in the matrix arm of the enzyme and one in PSST 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257621 11050436 353050 14260 7714 NDUFS7 PSST PSST 27 1.9 drawn with a single reduction site encompassing the 49-kDa and PSST subunits at the right-hand side of the complex 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257622 11050436 353051 14260 7714 NDUFS7 PSST PSST 20 1.9 49-kDa subunit and rotenone inhibition of the complex at the PSST subunit are shown but it is possible to draw a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257623 11050436 353052 14261 7715 NDUFS8 TYKY TYKY 4 1.9 Boxes depicted in the TYKY and PSST subunits show the cubic arrangement of the 4Fe-4S 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257624 11050436 353052 14260 7714 NDUFS7 PSST PSST 6 1.9 Boxes depicted in the TYKY and PSST subunits show the cubic arrangement of the 4Fe-4S centres with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257625 11050436 353061 18723 10261 ROS1 ROS ROS 6 0.3 The generation of reactive oxygen species (ROS) ROS by mitochondria 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 257626 11050436 353066 13735 7455 MT-ND1 ND1 ND1 8 0.9 MtDNA genes include those for complex I ( ND1 ND2 ND3 ND4 ND4L ND5 ND6 for complex III ( 1 JUMiner_v2.2 1 0 0 2 16951 TotalCon:2<>16951|IVNS1ABP|10625|Complete__7455|MT-ND1|4535|Complete__<>AvaiableGeneRif=2<>BEST:16951|IVNS1ABP|0.000657871550579749<>ScoreDetail__16951|IVNS1ABP|0.000657871550579749__7455|MT-ND1|0.000481349009480008__ 0 0 0 0 0 257627 11050436 353066 13736 7456 MT-ND2 ND2 ND2 10 0.9 MtDNA genes include those for complex I ( ND1 ND2 ND3 ND4 ND4L ND5 ND6 for complex III ( cyt 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257628 11050436 353066 13737 7458 MT-ND3 ND3 ND3 12 0.9 MtDNA genes include those for complex I ( ND1 ND2 ND3 ND4 ND4L ND5 ND6 for complex III ( cyt b 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257629 11050436 353066 13738 7459 MT-ND4 ND4 ND4 14 0.9 genes include those for complex I ( ND1 ND2 ND3 ND4 ND4L ND5 ND6 for complex III ( cyt b for 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257630 11050436 353066 13739 7460 MT-ND4L ND4L ND4L 16 1.9 include those for complex I ( ND1 ND2 ND3 ND4 ND4L ND5 ND6 for complex III ( cyt b for complex 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257631 11050436 353066 13740 7461 MT-ND5 ND5 ND5 18 0.9 those for complex I ( ND1 ND2 ND3 ND4 ND4L ND5 ND6 for complex III ( cyt b for complex IV 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257632 11050436 353066 13741 7462 MT-ND6 ND6 ND6 20 0.9 for complex I ( ND1 ND2 ND3 ND4 ND4L ND5 ND6 for complex III ( cyt b for complex IV ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257633 11050436 353066 13729 7414 MT-ATP6 ATP6 ATP6 43 1.9 IV ( COXI COXII COXIII and for complex V ( ATP6 ATP8 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257634 11050436 353066 13730 7415 MT-ATP8 ATP8 ATP8 45 1.9 ( COXI COXII COXIII and for complex V ( ATP6 ATP8 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257635 11050436 353067 13744 7475 MT-TA TRNA tRNA 2 2.1 Positions of tRNA genes in mtDNA which feature prominently in mutations prevalent in 14 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 257636 11050436 353067 13744 7475 MT-TA TRNA tRNA 34 2.1 single-letter amino acid code corresponding to the specificity of the tRNA 14 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 257637 11050436 353069 20997 11180 SOD2 MnSOD MnSOD 25 1.9 O 2 by CuZnSOD if in the matrix space by MnSOD 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 257638 11050436 353070 8759 4553 GPX1 GPX1 GPX-1 13 0.9 peroxide in both compartments is achieved by glutathione peroxidase (GPX-1), GPX-1 which exists both in the cytosol and in the mitochondrial 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 253638 11223912 347837 14533 7872 NOS1 nNOS nNOS 34 2.2 molecules such as calmodulin and neuronal nitric oxide synthase (nNOS), nNOS in the cytoplasm 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 253639 11223912 347838 20996 11179 SOD1 ALS ALS 28 0.9 part associated with the pathogenesis of amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000878945190887426<>ScoreDetail__5468|IGFALS|0.000293036389791678__11179|SOD1|0.000878945190887426__ 0 0 0 0 0 253640 11223912 347842 18723 10261 ROS1 ROS ROS 16 0.0 elevated promptly with subsequent accumulation of reactive oxygen species (ROS) ROS in the mitochondria 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 253641 11223912 347843 18723 10261 ROS1 ROS ROS 17 0.0 the increase in fluorescence of mitochondrial Ca(2+) Ca 2 and ROS indicators 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 253642 11223912 347844 18723 10261 ROS1 ROS ROS 16 0.0 neurons is mediated by mitochondrial Ca(2+) Ca 2 overload and ROS generation through the activation of NMDA receptors 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 253679 11228742 347972 3889 11919 CD40 p50 p50 14 0.3 in the nervous system is composed of the DNA-binding subunits p50 and p65 complexed with an inhibitory I kappa B-alpha molecule 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 253680 11228742 347972 8569 16769 GORASP1 p65 p65 16 0.1 nervous system is composed of the DNA-binding subunits p50 and p65 complexed with an inhibitory I kappa B-alpha molecule 6 JUMiner_v2.2 1 0 0 2 16769 TotalCon:2<>16769|GORASP1|64689|Complete__11509|SYT1|6857|Complete__<>AvaiableGeneRif=2<>BEST:16769|GORASP1|0.000546746856205577<>ScoreDetail__16769|GORASP1|0.000546746856205577__11509|SYT1|0.000512032770097286__ 0 0 0 0 0 249596 11328670 340452 20997 11180 SOD2 MnSOD MnSOD 3 2.9 Manganese superoxide dismutase (MnSOD) MnSOD is essential for life as dramatically illustrated by the neonatal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 249597 11328670 340452 20997 11180 SOD2 MnSOD MnSOD 21 2.9 by the neonatal lethality of mice that are deficient in MnSOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 249598 11328670 340453 20997 11180 SOD2 MnSOD MnSOD 11 2.9 addition mice expressing only 50% of the normal compliment of MnSOD demonstrate increased susceptibility to oxidative stress and severe mitochondrial dysfunction 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 249599 11328670 340454 20997 11180 SOD2 MnSOD MnSOD 10 2.9 Thus it is important to know the status of both MnSOD protein levels and activity in order to assess its role 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 249600 11328670 340455 20997 11180 SOD2 MnSOD MnSOD 5 2.9 Numerous studies have shown that MnSOD can be induced to protect against pro-oxidant insults resulting from 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 249601 11328670 340456 20997 11180 SOD2 MnSOD MnSOD 4 2.9 In addition overexpression of MnSOD has been shown to protect against pro-apoptotic stimuli as well 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 249602 11328670 340457 20997 11180 SOD2 MnSOD MnSOD 7 2.9 Conversely several studies have reported declines in MnSOD activity during diseases including cancer aging progeria asthma and transplant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 249603 11328670 340459 20997 11180 SOD2 MnSOD MnSOD 1 2.9 Certainly MnSOD gene expression or other defects could play a role in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 249604 11328670 340460 20997 11180 SOD2 MnSOD MnSOD 9 2.9 However based on recent findings regarding the susceptibility of MnSOD to oxidative inactivation it is equally likely that post-translational modification 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 249605 11328670 340460 20997 11180 SOD2 MnSOD MnSOD 21 2.9 oxidative inactivation it is equally likely that post-translational modification of MnSOD may account for the loss of activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 249606 11328670 340461 20997 11180 SOD2 MnSOD MnSOD 6 2.9 Our laboratory has recently demonstrated that MnSOD is tyrosine nitrated and inactivated during human kidney allograft rejection 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 249607 11328670 340462 20997 11180 SOD2 MnSOD MnSOD 29 2.9 nitrate critical tyrosine residues and to induce dityrosine formation in MnSOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 249608 11328670 340463 20997 11180 SOD2 MnSOD MnSOD 5 2.9 Tyrosine nitration and inactivation of MnSOD would lead to increased levels of superoxide and concomitant increases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 249609 11328670 340464 20997 11180 SOD2 MnSOD MnSOD 7 2.9 This article assesses the important role of MnSOD activity in various pathological states in light of this potentially 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 251203 11375746 342604 20996 11179 SOD1 ALS ALS 20 0.0 such as Parkinson's disease (PD), PD amyotrophic lateral sclerosis (ALS), ALS and Huntington's disease are characterized by the deposition of abnormal 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000785386566356046<>ScoreDetail__5468|IGFALS|0.000129764801297648__11179|SOD1|0.000785386566356046__ 0 0 0 0 0 251528 11396274 343499 20996 11179 SOD1 SOD1 SOD1 2 1.2 Neurochemistry of SOD1 and familial amyotrophic lateral sclerosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242766 11513882 330566 20996 11179 SOD1 SOD1 SOD1 17 6.0 lateral sclerosis (fALS) fALS are linked to mutations in the SOD1 gene which encodes the copper/zinc copper zinc superoxide dismutase (CuZnSOD) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242767 11513882 330569 20996 11179 SOD1 SOD SOD 13 4.3 monitored calcineurin activity in the presence of mutant and wild-type SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242768 11513882 330570 20996 11179 SOD1 SOD SOD 13 4.3 the degree of protection against inactivation of calcineurin by different SOD mutants correlates with the severity of the phenotype associated with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242769 11513882 330570 20996 11179 SOD1 SOD1 SOD1 32 6.0 with the different mutations suggesting a potential role for calcineurin_amp_#x2013 SOD1 interaction in the etiology of fALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242770 11513882 330573 20996 11179 SOD1 SOD1 SOD1 3 6.0 Mutations in the SOD1 gene which encodes the enzyme copper/zinc copper zinc superoxide dismutase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242771 11513882 330577 20996 11179 SOD1 SOD1 SOD1 8 6.0 Today more than 70 different mutations of the SOD1 gene are known ranging from mutations that are associated with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242772 11513882 330578 20996 11179 SOD1 SOD1 SOD1 5 6.0 Recently it was shown that SOD1 protects calcineurin a serine/threonine-specific serine threonine-specific calcium/calmodulin-dependent calcium calmodulin-dependent phosphoprotein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242773 11513882 330579 20996 11179 SOD1 ALS ALS 11 2.2 has been implicated in a wide range of diseases including ALS 6 7 8 and 9 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000714625490208973<>ScoreDetail__5468|IGFALS|0.000311934618503962__11179|SOD1|0.000714625490208973__ 0 0 0 0 0 242774 11513882 330581 20996 11179 SOD1 SOD1 SOD1 20 6.0 the last years the primary molecular targets of the mutated SOD1 in fALS are still unknown 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242775 11513882 330583 20996 11179 SOD1 SOD SODs 8 2.2 In this study we report that the mutant SODs were significantly less protective against calcineurin inactivation and that the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242776 11513882 330603 20996 11179 SOD1 SOD SODs 3 2.2 Wt and mutant SODs were purified and demetalated by Ni-NTA-affinity chromatography using imidazole (500 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242777 11513882 330608 20996 11179 SOD1 SOD SOD 0 4.3 SOD assay and activity staining 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242778 11513882 330614 20996 11179 SOD1 SOD SOD 5 4.3 For atomic emission spectrometry (AES), AES SOD proteins were washed five times in refolding buffer (Centrex Centrex 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242779 11513882 330614 408 307 AES AES AES 4 0.2 For atomic emission spectrometry (AES), AES SOD proteins were washed five times in refolding buffer (Centrex 5 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 242780 11513882 330615 19254 10472 RUNX2 CCD CCD 21 0.3 added and the samples were analyzed with a ICP-VISTA RL CCD simultaneous ICP-AES 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 242781 11513882 330618 20247 20116 SLC25A29 CACL CaCl 16 1.0 addition of 20 _amp_#x3bc l substrate buffer (0.67 0.67 mM CaCl 2 final concentration 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 242782 11513882 330627 20996 11179 SOD1 SOD SOD 28 4.3 okadaic acid (5 5 _amp_#x3bc m 200 _amp_#x3bc g of SOD proteins and water ad 40 _amp_#x3bc l 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242783 11513882 330632 20996 11179 SOD1 SOD1 SOD1 11 6.0 test the hypothesis that calcineurin is a target of mutated SOD1 we used recombinant wt enzyme and three variants associated with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242784 11513882 330633 20996 11179 SOD1 ALS ALS 22 2.2 classic (G93A) G93A or a benign (D90A) D90A course of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000714625490208973<>ScoreDetail__5468|IGFALS|0.000311934618503962__11179|SOD1|0.000714625490208973__ 0 0 0 0 0 242785 11513882 330635 20996 11179 SOD1 SOD SOD 13 4.3 native electropherograms with NBT showed a corresponding pattern with wt SOD showing the highest activity followed by the D90A mutant whereas 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242786 11513882 330642 20996 11179 SOD1 ALS ALS 16 2.2 more benign form of fALS which only gives rise to ALS in homozygous individuals conveyed the most protection of calcineurin activity 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000714625490208973<>ScoreDetail__5468|IGFALS|0.000311934618503962__11179|SOD1|0.000714625490208973__ 0 0 0 0 0 242787 11513882 330642 20996 11179 SOD1 SOD SODs 30 2.2 conveyed the most protection of calcineurin activity of the mutant SODs studied 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242788 11513882 330644 20996 11179 SOD1 SOD SOD 29 4.3 loss of over 60% of the protection confered by wt SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242789 11513882 330645 20996 11179 SOD1 SOD SOD 7 4.3 This effect was not due to reduced SOD activity of the mutant SODs compared to wt when the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242790 11513882 330645 20996 11179 SOD1 SOD SODs 12 2.2 was not due to reduced SOD activity of the mutant SODs compared to wt when the amounts of wt or mutant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242791 11513882 330645 20996 11179 SOD1 SOD SOD 23 4.3 compared to wt when the amounts of wt or mutant SOD were quadrupled (800 800 ng the loss of protection of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242792 11513882 330645 20996 11179 SOD1 SOD SOD 43 4.3 calcineurin activity was magnified rather than reduced for the fALS SOD mutants ( Fig 2b dark bars however the differences in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242793 11513882 330646 20996 11179 SOD1 SOD SOD 2 4.3 While wt SOD maintained its protective effect on calcineurin activity and co-incubation of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242794 11513882 330646 20996 11179 SOD1 SOD SODs 16 2.2 effect on calcineurin activity and co-incubation of calcineurin with the SODs associated with benign (D9OA) D9OA and classic (G93A) G93A fALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242795 11513882 330646 20996 11179 SOD1 SOD SOD 35 4.3 only showed a slight reduction compared to 200 ng of SOD the SOD associated with the most severe form of fALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242796 11513882 330646 20996 11179 SOD1 SOD SOD 37 4.3 a slight reduction compared to 200 ng of SOD the SOD associated with the most severe form of fALS (A4V) A4V 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242797 11513882 330646 20996 11179 SOD1 SOD hSOD 65 2.2 activity meaning that over 80% of the protection of wt hSOD were lost due to this mutation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242798 11513882 330648 20996 11179 SOD1 SOD SOD 9 4.3 To address the observation that increased amounts of mutant SOD compounded the loss of calcineurin activity we tested a mixture 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242799 11513882 330651 20996 11179 SOD1 SOD SODs 6 2.2 Our results thus demonstrate that mutant SODs can reduce the protection conferred by wt SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242800 11513882 330651 20996 11179 SOD1 SOD SOD 14 4.3 that mutant SODs can reduce the protection conferred by wt SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242801 11513882 330652 20996 11179 SOD1 SOD1 SOD1 7 6.0 This observation supports the hypothesis that the SOD1 mutations found in fALS result in a negative gain of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242802 11513882 330652 20996 11179 SOD1 SOD SOD 32 4.3 in a reduction of the protection of calcineurin by wt SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242803 11513882 330655 20996 11179 SOD1 SOD SOD 9 4.3 How the different mutations in the ubiquitously expressed enzyme SOD cause the highly specific neuropathological phenotype associated with fALS remains 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242804 11513882 330661 20996 11179 SOD1 SOD SOD 36 4.3 CuZnSOD 5 which itself accounts for 2% of brain protein SOD and calcineurin are both among the most abundant proteins in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242805 11513882 330663 20996 11179 SOD1 SOD SODs 7 2.2 In this study we report that mutated SODs loose their capacity to protect calcineurin from oxidative inactivation as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242806 11513882 330665 20996 11179 SOD1 SOD SOD 1 4.3 The SOD mutant showing the least protective effect (A4V) A4V is associated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242807 11513882 330666 20996 11179 SOD1 SOD1 SOD1 20 6.0 reduced calcineurin activity in human neuroblastoma cells transfected with mutated SOD1 and in the forebrains of fALS-transgenic mice 9 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242808 11513882 330667 20996 11179 SOD1 SOD SOD 5 4.3 Moreover when the amount of SOD protein was quadrupled in the assay the wt maintained its 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242809 11513882 330669 20996 11179 SOD1 SOD SOD 18 4.3 the wt CuZnSOD protein and not simply the presence of SOD activity is needed for the protection of calcineurin from oxidative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242810 11513882 330669 20996 11179 SOD1 SOD SOD-generated 41 2.2 that the increased inactivation of calcineurin is mediated by mutated SOD-generated oxidative species different from superoxide a hypothesis that has already 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242811 11513882 330670 20996 11179 SOD1 SOD SOD 13 4.3 be in accordance with the notion that overexpression of wt SOD together with fALS-associated SOD is not protective 21 an observation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242812 11513882 330670 20996 11179 SOD1 SOD SOD 17 4.3 the notion that overexpression of wt SOD together with fALS-associated SOD is not protective 21 an observation that is strengthened by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242813 11513882 330670 20996 11179 SOD1 SOD SODs 39 2.2 by the fact that a mixture of wt and mutant SODs only confers an intermediate rate of protection 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242814 11513882 330671 20996 11179 SOD1 SOD SOD 6 4.3 The partial protective effect of wt SOD when mixed with mutant SOD may be explained by the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242815 11513882 330671 20996 11179 SOD1 SOD SOD 11 4.3 partial protective effect of wt SOD when mixed with mutant SOD may be explained by the necessity of SOD to bind 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242816 11513882 330671 20996 11179 SOD1 SOD SOD 19 4.3 with mutant SOD may be explained by the necessity of SOD to bind to calcineurin to exert its protective effect 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242817 11513882 330672 20996 11179 SOD1 SOD SODs 3 2.2 Wt and mutant SODs therefore would compete for binding to calcineurin so that part 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242818 11513882 330672 20996 11179 SOD1 SOD SOD 24 4.3 of the calcineurin molecules still could be protected by wt SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242819 11513882 330673 20996 11179 SOD1 SOD1 SOD1 10 6.0 It has to be noted however that the recombinant reconstituted SOD1 proteins used in this study show an abnormal zinc content 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242820 11513882 330674 20996 11179 SOD1 SOD1 SOD1 4 6.0 A reduced affinity of SOD1 mutants for zinc is an observation that has already been 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242821 11513882 330676 20996 11179 SOD1 SOD1 SOD1 3 6.0 However our wt SOD1 gives exactly the same rate of protection as SOD1 purified 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242822 11513882 330676 20996 11179 SOD1 SOD1 SOD1 12 6.0 wt SOD1 gives exactly the same rate of protection as SOD1 purified from erythrocytes and the D90A mutation which shows a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242823 11513882 330678 20996 11179 SOD1 ALS ALS 5 2.2 Independent of its relevance for ALS our data give additional information that calcineurin is regulated not 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000714625490208973<>ScoreDetail__5468|IGFALS|0.000311934618503962__11179|SOD1|0.000714625490208973__ 0 0 0 0 0 242824 11513882 330682 20996 11179 SOD1 SOD SODs 12 2.2 of our results a reduction of calcineurin activity by mutant SODs would therefore lead to prolonged NMDA receptor-channel openings and therefore 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242825 11513882 330683 20996 11179 SOD1 SOD1 SOD1 10 6.0 This would explain why glutamate potentiates the toxicity of mutant SOD1 in motor neurons 22 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242826 11513882 330684 20996 11179 SOD1 SOD SODs 29 2.2 systems and a higher Ca content in cells expressing mutant SODs or in mutant SOD1 transgenic mice has been observed 23 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242827 11513882 330684 20996 11179 SOD1 SOD1 SOD1 33 6.0 Ca content in cells expressing mutant SODs or in mutant SOD1 transgenic mice has been observed 23 24 and 25 a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242828 11513882 330687 20996 11179 SOD1 ALS ALS 16 2.2 may therefore be a therapeutic approach in the treatment of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000714625490208973<>ScoreDetail__5468|IGFALS|0.000311934618503962__11179|SOD1|0.000714625490208973__ 0 0 0 0 0 242829 11513882 330689 20996 11179 SOD1 SOD1 SOD1 3 6.0 Characterization of the SOD1 proteins 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242830 11513882 330690 20996 11179 SOD1 SOD1 SOD1 2 6.0 The recombinant SOD1 proteins are characterized by a reduced activity and a reduced 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242831 11513882 330691 20996 11179 SOD1 SOD1 SOD1 6 6.0 Lower panel Activity staining of recombinant SOD1 proteins 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242832 11513882 330698 20996 11179 SOD1 SOD SOD 38 4.3 activity can be preserved by addition of erythrocyte (ery) ery SOD or recombinant human (hr) hr SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242833 11513882 330698 20996 11179 SOD1 SOD SOD 43 4.3 of erythrocyte (ery) ery SOD or recombinant human (hr) hr SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242834 11513882 330699 20996 11179 SOD1 SOD SODs 2 2.2 Recombinant mutant SODs associated with fALS are less protective 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242835 11513882 330700 20996 11179 SOD1 SOD SODs 8 2.2 Addition of quadruple amounts of wt or mutant SODs (black black bars reduces the protective ability of the mutants 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242836 11513882 330702 20996 11179 SOD1 SOD SOD 15 4.3 n =6 * P _amp_#x3c 0.05 significantly different from wt SOD by Student_amp_#x2019 s t -test ** P _amp_#x3c 0.01 significantly 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242837 11513882 330702 20996 11179 SOD1 SOD SOD 27 4.3 t -test ** P _amp_#x3c 0.01 significantly different from wt SOD by Student_amp_#x2019 s t -test 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242838 11513882 330704 20996 11179 SOD1 SOD SODs 6 2.2 A mixture of wt and mutant SODs confers intermediate protection 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242839 11513882 330705 20996 11179 SOD1 SOD SOD 3 4.3 Addition of wt SOD (400 400 ng to mutant SOD1s (400 400 ng results 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242840 11513882 330705 20996 11179 SOD1 SOD1 SOD1s 8 2.2 Addition of wt SOD (400 400 ng to mutant SOD1s (400 400 ng results in intermediate protective ability against oxidative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 242841 11513882 330707 20996 11179 SOD1 SOD SOD 15 4.3 n =4 ** P _amp_#x3c 0.01 significantly different from mutant SOD alone by Student_amp_#x2019 s t -test 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245292 11562447 333621 7552 3690 FGFR3 ACH ACh 32 0.0 al. 1993 where it can interfere with the acetylcholine (ACh) ACh release mechanism after diffusion and participates in the control of 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245293 11562447 333623 12361 18752 MAPKAP1 SIN1 SIN-1 15 0.3 for the last 30 years is hydrolyzed to 3-morpholinosydnonimine (SIN-1), SIN-1 which has been shown to release consecutively O 2 and 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245294 11562447 333632 7552 3690 FGFR3 ACH ACh 25 0.0 endings of T marmorata electroneurons and showed that NO increased ACh release whereas ONOO inhibited ACh synthesis (Morot Morot Gaudry-Talarmain et 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245295 11562447 333632 7552 3690 FGFR3 ACH ACh 30 0.0 and showed that NO increased ACh release whereas ONOO inhibited ACh synthesis (Morot Morot Gaudry-Talarmain et al. 1997 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245296 11562447 333633 7552 3690 FGFR3 ACH ACh 0 0.0 ACh in neuromuscular junctions is synthesized from two extracellular precursors 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245297 11562447 333636 7552 3690 FGFR3 ACH ACh 2 0.0 Synthesis of ACh from choline and acetyl-CoA is performed by choline acetyltransferase (ChAT), 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245298 11562447 333637 7552 3690 FGFR3 ACH ACh 6 0.0 In a subsequent step newly synthesized ACh is transported into synaptic vesicles by the energy-dependent vesicular ACh 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245299 11562447 333637 7552 3690 FGFR3 ACH ACh 16 0.0 ACh is transported into synaptic vesicles by the energy-dependent vesicular ACh transporter 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245300 11562447 333638 12361 18752 MAPKAP1 SIN1 SIN-1 9 0.3 This article presents the inhibitory effects of ONOO and SIN-1 a donor of ONOO on high-affinity choline uptake ACh synthesis 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245301 11562447 333638 7552 3690 FGFR3 ACH ACh 19 0.0 and SIN-1 a donor of ONOO on high-affinity choline uptake ACh synthesis from radiolabeled acetate and ChAT activity 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245302 11562447 333648 12361 18752 MAPKAP1 SIN1 SIN-1 3 0.3 Stock Solutions of SIN-1 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245303 11562447 333649 12361 18752 MAPKAP1 SIN1 SIN-1 0 0.3 SIN-1 was obtained from BIOMOL (Plymouth Plymouth Meeting PA 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245304 11562447 333650 12361 18752 MAPKAP1 SIN1 SIN-1 3 0.3 Aqueous solutions of SIN-1 (100 100 mM were stored at 20degreeC before use 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245305 11562447 333653 12705 7097 MIF GIF Gif-sur-Yvette 31 0.3 Nicolas Morel (Laboratoire Laboratoire de Neurobiologie Cellulaire et Moleculaire CNRS Gif-sur-Yvette France 11 JUMiner_v2.2 1 2 UserEdit 0 2 7408 TotalCon:3<>4268|GIF|2694|Complete__7097|MIF|4282|Complete__7408|MT3|4504|Complete__<>AvaiableGeneRif=3<>BEST:7408|MT3|0.00045766590389016<>ScoreDetail__7097|MIF|0.000263290488741501__7408|MT3|0.00045766590389016__4268|GIF|0.000296442687747036__ 1 1 0 0 0 245306 11562447 333668 12361 18752 MAPKAP1 SIN1 SIN-1 12 0.3 Synaptosomes Synaptic Vesicles and Bovine Brain ChAT to ONOO or SIN-1 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245307 11562447 333669 12361 18752 MAPKAP1 SIN1 SIN-1 26 0.3 in 50 mM sodium-phosphate buffer pH 7.3 with ONOO or SIN-1 was carried out at room temperature for 1 to 2 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245308 11562447 333670 12361 18752 MAPKAP1 SIN1 SIN-1 3 0.3 For ONOO and SIN-1 incubations various increasing concentrations of drugs were added in one 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245309 11562447 333680 7552 3690 FGFR3 ACH ACh 4 0.0 Synthesis and Compartmentalization of ACh 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245310 11562447 333681 7552 3690 FGFR3 ACH ACh 2 0.0 Synthesis of ACh by 400 microl of synaptosomes was measured using C acetate 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245311 11562447 333681 7552 3690 FGFR3 ACH ACh 20 0.0 acetate (100 100 microM and choline (100 100 microM as ACh precursors 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245312 11562447 333683 7552 3690 FGFR3 ACH ACh 5 0.0 Formation of newly synthesized radioactive ACh in synaptosomes (180 180 microl was stopped by the addition 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245313 11562447 333683 7552 3690 FGFR3 ACH ACh 28 0.0 TCA whereas in the other aliquot (180 180 microl radioactive ACh accumulation in the vesicular pool was determined after one freezing 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245314 11562447 333684 7552 3690 FGFR3 ACH ACh 17 0.0 from all the samples by three ether washes and radioactive ACh was extracted by an allylcyanide-tetraphenylboron organic extraction procedure (Fonnum, Fonnum 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245315 11562447 333685 7552 3690 FGFR3 ACH ACh 6 0.0 The organic lipophilic phase containing radioactive ACh was collected and radioactivity was counted in Lipoluma scintillation liquid 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245316 11562447 333691 7552 3690 FGFR3 ACH ACh 1 0.0 Radioactive ACh was extracted and determined according to the method used by 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245317 11562447 333695 12361 18752 MAPKAP1 SIN1 SIN-1 31 0.3 freshly prepared synaptosomes (300 300 microl were pretreated with ONOO SIN-1 or vehicle (0.1 0.1 N NaOH for 45 min 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245318 11562447 333699 19573 10691 SDS SDS SDS-polyacrylamide 10 0.0 -treated samples (synaptosomes synaptosomes or purified enzymes were analyzed by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) SDS-PAGE in reducing conditions ( beta-mercaptoethanol 10% 11 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.00029764887082707<>ScoreDetail__10691|SDS|2.63504611330698e-05__19440|SBDS|0.00029764887082707__ 0 0 0 0 0 245319 11562447 333701 3778 10620 CCL21 ECL ECL 18 0.0 horseradish peroxidase and visualized by the enhanced chemiluminescence kit (ECL; ECL Amersham Pharmacia Biotech AB Uppsala Sweden 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245320 11562447 333702 12361 18752 MAPKAP1 SIN1 SIN-1 3 0.3 Exogenous ONOO or SIN-1 Inhibits High-Affinity Choline Uptake and C ACh Synthesis from C 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245321 11562447 333702 7552 3690 FGFR3 ACH ACh 10 0.0 Exogenous ONOO or SIN-1 Inhibits High-Affinity Choline Uptake and C ACh Synthesis from C Acetate 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245322 11562447 333703 12361 18752 MAPKAP1 SIN1 SIN-1 14 0.3 1 increasing concentrations of ONOO (Fig Fig 1 A or SIN-1 (Fig Fig 1 B in the preincubation medium of synaptosomes 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245323 11562447 333704 12361 18752 MAPKAP1 SIN1 SIN-1 16 0.3 at approximately 500 microM for ONOO and 800 microM for SIN-1 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245324 11562447 333707 12361 18752 MAPKAP1 SIN1 SIN-1 28 0.3 a dose of the chemically synthesized ONOO or a donor SIN-1 which released ONOO by a regular flux associated with molecular 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245325 11562447 333711 7552 3690 FGFR3 ACH ACh 26 0.0 powerful inhibitor of two major cholinergic processes choline transport and ACh synthesis 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245326 11562447 333713 7552 3690 FGFR3 ACH ACh 6 0.0 In cholinergic neurons the synthesis of ACh by ChAT is dependent on intracellular pools of choline provided 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245327 11562447 333716 12361 18752 MAPKAP1 SIN1 SIN-1 18 0.3 be inactivated in a concentration-dependent manner both by ONOO and SIN-1 but not by millimolar ranges of H 2 O 2 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245328 11562447 333724 12361 18752 MAPKAP1 SIN1 SIN-1 8 0.3 ACh synthesis was inhibited by either ONOO or SIN-1 but neither was inhibited by H 2 O 2 up 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245329 11562447 333724 7552 3690 FGFR3 ACH ACh 0 0.0 ACh synthesis was inhibited by either ONOO or SIN-1 but neither 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245330 11562447 333730 14042 7625 NA NAC NAC 35 0.0 that maintain a high content of free reducing compounds (NAC, NAC GSH DTT 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 245331 11562447 333731 12361 18752 MAPKAP1 SIN1 SIN-1 20 0.3 synaptic vesicles and synaptosomes in the presence of ONOO and SIN-1 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245332 11562447 333745 12359 6876 MAPK14 p38 p38 6 0.3 Another protein that was affected was synaptophysin/p38 synaptophysin p38 1 JUMiner_v2.2 1 0 0 2 1189 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:1189|AHSA1|0.000600790513833992<>ScoreDetail__1189|AHSA1|0.000600790513833992__6878|MAPK4|0.000494635798983625__6871|MAPK1|0.000518538276873833__6876|MAPK14|0.000324932352982844__ 0 0 0 0 0 245333 11562447 333755 12361 18752 MAPKAP1 SIN1 SIN-1 2 0.3 ONOO and SIN-1 but not H 2 O 2 inhibit high-affinity choline uptake 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245334 11562447 333756 12361 18752 MAPKAP1 SIN1 SIN-1 14 0.3 (10 10 microM to 8 mM of ONOO (A), A SIN-1 (B), B or H 2 O 2 (C) C for 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245335 11562447 333759 12361 18752 MAPKAP1 SIN1 SIN-1 2 0.3 ONOO and SIN-1 inhibit ACh synthesis and ChAT activity but not compartmentalization of 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245336 11562447 333759 7552 3690 FGFR3 ACH ACh 4 0.1 ONOO and SIN-1 inhibit ACh synthesis and ChAT activity but not compartmentalization of ACh into 6 JUMiner_v2.2 1 2 acetylcholine 0 0 0 0 0 0 0 0 245337 11562447 333759 7552 3690 FGFR3 ACH ACh 13 0.0 inhibit ACh synthesis and ChAT activity but not compartmentalization of ACh into synaptic vesicles 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245338 11562447 333760 12361 18752 MAPKAP1 SIN1 SIN-1 28 0.3 synaptosomes with either chemically synthesized ONOO (open open symbols or SIN-1 (filled filled symbols 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245339 11562447 333761 7552 3690 FGFR3 ACH ACh 4 0.0 A A' total C ACh synthesis measured for 60 min after treatment using C acetate 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245340 11562447 333762 7552 3690 FGFR3 ACH ACh 6 0.0 B and B' incorporation of C ACh in synaptic vesicles measured for the same time after a 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245341 11562447 333762 7552 3690 FGFR3 ACH ACh 30 0.0 and expressed as a percentage of total newly synthesized C ACh 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245342 11562447 333765 12361 18752 MAPKAP1 SIN1 SIN-1 2 0.3 ONOO and SIN-1 inhibit purified bovine brain ChAT 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245343 11562447 333766 12361 18752 MAPKAP1 SIN1 SIN-1 7 0.3 After a 60-min preincubation with ONOO or SIN-1 the activity of 10 microl of bovine brain ChAT diluted 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245344 11562447 333774 3778 10620 CCL21 ECL ECL-peroxidase 18 0.0 antibody raised against nitrotyrosine (1/1000) 1 1000 and revealed by ECL-peroxidase system 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245345 11562447 333776 3778 10620 CCL21 ECL ECL-peroxidase 8 0.0 The immunoreactivity for ChAT was similarly revealed by ECL-peroxidase system 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245346 11562447 333784 3778 10620 CCL21 ECL ECL-peroxidase 30 0.0 incubated with different antibodies against neuronal proteins and revealed by ECL-peroxidase system 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245347 11562447 333793 14042 7625 NA NAC NAC 12 0.0 the drugs were as follows 5 mM GSH 1.25 mM NAC 1 mM uric acid 1 mM BSA 1 mM DTT 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 245348 11562447 333799 14042 7625 NA NAC NAC 17 0.0 uptake protection assay (A): A 5 mM GSH 1 mM NAC 1 mM DTT 0.5 mM uric acid 1 mM BSA 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 245349 11562447 333799 14042 7625 NA NAC NAC 48 0.0 activity protection assay (B): B 5 mM GSH 5 mM NAC 1 mM DTT 1 mM uric acid 1 mM BSA 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 245350 11562447 333805 7552 3690 FGFR3 ACH ACh 13 0.0 in Fig 2 increasing concentrations of ONOO dose-dependently inhibited C ACh synthesis (IC IC 50 = 300 microM Fig 2 A 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245351 11562447 333806 12361 18752 MAPKAP1 SIN1 SIN-1 3 0.3 Continuous infusion with SIN-1 (Fig Fig 2A' 2B' led to similar results with a 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245352 11562447 333807 7552 3690 FGFR3 ACH ACh 18 0.0 induce any significant changes in the synthesis and incorporation of ACh (data data not shown 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245353 11562447 333809 7552 3690 FGFR3 ACH ACh 3 0.0 Having shown that ACh synthesis from acetate was defective in ONOO -treated synaptosomes we 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245354 11562447 333809 7552 3690 FGFR3 ACH ACh 27 0.0 whether the enzymatic activity of ChAT the enzyme responsible for ACh synthesis from acetyl-CoA and choline was altered or if this 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245355 11562447 333809 7552 3690 FGFR3 ACH ACh 51 0.0 to the inactivation of choline uptake which provides the other ACh precursor choline 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245356 11562447 333810 12361 18752 MAPKAP1 SIN1 SIN-1 6 0.3 Therefore synaptosomes pretreated with ONOO or SIN-1 were lysed by Triton X-100 (0.02%) 0.02% and assessed for 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245357 11562447 333810 7552 3690 FGFR3 ACH ACh 29 0.0 intracellular ChAT at the end of the measurement of the ACh synthesis 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245358 11562447 333811 12361 18752 MAPKAP1 SIN1 SIN-1 14 0.3 by ONOO (IC IC 50 = 350 microM and by SIN-1 (IC IC 50 = 40 microM (Fig Fig 2 C 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245359 11562447 333812 12361 18752 MAPKAP1 SIN1 SIN-1 0 0.3 SIN-1 was surprisingly a more potent inhibitor of ChAT activity of 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245360 11562447 333813 12361 18752 MAPKAP1 SIN1 SIN-1 25 0.3 of the cytosol which leads to better oxygen accessibility during SIN-1 decomposition 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245361 11562447 333814 12361 18752 MAPKAP1 SIN1 SIN-1 1 0.3 Moreover SIN-1 decomposition in tissues can lead to the continuous formation of 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245362 11562447 333818 12361 18752 MAPKAP1 SIN1 SIN-1 22 0.3 an inhibition of the activity of ChAT by ONOO and SIN-1 we investigated the effect of ONOO and SIN-1 on partially 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245363 11562447 333818 12361 18752 MAPKAP1 SIN1 SIN-1 30 0.3 ONOO and SIN-1 we investigated the effect of ONOO and SIN-1 on partially purified bovine brain ChAT in the presence of 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245364 11562447 333819 12361 18752 MAPKAP1 SIN1 SIN-1 12 0.3 was inhibited by ONOO and to a lesser extent by SIN-1 possibly because of a lack of oxygen in the medium 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245365 11562447 333834 12361 18752 MAPKAP1 SIN1 SIN-1 7 0.3 We were unable to detect nitration by SIN-1 and no significant change in the immunoreactivity for ChAT was 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245366 11562447 333834 12361 18752 MAPKAP1 SIN1 SIN-1 20 0.3 significant change in the immunoreactivity for ChAT was noticed after SIN-1 treatment 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245367 11562447 333847 19573 10691 SDS SDS SDS 15 0.0 immunoreactivity of a 30- to 32-kDa VAMP-containing complex resistant to SDS beta-mercaptoethanol and boiling increased after ONOO treatment of synaptic vesicles 11 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.00029764887082707<>ScoreDetail__10691|SDS|2.63504611330698e-05__19440|SBDS|0.00029764887082707__ 0 0 0 0 0 245368 11562447 333852 12361 18752 MAPKAP1 SIN1 SIN-1 8 0.3 When synaptosomes were treated with increasing concentrations of SIN-1 (100-4000 100-4000 microM for 1 h under continuous agitation and 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245369 11562447 333852 12361 18752 MAPKAP1 SIN1 SIN-1 35 0.3 was detected and only faint bands appeared at 4 mM SIN-1 (data data not shown 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245370 11562447 333855 14042 7625 NA NAC NAC 15 0.0 5 mM glutathione (GSH), GSH 1.25 mM N -acetylcysteine (NAC), NAC and 1 mM dithiothreitol (DTT); DTT and with the following 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 245371 11562447 333858 14042 7625 NA NAC NAC 16 0.0 oxidation state by pretreatment with the same thioreductants (GSH, GSH NAC DTT and antioxidants (uric uric acid BSA desferrioxamine melatonin 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 245372 11562447 333872 12705 7097 MIF GIF Gif-sur-Yvette-Cedex 16 0.3 et Mol_amp_eacute culaire Center National de la Recherche Scientifique 91198 Gif-sur-Yvette-Cedex France 11 JUMiner_v2.2 1 0 0 2 7408 TotalCon:3<>4268|GIF|2694|Complete__7097|MIF|4282|Complete__7408|MT3|4504|Complete__<>AvaiableGeneRif=3<>BEST:7408|MT3|0.00045766590389016<>ScoreDetail__7097|MIF|0.000263290488741501__7408|MT3|0.00045766590389016__4268|GIF|0.000296442687747036__ 0 0 0 0 0 245373 11562447 333874 12361 18752 MAPKAP1 SIN1 SIN-1 5 0.3 ONOO peroxynitrite ACh acetylcholine SIN-1 3-morpholinosydnonimine CoA Coenzyme A ChAT choline acetyltransferase VAMP/synaptobrevin, VAMP synaptobrevin 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 245374 11562447 333874 7552 3690 FGFR3 ACH ACh 3 0.1 ONOO peroxynitrite ACh acetylcholine SIN-1 3-morpholinosydnonimine CoA Coenzyme A ChAT choline acetyltransferase VAMP/synaptobrevin, 6 JUMiner_v2.2 1 2 acetylcholine 0 0 0 0 0 0 0 0 245375 11562447 333874 3778 10620 CCL21 ECL ECL 28 0.0 trichloroacetic acid BSA bovine serum albumin PAGE polyacrylamide gel electrophoresis ECL enhanced chemiluminescence GSH glutathione NAC N -acetylcysteine DTT dithiothreitol 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 245376 11562447 333874 14042 7625 NA NAC NAC 33 0.0 albumin PAGE polyacrylamide gel electrophoresis ECL enhanced chemiluminescence GSH glutathione NAC N -acetylcysteine DTT dithiothreitol 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 238884 11679167 325565 20996 11179 SOD1 ALS ALS 25 1.9 oxygen species in diseases related to oxidative stress such as ALS or FRDA (see see Sections 4.3 and 4.4 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000541303533462508<>ScoreDetail__5468|IGFALS|0.000329558764810429__11179|SOD1|0.000541303533462508__ 0 0 0 0 0 238885 11679167 325565 7975 3951 FXN FRDA FRDA 27 2.0 in diseases related to oxidative stress such as ALS or FRDA (see see Sections 4.3 and 4.4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238886 11679167 325585 166 118 ACO2 aconitase aconitase 12 1.3 oxidise 4Fe_amp_#x2013 4S clusters in enzymes such as the mitochondrial aconitase (citric citric acid cycle homoaconitase (lysine lysine biosynthesis and isopropyl 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238887 11679167 325586 20997 11180 SOD2 MnSOD MnSOD 33 2.4 superoxide dismutases (either either the cytosolic CuZnSOD or the mitochondrial MnSOD or both ( Srinivasan et al. 2000 De Freitas et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238888 11679167 325587 166 118 ACO2 aconitase aconitase 5 1.3 The inactivation of mitochondrial enzymes (aconitase) aconitase results in an impaired respiratory activity that limits the capacity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238889 11679167 325627 14948 8140 OPA1 NTG ntg 3 0.0 The triple mutant ntg 1_amp_#x394 ntg 2_amp_#x394 rad 1_amp_#x394 shows an increased rate of 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238890 11679167 325627 14948 8140 OPA1 NTG ntg 5 0.0 The triple mutant ntg 1_amp_#x394 ntg 2_amp_#x394 rad 1_amp_#x394 shows an increased rate of spontaneous and 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238891 11679167 325627 22000 11730 TERT TERT tert 28 0.0 mutagenesis which is correlated to a hypersensitivity to hydrogen peroxide tert -butylhydroperoxide and superoxide generating drugs ( Gellon et al. 2001 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238892 11679167 325628 23725 29369 UNK UNK Unk 48 0.0 the apurinic or apyrimidinic site ( Girard and Boiteux 1997 Unk et al. 2001 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238893 11679167 325629 23725 29369 UNK UNK Unk 15 0.0 3 _amp_#x2032 -blocking groups present at single strand breaks ( Unk et al. 2001 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238894 11679167 325634 8885 20374 GSX1 GSH1 GSH1 3 1.5 The disruption of GSH1 gene encoding the rate-limiting enzyme of glutathione biosynthesis increases hydrogen 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238895 11679167 325635 8885 20374 GSX1 GSH1 gsh1 23 1.5 its role in oxidative stress resistance as suppressors of the gsh1 mutation that decreased the rate of generation of petites did 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238896 11679167 325636 58 48 ABCB7 Atm1p Atm1p 0 1.9 Atm1p an ATP-binding cassette transporter that controls iron homeostasis within the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238897 11679167 325637 58 48 ABCB7 Atm1p Atm1p 2 1.9 Loss of Atm1p increases free iron levels and leads to the accumulation of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238898 11679167 325657 17875 9827 RAD9A RAD9 RAD9-dependent 27 1.0 the level of cell cycle arrest hydrogen peroxide induces a RAD9-dependent arrest in G 2 while superoxide causes a RAD9-independent arrest 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238899 11679167 325657 17875 9827 RAD9A RAD9 RAD9-independent 37 1.0 a RAD9-dependent arrest in G 2 while superoxide causes a RAD9-independent arrest in G 1 ( Flattery-O'Brien and Dawes 1998 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238900 11679167 325674 8885 20374 GSX1 GSH1 GSH1 14 1.5 is also correlated with glutathione levels as the expression of GSH1 and GSH2 genes coding for the two enzymes involved in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238901 11679167 325674 8886 24959 GSX2 GSH2 GSH2 14 1.5 is also correlated with glutathione levels as the expression of GSH1 and GSH2 genes coding for the two enzymes involved in 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238902 11679167 325674 8886 24959 GSX2 GSH2 GSH2 16 1.5 correlated with glutathione levels as the expression of GSH1 and GSH2 genes coding for the two enzymes involved in glutathione synthesis 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238903 11679167 325678 20997 11180 SOD2 MnSOD MnSOD 22 2.4 such as the increase of the mitochondrial superoxide dismutase (MnSOD) MnSOD activity by ethanol the high ethanol sensitivity of S cerevisiae 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238904 11679167 325678 20997 11180 SOD2 MnSOD MnSOD 36 2.4 the high ethanol sensitivity of S cerevisiae cells deficient in MnSOD ( Costa and Costa and the induction of CTT1 gene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238905 11679167 325683 20996 11179 SOD1 SOD SODs 14 1.9 glucose consuming cultures some of the antioxidant defences such as SODs catalases and peroxidases are present at a very low level 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238906 11679167 325688 14366 7804 NFYA HAP2 Hap2 23 1.6 sensing of oxygen and different trans-acting factors _amp_#x2013 Hap1p Hap2/3/4/5p Hap2 3 4 5p and Rox1p are involved in this gene 2 JUMiner_v2.2 1 0 0 2 7804 TotalCon:2<>4812|HAP1|9001|Complete__7804|NFYA|4800|Complete__<>AvaiableGeneRif=2<>BEST:7804|NFYA|0.000672883733272679<>ScoreDetail__4812|HAP1|0.000235388086189067__7804|NFYA|0.000672883733272679__ 0 0 0 0 0 238907 11679167 325699 20997 11180 SOD2 SOD2 SOD2 14 2.7 in oxidative stress only two genes are under Hap1p regulation SOD2 and CTT1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238908 11679167 325702 20997 11180 SOD2 SOD2 SOD2 6 2.7 Hap1p is a positive regulator of SOD2 promoter in glucose growing cells ensuring a basel level of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238909 11679167 325704 4829 2294 COX8A COX COX 20 1.4 of anoxia on the expression of the nuclear aerobic genes COX indicated the existence of a signalling pathway from the mitochondria 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 238910 11679167 325711 8413 4330 GLRX GRX grx 42 0.3 sod 1_amp_#x394 sod 2_amp_#x394 glutathione ( gsh 1_amp_#x394 glutaredoxin ( grx 5_amp_#x394 ubiquinol ( coq 3_amp_#x394 or poliamines ( spe 2_amp_#x394 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238911 11679167 325714 20997 11180 SOD2 SOD2 SOD2 11 2.7 regulates the transcriptional activation of the antioxidant genes such as SOD2 (mitochondrial mitochondrial superoxide dismutase CTA1 (peroxisomal peroxisomal catalase CTT1 (cytosolic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238912 11679167 325715 14366 7804 NFYA HAP2 Hap2 3 1.6 The heteromeric complex Hap2/3/4/5p Hap2 3 4 5p binds CCAAT sequences and is responsible for 2 JUMiner_v2.2 1 0 0 2 7804 TotalCon:2<>4812|HAP1|9001|Complete__7804|NFYA|4800|Complete__<>AvaiableGeneRif=2<>BEST:7804|NFYA|0.000672883733272679<>ScoreDetail__4812|HAP1|0.000235388086189067__7804|NFYA|0.000672883733272679__ 0 0 0 0 0 238913 11679167 325715 20997 11180 SOD2 SOD2 SOD2 22 2.7 induction of several genes important for respiration as well as SOD2 and UBI4 ( Pinkham et al. 1997 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238914 11679167 325716 20997 11180 SOD2 SOD2 SOD2 16 2.7 growth in a non-fermentable carbon source the transcriptional activation of SOD2 and CTT1 genes is also regulated by Msn2p and Msn4p 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238915 11679167 325717 13705 7373 MSN MSN msn 18 0.0 61 genes upregulated at the diauxic shift and stationary phase msn 2_amp_#x394 msn 4_amp_#x394 mutants are resistant to several stress conditions 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238916 11679167 325717 13705 7373 MSN MSN msn 20 0.0 upregulated at the diauxic shift and stationary phase msn 2_amp_#x394 msn 4_amp_#x394 mutants are resistant to several stress conditions 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238917 11679167 325721 22704 12015 TPO TPX mTpx 10 0.3 Other antioxidant defences such as Ccp1p Cta1p Cup1p Gpx1p and mTpx are induced during respiratory growth however the regulatory mechanisms remain 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238918 11679167 325730 23451 12434 TXK TKL tkl 29 0.6 of the pentose phosphate pathway ( zwf 1_amp_#x394 rpe 1_amp_#x394 tkl 1_amp_#x394 tkl 2_amp_#x394 tal 1_amp_#x394 and gnd 1_amp_#x394 which exhibit 14 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 238919 11679167 325730 23451 12434 TXK TKL tkl 31 0.6 pentose phosphate pathway ( zwf 1_amp_#x394 rpe 1_amp_#x394 tkl 1_amp_#x394 tkl 2_amp_#x394 tal 1_amp_#x394 and gnd 1_amp_#x394 which exhibit a higher 14 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 238920 11679167 325730 12082 25135 LRSAM1 TAL tal 33 0.6 pathway ( zwf 1_amp_#x394 rpe 1_amp_#x394 tkl 1_amp_#x394 tkl 2_amp_#x394 tal 1_amp_#x394 and gnd 1_amp_#x394 which exhibit a higher sensitivity to 14 JUMiner_v2.2 1 2 UserEdit 0 2 25135 TotalCon:2<>25135|LRSAM1|90678|Complete__11559|TALDO1|6888|Complete__<>AvaiableGeneRif=2<>BEST:25135|LRSAM1|0.000722499849479198<>ScoreDetail__11559|TALDO1|0.000288691179172244__25135|LRSAM1|0.000722499849479198__ 1 1 0 0 0 238921 11679167 325730 18750 10293 RPE RPE rpe 27 0.1 in enzymes of the pentose phosphate pathway ( zwf 1_amp_#x394 rpe 1_amp_#x394 tkl 1_amp_#x394 tkl 2_amp_#x394 tal 1_amp_#x394 and gnd 1_amp_#x394 6 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 238922 11679167 325736 8046 4092 GAD1 GAD1 GAD1 27 1.2 and the loss/overexpression loss overexpression of glutamate decarboxylase gene ( GAD1 decreases/increases decreases increases hydrogen peroxide resistance ( Coleman et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238923 11679167 325747 18752 10295 RPGR CRD CRD 11 0.0 second cysteine rich domain at the N terminus ( n -CRD also containing three cysteine residues is important for hydrogen peroxide 11 JUMiner_v2.2 1 0 0 2 2383 TotalCon:2<>10295|RPGR|6103|Complete__2383|CRX|1406|Complete__<>AvaiableGeneRif=2<>BEST:2383|CRX|0.000351519287036175<>ScoreDetail__10295|RPGR|0.000261942790384866__2383|CRX|0.000351519287036175__ 0 0 0 0 0 238924 11679167 325749 18752 10295 RPGR CRD CRD 3 0.0 Both the n -CRD and the c-CRD contain nuclear export signals 11 JUMiner_v2.2 1 0 0 2 2383 TotalCon:2<>10295|RPGR|6103|Complete__2383|CRX|1406|Complete__<>AvaiableGeneRif=2<>BEST:2383|CRX|0.000351519287036175<>ScoreDetail__10295|RPGR|0.000261942790384866__2383|CRX|0.000351519287036175__ 0 0 0 0 0 238925 11679167 325750 18752 10295 RPGR CRD CRD 6 0.0 Oxidation of cysteine residues at the CRD inhibits the Crm1p-dependent nuclear export of Yap1p but not the 11 JUMiner_v2.2 1 0 0 2 2383 TotalCon:2<>10295|RPGR|6103|Complete__2383|CRX|1406|Complete__<>AvaiableGeneRif=2<>BEST:2383|CRX|0.000351519287036175<>ScoreDetail__10295|RPGR|0.000261942790384866__2383|CRX|0.000351519287036175__ 0 0 0 0 0 238926 11679167 325753 23454 12435 TXN TRX trx 10 1.0 Indeed Yap1p is constitutively active in thioredoxin deficient mutants ( trx 1_amp_#x394 trx 2_amp_#x394 ( Izawa et al. 1999 and the 14 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000786057063757646<>ScoreDetail__12435|TXN|0.000786057063757646__25507|VAC14|0.000445103275724812__ 0 0 0 0 0 238927 11679167 325753 23454 12435 TXN TRX trx 12 1.0 is constitutively active in thioredoxin deficient mutants ( trx 1_amp_#x394 trx 2_amp_#x394 ( Izawa et al. 1999 and the whole genome 14 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000786057063757646<>ScoreDetail__12435|TXN|0.000786057063757646__25507|VAC14|0.000445103275724812__ 0 0 0 0 0 238928 11679167 325754 23455 17772 TXN2 TRX2 TRX2 13 1.3 thioredoxin peroxidase Tpx1p is essential for the transcriptional activation of TRX2 and TRR1 genes ( Ross et al. 2000 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238929 11679167 325754 23154 12343 TRNAR1 TRR1 TRR1 15 2.1 Tpx1p is essential for the transcriptional activation of TRX2 and TRR1 genes ( Ross et al. 2000 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238930 11679167 325763 7683 3796 FOS AP-1 AP-1 3 1.0 Interestingly the yeast AP-1 family (Yap1p) Yap1p of proteins are involved in the sensing 1 JUMiner_v2.2 1 0 0 2 6204 TotalCon:5<>3796|FOS|2353|Complete__3797|FOSB|2354|Complete__6204|JUN|3725|Complete__6205|JUNB|3726|Complete__6206|JUND|3727|Complete__<>AvaiableGeneRif=5<>BEST:6204|JUN|0.000690327903657676<>ScoreDetail__3796|FOS|0.000589427478778065__3797|FOSB|0.000430286040559442__6205|JUNB|0.000524076987970417__6204|JUN|0.000690327903657676__6206|JUND|0.000602707937557334__ 0 0 0 0 0 238931 11679167 325768 9652 23316 HSD17B6 HSE HSE 45 0.3 to hydrogen peroxide through binding to heat shock elements (HSE) HSE ( Raitt et al. 2000 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 238932 11679167 325772 4940 12024 CRISP2 TPX1 TPX1 4 1.6 Indeed the induction of TPX1 (thioredoxin thioredoxin peroxidase gene is Skn7p- and Yap1p-dependent and is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238933 11679167 325772 4985 2411 CRYGD CCP ccp 20 0.0 and Yap1p-dependent and is lower in respiration deficient mutants and ccp 1_amp_#x394 cells ( Charizanis et al. 1999 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238934 11679167 325775 13812 32159 MTG1 GTP GTP 9 0.3 is an essential protein that contains a putative ATP/GTP ATP GTP binding domain and activates the Skn7p factor in cells exposed 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 238935 11679167 325800 166 118 ACO2 aconitase aconitase 21 1.3 destroy the 4Fe_amp_#x2013 4S clusters of mitochondrial enzymes (e.g., e.g. aconitase leading to an impaired respiratory activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238936 11679167 325809 166 118 ACO2 aconitase aconitase 23 1.3 a delay in the reversible inactivation of the superoxide-sensitive enzyme aconitase suggesting that the extension of life-span is associated with the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238937 11679167 325809 14334 7773 NF2 SCH sch 7 0.0 The increased life-span of cyr 1_amp_#x394 and sch 9_amp_#x394 mutants is correlated with a delay in the reversible 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238938 11679167 325810 543 391 AKT1 AKT Akt 9 0.0 is an homologue of the mammalian protein kinase B/Akt, B Akt which is involved in insulin signalling apoptosis and cellular proliferation 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 238939 11679167 325811 543 391 AKT1 AKT Akt 10 0.0 Sch9/Rim15 Sch9 Rim15 and the C elegans DAF-2/AGE-1/Akt/DAF16 DAF-2 AGE-1 Akt DAF16 pathways play similar roles in regulating ageing and stress 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 238940 11679167 325817 1576 990 BCL2 Bcl-2 Bcl-2 13 2.6 been identified as being major regulators of apoptosis including the Bcl-2 family and caspases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238941 11679167 325818 1576 990 BCL2 Bcl-2 Bcl-2 1 2.6 The Bcl-2 family of proteins consist of anti-apoptotic proteins such as Bcl-2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238942 11679167 325818 1576 990 BCL2 Bcl-2 Bcl-2 11 2.6 Bcl-2 family of proteins consist of anti-apoptotic proteins such as Bcl-2 and Bcl-x(L), Bcl-x L and pro-apoptotic proteins such as Bax 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238943 11679167 325818 1578 992 BCL2L1 Bcl-X Bcl-x 13 1.0 proteins consist of anti-apoptotic proteins such as Bcl-2 and Bcl-x(L), Bcl-x L and pro-apoptotic proteins such as Bax and Bak ( 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238944 11679167 325818 1514 949 BAK1 BAK Bak 21 0.0 Bcl-x(L), Bcl-x L and pro-apoptotic proteins such as Bax and Bak ( Gross et al. 1999 2 JUMiner_v2.2 1 1 bak; 0 0 0 0 0 0 0 0 238945 11679167 325826 1540 959 BAX BAX BAX 4 0.3 Indeed the expression of BAX stimulates the production of reactive oxygen species ( Madeo et 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238946 11679167 325827 23890 12666 VCP VCP VCP 20 0.0 putative ATPase homologous to the mammalian anti-apoptotic valosine-containing protein (VCP) VCP ( Shirogane et al. 1999 also induces both apoptosis and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238947 11679167 325828 1540 959 BAX BAX BAX 33 0.3 apoptosis ( Madeo et al. 1999 (ii) ii expression of BAX decreases the intracellular levels of glutathione decreases the mitochondrial membrane 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238948 11679167 325828 1540 959 BAX BAX BAX 72 0.3 S-transferase/peroxidase S-transferase peroxidase ( Kampranis et al. 2000 (iii) iii BAX lethality is higher under respiratory conditions and is suppressed in 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238949 11679167 325828 1576 990 BCL2 Bcl-2 Bcl-2 163 2.6 lacking superoxide dismutase is extended by overexpressing the anti-apoptotic protein Bcl-2 ( Longo et al. 1999 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238950 11679167 325832 1576 990 BCL2 Bcl-2 Bcl-2 5 2.6 The regulatory role of the Bcl-2 members e.g. depends on their ability to regulate the mitochondrial 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238951 11679167 325833 1576 990 BCL2 Bcl-2 Bcl-2 2 2.6 In yeast Bcl-2 proteins interact with the voltage-dependent anion channel (VDAC) VDAC and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238952 11679167 325833 20221 10990 SLC25A4 ANT ANT 16 0.6 anion channel (VDAC) VDAC and the adenine nucleotide translocator (ANT), ANT and these proteins are components of the mitochondrial permeability transition 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238953 11679167 325835 20221 10990 SLC25A4 ANT ANT 1 0.6 However ANT is not essential for Bax-induced cytochrome c release from the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238954 11679167 325845 20996 11179 SOD1 ALS ALS 3 1.9 Amyotrophic lateral sclerosis (ALS) ALS is a neurodegenerative disease characterised by the selective degeneration of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000541303533462508<>ScoreDetail__5468|IGFALS|0.000329558764810429__11179|SOD1|0.000541303533462508__ 0 0 0 0 0 238955 11679167 325846 20996 11179 SOD1 ALS ALS 28 1.9 al. 1993 the yeast Saccharomyces cerevisiae has been utilised for ALS research on clarifying the role of SOD mutations 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000541303533462508<>ScoreDetail__5468|IGFALS|0.000329558764810429__11179|SOD1|0.000541303533462508__ 0 0 0 0 0 238956 11679167 325846 20996 11179 SOD1 SOD SOD 35 1.9 been utilised for ALS research on clarifying the role of SOD mutations 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238957 11679167 325848 117 77 ABL2 ARG Arg 4 0.0 While the Gly 85_amp_#x2192 Arg CuZnSOD failed to rescue the phenotype the other mutant proteins 2 JUMiner_v2.2 1 0 0 2 77 TotalCon:2<>77|ABL2|27|Complete__9965|RERE|473|Complete__<>AvaiableGeneRif=2<>BEST:77|ABL2|0.00127258881129552<>ScoreDetail__77|ABL2|0.00127258881129552__9965|RERE|3.79089427195876e-05__ 0 0 0 0 0 238958 11679167 325851 20996 11179 SOD1 ALS ALS 3 1.9 The ability of ALS mutant CuZnSOD proteins to bind copper and zinc has been 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000541303533462508<>ScoreDetail__5468|IGFALS|0.000329558764810429__11179|SOD1|0.000541303533462508__ 0 0 0 0 0 238959 11679167 325852 20996 11179 SOD1 SOD1 SOD1 26 1.9 the use of S cerevisiae in elucidating the mechanism of SOD1 mediated disease 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238960 11679167 325854 7975 3951 FXN FRDA FRDA 2 2.0 Friedreich's ataxia (FRDA) FRDA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238961 11679167 325902 8604 4455 GPD1 GPD1 Gpd1 3 0.3 Zwf1 glucose-6-phosphate dehydrogenase Gpd1 glycerol phosphate dehydrogenase Gpp2 glycerol phosphate phosphatase YBR149W glycerol dehydrogenase 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238962 11679167 325902 8046 4092 GAD1 GAD1 Gad1 17 1.2 Gpp2 glycerol phosphate phosphatase YBR149W glycerol dehydrogenase Dak1 dihydroxyacetone kinase Gad1 glutamate decarboxylase Uga5 succinate semialdehyde dehydrogenase 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238963 11679167 325905 9691 5232 HSPA1A HSP HSP 37 0.9 the Hsf1p increase the expression of heat shock proteins (HSP) HSP and chaperones Yap1p and Skn7p upregulate antioxidant genes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238964 11679167 325908 18752 10295 RPGR CRD CRD 2 0.0 Cysteine-rich domains (CRD), CRD containing the nuclear export signal (NES) NES that binds the 11 JUMiner_v2.2 1 0 0 2 2383 TotalCon:2<>10295|RPGR|6103|Complete__2383|CRX|1406|Complete__<>AvaiableGeneRif=2<>BEST:2383|CRX|0.000351519287036175<>ScoreDetail__10295|RPGR|0.000261942790384866__2383|CRX|0.000351519287036175__ 0 0 0 0 0 238965 11679167 325908 14307 7756 NES NES NES 8 0.0 Cysteine-rich domains (CRD), CRD containing the nuclear export signal (NES) NES that binds the Crm1p transporter controls intracellular localisation of Yap1p 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238966 11679167 325909 14307 7756 NES NES NES 12 0.0 non-stress conditions thioredoxin reduces the cysteine residues and exposes the NES 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 238967 11679167 325911 18752 10295 RPGR CRD CRD 4 0.0 (b) b Oxidation of the CRD by hydrogen peroxide impairs binding of Crm1p 11 JUMiner_v2.2 1 0 0 2 2383 TotalCon:2<>10295|RPGR|6103|Complete__2383|CRX|1406|Complete__<>AvaiableGeneRif=2<>BEST:2383|CRX|0.000351519287036175<>ScoreDetail__10295|RPGR|0.000261942790384866__2383|CRX|0.000351519287036175__ 0 0 0 0 0 239731 11701756 326726 20996 11179 SOD1 SOD1 SOD1 31 0.9 mutations of the antioxidant enzyme Cu Zn superoxide dismutase (SOD1), SOD1 namely in neuroblastoma cells expressing either SOD1 mutant G93A or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 239732 11701756 326726 20996 11179 SOD1 SOD1 SOD1 38 0.9 superoxide dismutase (SOD1), SOD1 namely in neuroblastoma cells expressing either SOD1 mutant G93A or mutant H46R and in brain areas from 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 239733 11701756 326727 20996 11179 SOD1 SOD1 SOD1 8 0.9 In this work we report that while wild-type SOD1 has a protective effect calcineurin is oxidatively inactivated by mutant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 239734 11701756 326727 20996 11179 SOD1 SOD1 SOD1s 19 0.9 has a protective effect calcineurin is oxidatively inactivated by mutant SOD1s in vitro this inactivation is mediated by reactive oxygen species 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 239735 11701756 326729 20996 11179 SOD1 SOD1 SOD1s 8 0.9 These findings demonstrate that both wild-type and mutant SOD1s can interfere directly with calcineurin activity and further support the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 234232 11795894 317427 18723 10261 ROS1 ROS ROS 6 0.0 Free radicals and reactive oxygen species (ROS) ROS have been associated with the etiology and/or and or progression 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 234233 11796206 317437 20996 11179 SOD1 ALS ALS 3 1.9 Amyotrophic lateral sclerosis (ALS) ALS is a neurodegenerative disorder leading to loss of motor neurons 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00233181408547475<>ScoreDetail__5468|IGFALS|0.000334828902430858__11179|SOD1|0.00233181408547475__ 0 0 0 0 0 234234 11796206 317438 20996 11179 SOD1 ALS ALS 11 1.9 previously characterized the enhanced peroxidative activity of the human familial ALS (FALS) FALS mutants of copper-zinc superoxide dismutase (CuZnSOD) CuZnSOD A4V 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00233181408547475<>ScoreDetail__5468|IGFALS|0.000334828902430858__11179|SOD1|0.00233181408547475__ 0 0 0 0 0 234235 11796206 317446 20996 11179 SOD1 ALS ALS 3 1.9 Amyotrophic lateral sclerosis (ALS) ALS is a progressive neurodegenerative disease 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00233181408547475<>ScoreDetail__5468|IGFALS|0.000334828902430858__11179|SOD1|0.00233181408547475__ 0 0 0 0 0 234236 11796206 317448 20996 11179 SOD1 ALS ALS 6 1.9 In the vast majority of cases ALS is sporadic and has no known cause (sporadic sporadic ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00233181408547475<>ScoreDetail__5468|IGFALS|0.000334828902430858__11179|SOD1|0.00233181408547475__ 0 0 0 0 0 234237 11796206 317448 20996 11179 SOD1 ALS ALS 15 1.9 ALS is sporadic and has no known cause (sporadic sporadic ALS or SALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00233181408547475<>ScoreDetail__5468|IGFALS|0.000334828902430858__11179|SOD1|0.00233181408547475__ 0 0 0 0 0 234238 11796206 317449 20996 11179 SOD1 ALS ALS 5 1.9 However in approximately 10% of ALS cases the disease is inherited 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00233181408547475<>ScoreDetail__5468|IGFALS|0.000334828902430858__11179|SOD1|0.00233181408547475__ 0 0 0 0 0 234239 11796206 317450 20996 11179 SOD1 ALS ALS 2 1.9 Most familial ALS (FALS) FALS shows autosomal dominant inheritance approximately one fifth of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00233181408547475<>ScoreDetail__5468|IGFALS|0.000334828902430858__11179|SOD1|0.00233181408547475__ 0 0 0 0 0 234240 11796206 317450 20996 11179 SOD1 SOD1 sod1 19 1.9 one fifth of these cases are associated with mutations in sod1 the gene that encodes human CuZnSOD 1 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 234241 11796206 317453 20996 11179 SOD1 SOD SOD 14 1.9 severe motor neuron degenerative syndrome despite normal or above normal SOD activities 2 3 4 and 5 whereas neither transgenic mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 234242 11796206 317458 20996 11179 SOD1 SOD SOD 25 1.9 because in vitro remetallation may not reflect the state of SOD mutants in vivo we developed a yeast model system to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 234243 11796206 317470 20996 11179 SOD1 SOD1 SOD-1 5 1.9 Yeast strains expressing the human SOD-1 mutant genes (G93A, G93A G93C A4V and L38V or the 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 234244 11796206 317471 20996 11179 SOD1 SOD1 SOD1 12 1.9 were placed under the control of the wild type yeast SOD1 promoter and inserted into the high copy yeast/ yeast E 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 234245 11796206 317471 5896 13748 DLEU2 LEU2 LEU2 29 1.0 yeast/ yeast E coli shuttle vector YEP351 which contains the LEU2 selectable marker 1 JUMiner_v2.2 1 0 0 2 1706 TotalCon:4<>13748|DLEU2|8847|No_GeneRif__13747|DLEU1|10301|Complete__1706|CD8A|925|Complete__1707|CD8B|926|Complete__<>AvaiableGeneRif=3<>BEST:1706|CD8A|0.000593707536322776<>ScoreDetail__1706|CD8A|0.000593707536322776__1707|CD8B|0.000376293508936971__13747|DLEU1|0.000128281878046695__ 0 0 0 0 0 234246 11796206 317472 20996 11179 SOD1 SOD1 sod1 11 1.9 plasmid was transformed into the Saccharomyces cerevisiae strain EG118 ( sod1 _amp_#x2212 which lacks the CuZnSOD polypeptide 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 234247 11796206 317490 20996 11179 SOD1 SOD1 sod1 26 1.9 human and FALS mutant CuZnSOD proteins were expressed in an sod1 _amp_#x2212 strain of the yeast Saccharomyces cerevisiae in order to 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 234248 11796206 317491 20996 11179 SOD1 SOD SOD 15 1.9 of expression of the CuZnSOD proteins as well as the SOD activities of crude cytosol preparations were similar in the strains 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 234249 11796206 317491 20996 11179 SOD1 SOD SOD 40 1.9 those expressing FALS mutant CuZnSODs although slightly higher levels of SOD activity were sometimes found for the strains expressing the human 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 234250 11796206 317495 20996 11179 SOD1 SOD SOD 36 1.9 in the copper site of the enzyme and is fully SOD active 11 making it highly likely that the same situation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 230203 11884366 310521 18723 10261 ROS1 ROS ROS 7 0.0 The endogenous production of reactive oxygen species (ROS) ROS is a major limiter of life as illustrated by studies 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 230204 11884366 310522 18723 10261 ROS1 ROS ROS 10 0.0 Mitochondria have received considerable attention as a principal source---and target---of ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 230205 11884366 310524 20996 11179 SOD1 ALS ALS 23 0.0 disease Parkinson's disease prion diseases and amyotrophic lateral sclerosis (ALS) ALS as well as aging itself 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000720144431201565<>ScoreDetail__5468|IGFALS|0.00025762129669386__11179|SOD1|0.000720144431201565__ 0 0 0 0 0 230677 11905995 311193 20996 11179 SOD1 SOD1 SOD1-mediated 12 2.2 antioxidative activity or decreased oxygen free radical propagation prevent mutant SOD1-mediated motor neuron cell death and increase amyotrophic lateral sclerosis-like transgenic 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 230678 11905995 311194 20996 11179 SOD1 ALS ALS 13 2.2 selective motor neuron degeneration in human amyotrophic lateral sclerosis (ALS) ALS disease remain largely unknown and effective therapies are not currently 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0025256035507245<>ScoreDetail__5468|IGFALS|0.000668635426533683__11179|SOD1|0.0025256035507245__ 0 0 0 0 0 230679 11905995 311195 20996 11179 SOD1 SOD SOD 17 2.2 neuron degeneration in transgenic mice overexpressing mutant superoxide dismutase (SOD)1 SOD 1 gene and mitochondrial abnormality is observed in human ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 230680 11905995 311195 20996 11179 SOD1 ALS ALS 26 2.2 SOD 1 gene and mitochondrial abnormality is observed in human ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0025256035507245<>ScoreDetail__5468|IGFALS|0.000668635426533683__11179|SOD1|0.0025256035507245__ 0 0 0 0 0 230681 11905995 311197 20996 11179 SOD1 SOD1 SOD1 25 2.7 neuron-like cell death with mutant G93A-SOD1 but not with wild-type SOD1 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 230682 11905995 311198 20997 11180 SOD2 MnSOD MnSOD 6 2.2 Similarly overexpression of mitochondrial antioxidative genes MnSOD and GPX4 by stable transfection significantly increased NSC-34 motor neuron-like 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 230683 11905995 311198 8762 4556 GPX4 GPX4 GPX4 8 1.2 Similarly overexpression of mitochondrial antioxidative genes MnSOD and GPX4 by stable transfection significantly increased NSC-34 motor neuron-like cell resistance 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 230684 11905995 311198 20996 11179 SOD1 SOD1 SOD1 21 2.7 transfection significantly increased NSC-34 motor neuron-like cell resistance to mutant SOD1 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 230685 11905995 311199 20996 11179 SOD1 SOD1 SOD1-mediated 11 2.2 with spin trapping molecule 5' 5'-dimethylpryrroline-N-oxide (DMPO), DMPO prevented mutant SOD1-mediated mitochondrial dysfunction and cell death 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 230686 11905995 311201 20996 11179 SOD1 SOD1 SOD1-mediated 12 2.2 suggest a causal relationship between enhanced oxidative stress and mutant SOD1-mediated motor neuron degeneration considering that enhanced oxygen free radical production 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 230687 11905995 311201 20996 11179 SOD1 SOD1 SOD1 26 2.7 considering that enhanced oxygen free radical production results from the SOD1 structural alterations 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 230688 11905995 311202 20996 11179 SOD1 ALS ALS 24 2.2 can be potentially useful in the clinical management of human ALS disease 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0025256035507245<>ScoreDetail__5468|IGFALS|0.000668635426533683__11179|SOD1|0.0025256035507245__ 0 0 0 0 0 232190 11978481 313813 20996 11179 SOD1 ALS ALS 29 2.5 Parkinson_amp_#x2019 s disease (PD), PD and amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232191 11978481 313816 18723 10261 ROS1 ROS ROS 8 0.3 Oxidative modification of proteins by reactive oxygen species (ROS) ROS or reactive nitrogen species (RNS) RNS is implicated in the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 232192 11978481 313816 6981 22140 FAM20C RNS RNS 13 0.0 reactive oxygen species (ROS) ROS or reactive nitrogen species (RNS) RNS is implicated in the pathogenesis of both normal aging and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 232193 11978481 313817 18723 10261 ROS1 ROS ROS 3 0.3 The generation of ROS and RNS may occur by a large number of physiological 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 232194 11978481 313817 6981 22140 FAM20C RNS RNS 5 0.1 The generation of ROS and RNS may occur by a large number of physiological and nonphysiological 6 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 232195 11978481 313820 14533 7872 NOS1 nNOS nNOS 18 2.7 isoforms of nitric oxide synthase neuronal nitric oxide synthase (nNOS), nNOS endothelial nitric oxide synthase (eNOS), eNOS and inducible nitric oxide 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 232196 11978481 313820 14538 7876 NOS3 eNOS eNOS 23 2.2 nitric oxide synthase (nNOS), nNOS endothelial nitric oxide synthase (eNOS), eNOS and inducible nitric oxide synthase (iNOS) iNOS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 232197 11978481 313820 14535 7873 NOS2A iNOS iNOS 29 2.7 oxide synthase (eNOS), eNOS and inducible nitric oxide synthase (iNOS) iNOS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 232198 11978481 313848 166 118 ACO2 aconitase aconitase 12 1.3 immunochemical probe for oxidative damage it was demonstrated that mitochondrial aconitase was particularly vulnerable to oxidative damage accompanying aging in drosophila 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 232199 11978481 313856 1647 1044 BGN PGI PGI 2 0.0 Prostacyclin synthase (PGI PGI 2 is another heme protein that is nitrated and inactivated 1 JUMiner_v2.2 1 0 0 2 1044 TotalCon:2<>1044|BGN|633|Complete__4458|GPI|2821|Complete__<>AvaiableGeneRif=2<>BEST:1044|BGN|0.000754795967232975<>ScoreDetail__1044|BGN|0.000754795967232975__4458|GPI|0.000362550550905676__ 0 0 0 0 0 232200 11978481 313865 926 620 APP amyloid amyloid 7 1.0 The neuropathologic hallmarks are senile plaques containing _amp_#x3b2 -amyloid and neurofibrillary tangles which occur in pyramidal neurons of the 11 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 232201 11978481 313875 12369 6893 MAPT tau tau 14 2.7 aggregates which are largely made up of the microtubule-associated protein tau 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 232202 11978481 313878 926 620 APP amyloid amyloid 6 1.0 Histochemical methods showed 4-hydroxynonenal staining of amyloid deposits 32 11 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 232203 11978481 313902 14533 7872 NOS1 NOS NOS 13 2.7 3-nitrotyrosine generation are also attenuated in mice deficient in inducible NOS 48 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000842862777810578<>ScoreDetail__7873|NOS2A|0.000732793134912405__7872|NOS1|0.000842862777810578__ 0 0 0 0 0 232204 11978481 313915 20996 11179 SOD1 ALS ALS 0 2.5 ALS is a rapidly progressive neurodegenerative disease leading to progressive motor 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232205 11978481 313917 20996 11179 SOD1 ALS ALS 4 2.5 In amyotrophic lateral sclerosis (ALS) ALS there is a large amount of evidence implicating oxidative damage 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232206 11978481 313919 20996 11179 SOD1 ALS ALS 15 2.5 were increased by 119% in spinal cord tissue of sporadic ALS patients 59 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232207 11978481 313920 20996 11179 SOD1 ALS ALS 14 2.5 there was no change in levels of protein carbonyls in ALS motor cortex 60 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232208 11978481 313921 20996 11179 SOD1 ALS ALS 12 2.5 of hydroxynonenal modified protein by immunohistochemistry showed an increase in ALS spinal cord motor neurons and immunoprecipitation showed that one of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232209 11978481 313922 20996 11179 SOD1 ALS ALS 9 2.5 There is substantial evidence for increased protein nitration in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232210 11978481 313923 20996 11179 SOD1 ALS ALS 17 2.5 in spinal cord motor neurons of both sporadic and familial ALS patients 5 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232211 11978481 313924 20996 11179 SOD1 ALS ALS 19 2.5 significant increases in the lumbar and thoracic spinal cord of ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232212 11978481 313925 20996 11179 SOD1 ALS ALS 20 2.5 nitrated manganese superoxide dismutase in the cerebrospinal fluid of sporadic ALS patients 42 and 62 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232213 11978481 313926 20996 11179 SOD1 ALS ALS 5 2.5 In transgenic mouse models of ALS protein carbonyls are significantly increased in the spinal cord and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232214 11978481 313927 20996 11179 SOD1 ALS ALS 11 2.5 found significant decreases in creatine kinase activity in the transgenic ALS mice that were mimicked by exposure of brain extracts of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232215 11978481 313928 20996 11179 SOD1 ALS ALS 16 2.5 showed increased 3-nitrotyrosine staining in spinal cord motor neurons of ALS patients 64 65 and 66 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232216 11978481 313929 14533 7872 NOS1 nNOS nNOS 7 2.7 An increase in neuronal nitric oxide synthase (nNOS) nNOS was found in motor neurons in one study 65 66 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 232217 11978481 313930 14533 7872 NOS1 nNOS nNOS 7 2.7 Other recent studies showed no alteration in nNOS in motor neurons but showed an increase in nNOS in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 232218 11978481 313930 14533 7872 NOS1 nNOS nNOS 16 2.7 in nNOS in motor neurons but showed an increase in nNOS in reactive astrocytes in ALS spinal cord and subcortical white 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 232219 11978481 313930 20996 11179 SOD1 ALS ALS 21 2.5 but showed an increase in nNOS in reactive astrocytes in ALS spinal cord and subcortical white matter 68 and 69 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232220 11978481 313931 20996 11179 SOD1 ALS ALS 8 2.5 A potential source of O 2 _amp_#x2022 _amp_#x2212 in ALS is the proinflammatory enzyme cyclooxygenase-2 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 232221 11978481 313932 20996 11179 SOD1 ALS ALS 11 2.5 activity is dramatically increased in spinal cord tissue of sporadic ALS patients and immunochemistry shows increased staining in glial cells 70 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00132794317255692<>ScoreDetail__5468|IGFALS|0.000920251814360111__11179|SOD1|0.00132794317255692__ 0 0 0 0 0 224375 12215226 300341 20996 11179 SOD1 ALS ALS 10 0.0 Impaired oxidative metabolism and lipid peroxidation in exercising muscle from ALS patients 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00085447710120969<>ScoreDetail__5468|IGFALS|0.000718580991641769__11179|SOD1|0.00085447710120969__ 0 0 0 0 0 224376 12215226 300342 20996 11179 SOD1 ALS ALS 15 0.0 selective loss of motor neurons in amyotrophic lateral sclerosis (ALS) ALS are unknown there is increasing evidence for the hypothesis of 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00085447710120969<>ScoreDetail__5468|IGFALS|0.000718580991641769__11179|SOD1|0.00085447710120969__ 0 0 0 0 0 224377 12215226 300342 20996 11179 SOD1 ALS ALS 68 0.0 in-vivo oxidative metabolism in exercising muscle in patients affected by ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00085447710120969<>ScoreDetail__5468|IGFALS|0.000718580991641769__11179|SOD1|0.00085447710120969__ 0 0 0 0 0 224378 12215226 300344 20996 11179 SOD1 ALS ALS 4 0.0 RESULTS At rest the ALS patients had higher than normal levels of both lactate (2.82 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00085447710120969<>ScoreDetail__5468|IGFALS|0.000718580991641769__11179|SOD1|0.00085447710120969__ 0 0 0 0 0 224379 12215226 300347 20996 11179 SOD1 ALS ALS 23 0.0 free radical pool in resting conditions and during exercise in ALS patients 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00085447710120969<>ScoreDetail__5468|IGFALS|0.000718580991641769__11179|SOD1|0.00085447710120969__ 0 0 0 0 0 224380 12215226 300348 20996 11179 SOD1 ALS ALS 25 0.0 a tight link between mitochondrial function and oxidative stress in ALS gsicilia@med.unip.it publication of the World Federation of Neurology Research Group 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00085447710120969<>ScoreDetail__5468|IGFALS|0.000718580991641769__11179|SOD1|0.00085447710120969__ 0 0 0 0 0 224443 12218958 300508 20996 11179 SOD1 SOD SOD 2 1.9 Superoxide dismutase (SOD) SOD catalyzes the conversion of single electron reduced species of molecular 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 224444 12218958 300509 20996 11179 SOD1 SOD SOD 5 1.9 There are several classes of SOD that differ in their metal binding ability distribution in different 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 224445 12218958 300510 20996 11179 SOD1 SOD1 SOD1 6 2.4 Among these Cu Zn superoxide dismutase (SOD1) SOD1 is widely distributed and comprises 90% of the total SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 224446 12218958 300510 20996 11179 SOD1 SOD SOD 16 1.9 SOD1 is widely distributed and comprises 90% of the total SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 224447 12218958 300512 20996 11179 SOD1 SOD SODs 7 1.9 The present review describes the role of SODs especially Cu Zn SOD in several diseases such as familial 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 224448 12218958 300512 20996 11179 SOD1 SOD SOD 11 1.9 present review describes the role of SODs especially Cu Zn SOD in several diseases such as familial amyotrophic lateral sclerosis (FALS), 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 224449 12218958 300513 20996 11179 SOD1 SOD1 SOD1 3 2.4 Mutations in the SOD1 gene cause a familial form of amyotrophic lateral sclerosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 224450 12218958 300514 20996 11179 SOD1 SOD1 SOD1 5 2.4 The mechanism by which mutant SOD1 causes the degeneration of motor neurons is not well understood 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 224451 12218958 300515 20996 11179 SOD1 SOD1 SOD1s 7 1.9 Transgenic mice expressing multiple copies of FALS-mutant SOD1s develop an ALS-like motor neuron disease 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 224452 12218958 300515 20996 11179 SOD1 ALS ALS-like 10 1.9 Transgenic mice expressing multiple copies of FALS-mutant SOD1s develop an ALS-like motor neuron disease 11 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00235510122660674<>ScoreDetail__5468|IGFALS|0.00040551500405515__11179|SOD1|0.00235510122660674__ 0 0 0 0 0 224453 12218958 300517 20996 11179 SOD1 SOD1 SOD1 6 2.4 Various observations and conclusions linking mutant SOD1 and FALS are discussed in this review in detail 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 226056 12368231 302530 20996 11179 SOD1 SOD1 SOD1 2 1.2 Overexpression of SOD1 protects vulnerable motor neurons after spinal cord injury by attenuating 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 226057 12368231 302531 20996 11179 SOD1 SOD1 SOD1 3 1.2 Defective Cu Zn-superoxide dismutase (SOD1) SOD1 is responsible for some types of amyotrophic lateral sclerosis and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 226058 12368231 302531 18723 10261 ROS1 ROS ROS 39 0.0 chronic exposure to high levels of reactive oxygen species (ROS) ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 226059 12368231 302532 20996 11179 SOD1 SOD1 SOD1 15 1.2 mild spinal cord injury (SCI); SCI however the involvement of SOD1 ROS and apoptosis in their death has not been clarified 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 226060 12368231 302532 18723 10261 ROS1 ROS ROS 16 0.2 spinal cord injury (SCI); SCI however the involvement of SOD1 ROS and apoptosis in their death has not been clarified 5 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 226061 12368231 302533 20996 11179 SOD1 SOD1 SOD1-overexpressing 6 1.2 Mild compression SCI was induced in SOD1-overexpressing transgenic rats and wild-type littermates 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 226062 12368231 302538 20996 11179 SOD1 SOD1 SOD1 25 1.2 apoptotic VMN death after SCI and that increased levels of SOD1 in VMN reduce oxidative stress thereby attenuating the activation of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 226063 12368231 302538 18723 10261 ROS1 ROS ROS-initiated 5 0.0 These results suggest that the ROS-initiated mitochondrial signaling pathway possibly plays a pivotal role in apoptotic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 226207 12373523 302675 20996 11179 SOD1 ALS ALS 44 0.0 PD Alzheimer's disease (AD) AD and amyotrophic lateral sclerosis (ALS)] ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000484159394309067<>ScoreDetail__5468|IGFALS|0.000252133681277813__11179|SOD1|0.000484159394309067__ 0 0 0 0 0 226208 12373523 302676 18723 10261 ROS1 ROS ROS 12 0.0 tyrosine per se can interact with reactive oxygen species (ROS) ROS and reactive nitrogen species (RNS) RNS via radical mechanisms and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 226209 12373523 302676 6981 22140 FAM20C RNS RNS 17 0.0 reactive oxygen species (ROS) ROS and reactive nitrogen species (RNS) RNS via radical mechanisms and chain propagating reactions 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 226210 12373523 302677 18723 10261 ROS1 ROS ROS 6 0.0 The concentration of TyrO _amp_#8226 ROS and RNS can increase dramatically under conditions of generalized stress 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 226211 12373523 302677 6981 22140 FAM20C RNS RNS 8 0.0 The concentration of TyrO _amp_#8226 ROS and RNS can increase dramatically under conditions of generalized stress oxidative nitrative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 226212 12373523 302682 18723 10261 ROS1 ROS ROS 27 0.0 in brain and/or and or imbalance of the ratios ROS/RNS/TyrO ROS RNS TyrO _amp_#8226 may be all important in defining whether 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 226213 12373523 302682 6981 22140 FAM20C RNS RNS 27 0.0 brain and/or and or imbalance of the ratios ROS/RNS/TyrO ROS RNS TyrO _amp_#8226 may be all important in defining whether oxidative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218344 12392777 291978 20996 11179 SOD1 ALS ALS 20 2.4 Parkinson_amp_#x2019 s disease (PD), PD and amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218345 12392777 291979 18723 10261 ROS1 ROS ROS 7 0.0 An unbalanced overproduction of reactive oxygen species (ROS) ROS may give rise to oxidative stress which can induce neuronal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218346 12392777 291980 20996 11179 SOD1 ALS ALS 18 2.4 stress is involved in the pathogenesis of AD PD and ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218347 12392777 291981 20996 11179 SOD1 ALS ALS 35 2.4 in animal models of neurodegenerative diseases including AD PD and ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218348 12392777 291982 20996 11179 SOD1 ALS ALS 16 2.4 antioxidants might exert some protective effect against AD PD and ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218349 12392777 291984 20996 11179 SOD1 ALS ALS 29 2.4 the pathogenesis of neurodegenerative disorders such as AD PD and ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218350 12392777 291985 18723 10261 ROS1 ROS ROS 3 0.0 The effects of ROS and antioxidants on NF-_amp_#x3ba B function and their relevance in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218351 12392777 291988 20996 11179 SOD1 ALS ALS 21 2.4 Parkinson_amp_#x2019 s disease (PD), PD and amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218352 12392777 291991 20996 11179 SOD1 ALS ALS 25 2.4 the only one that is common to AD PD and ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218353 12392777 291993 20996 11179 SOD1 ALS ALS 35 2.4 characteristic of several different neurodegenerative disorders including AD PD and ALS 33 124 125 127 and 197 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218354 12392777 292000 18723 10261 ROS1 ROS ROS 10 0.0 these molecules are referred to as reactive oxygen species (ROS) ROS to signify their ability to lead to oxidative changes within 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218355 12392777 292001 18723 10261 ROS1 ROS ROS 6 0.0 Problems occur when the production of ROS exceeds the ability of cells to defend themselves against these 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218356 12392777 292002 18723 10261 ROS1 ROS ROS 6 0.0 This imbalance between cellular production of ROS and the ability of cells to defend themselves against them 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218357 12392777 292003 18723 10261 ROS1 ROS ROS 7 0.0 Oxidative stress can cause cellular damage and ROS oxidize critical cellular components such as membrane lipids proteins and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218358 12392777 292005 18723 10261 ROS1 ROS ROS 10 0.0 There is a large scientific literature regarding the relation between ROS production the induction of apoptosis (or or necrosis and the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218359 12392777 292006 20996 11179 SOD1 ALS ALS 27 2.4 may occur primarily by apoptotic mechanisms in AD PD and ALS 129 178 190 193 and 263 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218360 12392777 292007 20996 11179 SOD1 ALS ALS 13 2.4 shows signs of apoptosis in patients with AD PD and ALS 8 193 263 and 264 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218361 12392777 292016 20996 11179 SOD1 SOD1 SOD-1 10 2.4 in the brain include Cu/Zn Cu Zn superoxide dismutase (SOD-1) SOD-1 and Mn superoxide dismutase (SOD-2) SOD-2 which catalyze the conversion 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218362 12392777 292016 20997 11180 SOD2 SOD2 SOD-2 15 1.2 Zn superoxide dismutase (SOD-1) SOD-1 and Mn superoxide dismutase (SOD-2) SOD-2 which catalyze the conversion of O 2 _amp_#x221a _amp_#x2212 to 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218363 12392777 292018 18723 10261 ROS1 ROS ROS 10 0.0 Antioxidant defense mechanisms can be upregulated in response to increased ROS or peroxide production 42 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218364 12392777 292019 18723 10261 ROS1 ROS ROS 9 0.0 Although upregulating antioxidant defense systems may confer protection against ROS they are not completely effective in preventing oxidative damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218365 12392777 292021 18723 10261 ROS1 ROS ROS 9 0.0 As already mentioned the brain is especially vulnerable to ROS damage because of its high oxygen consumption rate abundant lipid 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218366 12392777 292022 18723 10261 ROS1 ROS ROS 10 0.0 the increased demand on the cell_amp_#x2019 s capacity to detoxify ROS is not met alterations such as aldehydes or isoprostanes from 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218367 12392777 292025 18723 10261 ROS1 ROS ROS 8 0.0 These findings suggest that in addition to direct ROS damage to phospholipid membranes there is an indirect mechanism involving 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218368 12392777 292027 20996 11179 SOD1 ALS ALS 24 2.4 262 which was found to be elevated in AD and ALS patients 108 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218369 12392777 292029 20996 11179 SOD1 ALS ALS 31 2.4 levels of nitrotyrosine have been found in AD PD and ALS 1 18 84 85 109 257 and 265 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218370 12392777 292030 20996 11179 SOD1 ALS ALS 19 2.4 8-OHdG which is elevated in patients with AD PD and ALS 5 69 74 185 and 291 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218371 12392777 292032 18723 10261 ROS1 ROS ROS 8 0.0 Thus a large body of evidences indicate that ROS can act as second messengers mediating intracellular responses including NF-_amp_#x3ba 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218372 12392777 292033 20997 11180 SOD2 SOD2 SOD-2 15 1.2 influence the expression of a large number of genes including SOD-2 50 179 and 180 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218373 12392777 292034 18723 10261 ROS1 ROS ROS 22 0.0 feed-back mechanism that operates to regulate the intracellular concentration of ROS trying to dampen an excessive accumulation of ROS which can 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218374 12392777 292034 18723 10261 ROS1 ROS ROS 30 0.0 concentration of ROS trying to dampen an excessive accumulation of ROS which can be dangerous for the cell 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218375 12392777 292035 3893 1682 CD47 IAP IAPs 11 0.3 induces the expression of the so-called inhibitor-of apoptosis proteins (IAPs), IAPs Bcl-2 and calbindins 179 and 270 13 JUMiner_v2.2 1 0 0 2 5329 TotalCon:4<>1682|CD47|961|Complete__5329|IAPP|3375|Complete__28880|MAGT1|84061|Complete__437|ALPI|248|Complete__<>AvaiableGeneRif=4<>BEST:5329|IAPP|0.000451216596741021<>ScoreDetail__437|ALPI|0.000281395722785014__1682|CD47|0.000379486163350659__5329|IAPP|0.000451216596741021__28880|MAGT1|0.000440445479141761__ 0 0 0 0 0 218376 12392777 292035 1576 990 BCL2 Bcl-2 Bcl-2 12 1.3 the expression of the so-called inhibitor-of apoptosis proteins (IAPs), IAPs Bcl-2 and calbindins 179 and 270 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218377 12392777 292037 20996 11179 SOD1 ALS ALS 29 2.4 regions of the central nervous system of AD PD and ALS 117 133 and 189 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218378 12392777 292047 18723 10261 ROS1 ROS ROS 11 0.0 capability of these compounds to counteract the damaging effects of ROS and the relevance of this biochemical effect in their putative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218379 12392777 292048 18723 10261 ROS1 ROS ROS 6 0.0 Among the numerous biochemical effects of ROS and antioxidants particular emphasis will be given to their interference 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218380 12392777 292049 20996 11179 SOD1 ALS ALS 22 2.4 in animal models and in patients with AD PD and ALS will be reviewed 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218381 12392777 292065 18723 10261 ROS1 ROS ROS 25 0.0 and lipid hydroperoxides 220 and may stabilize catecholamines from forming ROS _amp_#x3b1 -Tocopherol is a powerful chain-breaking antioxidant that inhibits lipid 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218382 12392777 292066 18723 10261 ROS1 ROS ROS 10 0.0 Carotenoids can scavenge singlet oxygen and a range of other ROS in vitro but there is still little evidence that they 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218383 12392777 292079 18723 10261 ROS1 ROS ROS 6 0.0 Flavonoids can prevent injury caused by ROS in various ways 38 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218384 12392777 292082 18723 10261 ROS1 ROS ROS 5 0.0 In other words flavonoids stabilize ROS by reacting with the compound of the radical 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 218385 12392777 292087 20996 11179 SOD1 ALS ALS 19 2.4 an important role in the pathogenesis of AD PD and ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218386 12392777 292091 20996 11179 SOD1 ALS ALS 23 2.4 of multiple antioxidants in the treatment of AD PD and ALS 213 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218387 12392777 292094 20996 11179 SOD1 ALS ALS 25 2.4 the fact that when overt symptomatology of AD PD and ALS occurs a certain amount of neuronal death has already occurred 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 218388 12392777 292100 20996 11179 SOD1 ALS ALS 28 2.4 relative risk for neurodegenerative disorders such as AD PD and ALS will throw more light on this very important aspect of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000626428838975498<>ScoreDetail__5468|IGFALS|0.000459486425458174__11179|SOD1|0.000626428838975498__ 0 0 0 0 0 221142 12437573 295643 20996 11179 SOD1 SOD1 SOD1 17 1.2 in human neuroblastoma cells expressing Cu Zn superoxide dismutase (SOD1) SOD1 mutant G93A and in brain areas from G93A transgenic mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 221143 12437573 295644 20996 11179 SOD1 SOD1 SOD1 13 1.2 the possibility that by interfering directly with calcineurin activity mutant SOD1 can modulate pathways of signal transduction mediated by redox-sensitive transcription 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 221144 12437573 295645 14352 7794 NFKB1 NF-kappaB NF-kappaB 11 0.6 paper we report a calcineurin-dependent activation of nuclear factor-kappaB (NF-kappaB) NF-kappaB induced by the expression of familial amyotrophic lateral sclerosis (fALS)-SOD1s 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 221145 12437573 295646 14352 7794 NFKB1 NF-kappaB NF-kappaB 10 0.6 of the phosphorylation state of IkappaBalpha (the the inhibitor of NF-kappaB translocation into the nucleus and induction of cyclooxygenase 2 are 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 221215 12447931 295853 20996 11179 SOD1 ALS ALS 15 0.0 neurons and prolongs survival in a transgenic mouse model of ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136489846894967<>ScoreDetail__5468|IGFALS|0.000444303395747382__11179|SOD1|0.00136489846894967__ 0 0 0 0 0 221216 12447931 295854 20996 11179 SOD1 ALS ALS 9 0.0 The pathogenesis of cell death in amyotrophic lateral sclerosis (ALS) ALS may involve glutamate-mediated excitotoxicity oxidative damage and apoptosis 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136489846894967<>ScoreDetail__5468|IGFALS|0.000444303395747382__11179|SOD1|0.00136489846894967__ 0 0 0 0 0 221217 12447931 295855 20996 11179 SOD1 ALS ALS 7 0.0 We used a transgenic mouse model of ALS to determine the effect of inhibition of cyclooxygenase-2 in treating 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136489846894967<>ScoreDetail__5468|IGFALS|0.000444303395747382__11179|SOD1|0.00136489846894967__ 0 0 0 0 0 221218 12447931 295858 20996 11179 SOD1 ALS ALS 18 0.0 inhibited production of prostaglandin E2 in the spinal cords of ALS mice 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136489846894967<>ScoreDetail__5468|IGFALS|0.000444303395747382__11179|SOD1|0.00136489846894967__ 0 0 0 0 0 221219 12447931 295860 20996 11179 SOD1 ALS ALS 4 0.0 Spinal cords of treated ALS mice showed significant preservation of spinal neurons and diminished astrogliosis 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136489846894967<>ScoreDetail__5468|IGFALS|0.000444303395747382__11179|SOD1|0.00136489846894967__ 0 0 0 0 0 221220 12447931 295861 20996 11179 SOD1 ALS ALS 8 0.0 Our results suggest that cyclooxygenase-2 inhibition may benefit ALS patients of Medicine Meyer 6-109 600 N Wolfe Street Baltimore 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136489846894967<>ScoreDetail__5468|IGFALS|0.000444303395747382__11179|SOD1|0.00136489846894967__ 0 0 0 0 0 216910 12548704 290247 18723 10261 ROS1 ROS ROS 17 0.0 protects spinal motor neurons against acute reactive oxygen species (ROS)-induced ROS -induced toxicity but not against chronic ROS-induced or glutamate (Glu)-induced 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 216911 12548704 290247 18723 10261 ROS1 ROS ROS-induced 23 0.0 oxygen species (ROS)-induced ROS -induced toxicity but not against chronic ROS-induced or glutamate (Glu)-induced Glu -induced toxicity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 216912 12548704 290248 567 877 ALDH7A1 PDE PDE 9 0.0 In this study we investigated the effects of phosphodiesterase (PDE) PDE inhibitors on the survival of cultured spinal motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 216913 12548704 290249 16300 8784 PDE5A PDE5 PDE5 1 1.3 Selective PDE5 inhibitors (dipyridamole, dipyridamole T-1032 and zaprinast as well as a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 216914 12548704 290249 567 877 ALDH7A1 PDE PDE 12 0.0 (dipyridamole, dipyridamole T-1032 and zaprinast as well as a nonselective PDE inhibitor (aminophylline) aminophylline protected motor and nonmotor neurons against both 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 216915 12548704 290249 18723 10261 ROS1 ROS ROS-induced 23 0.0 (aminophylline) aminophylline protected motor and nonmotor neurons against both acute ROS-induced and chronic Glu-induced neurotoxicity whereas selective inhibitors of PDE1-4 offered 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 216916 12548704 290249 18723 10261 ROS1 ROS ROS-induced 49 0.0 cGMP analogue protected both motor and nonmotor neurons against acute ROS-induced toxicity but protected only nonmotor neurons against chronic Glu-induced toxicity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 216917 12548704 290251 16300 8784 PDE5A PDE5 PDE5 4 1.3 Immunohistochemical staining confirmed that PDE5 and PKG are located in almost all rat lumbar spinal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 216918 12548704 290252 16300 8784 PDE5A PDE5 PDE5 9 1.3 Furthermore semiquantitative analysis of the immunostaining intensity revealed that PDE5 was more abundant in motor neurons than in nonmotor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 216919 12548704 290253 16300 8784 PDE5A PDE5 PDE5 10 1.3 Our results suggest that this difference in the amount of PDE5 may be responsible for the vulnerability of motor neurons to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 216920 12548704 290254 16300 8784 PDE5A PDE5 PDE5 11 1.3 addition the results of this study raise the possibility that PDE5 inhibitors might be used as a treatment for amyotrophic lateral 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207521 12614931 278042 18723 10261 ROS1 ROS ROS 11 0.6 was accompanied by enhanced generation of reactive oxygen species (ROS) ROS with a peak after 2 h of exposure and by 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207522 12614931 278043 18723 10261 ROS1 ROS ROS 3 0.6 The increase in ROS and the MTT reduction were both EA concentration-dependent 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207523 12614931 278044 9462 5013 HMOX1 HO-1 HO-1 4 3.4 Expression of heme oxygenase-1 (HO-1), HO-1 a marker of oxidative stress also increased 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207524 12614931 278049 20996 11179 SOD1 ALS ALS 23 0.9 spinal cord injury (SCI) SCI and amyotrophic lateral sclerosis (ALS), ALS where motor neurons are the vulnerable population and oxidative stress 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109400288314422<>ScoreDetail__5468|IGFALS|0.000604077523282155__11179|SOD1|0.00109400288314422__ 0 0 0 0 0 207525 12614931 278052 18723 10261 ROS1 ROS ROS 25 0.6 role both as a scavenger of reactive oxygen species (ROS), ROS reactive nitrogen species (RNS) RNS and potentially toxic oxidation products 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207526 12614931 278052 6981 22140 FAM20C RNS RNS 29 0.3 of reactive oxygen species (ROS), ROS reactive nitrogen species (RNS) RNS and potentially toxic oxidation products and as a substrate for 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 207527 12614931 278057 20996 11179 SOD1 ALS ALS 20 0.9 pathogenic factor in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), ALS Parkinson's disease (PD) PD and Alzheimer's disease (AD) AD and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109400288314422<>ScoreDetail__5468|IGFALS|0.000604077523282155__11179|SOD1|0.00109400288314422__ 0 0 0 0 0 207528 12614931 278058 20996 11179 SOD1 ALS ALS 11 0.9 neurons are selectively vulnerable in some neurodegenerative conditions such as ALS and spinal cord injury (SCI) SCI 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109400288314422<>ScoreDetail__5468|IGFALS|0.000604077523282155__11179|SOD1|0.00109400288314422__ 0 0 0 0 0 207529 12614931 278060 20017 10940 SLC1A2 EAAT2 EAAT2 20 1.5 receptor subunit and a much greater perisomatic expression of the EAAT2 protein the glial glutamate transporter which is particularly vulnerable to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207530 12614931 278061 20996 11179 SOD1 ALS ALS 5 0.9 An altered GSH metabolism in ALS could contribute to motor neuron degeneration 10 11 and 12 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109400288314422<>ScoreDetail__5468|IGFALS|0.000604077523282155__11179|SOD1|0.00109400288314422__ 0 0 0 0 0 207531 12614931 278062 20996 11179 SOD1 ALS ALS 9 0.9 GSH binding sites increase in the spinal cord of ALS patients 13 and this may be interpreted as an upregulation 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109400288314422<>ScoreDetail__5468|IGFALS|0.000604077523282155__11179|SOD1|0.00109400288314422__ 0 0 0 0 0 207532 12614931 278063 20996 11179 SOD1 ALS ALS 24 0.9 14 in a mouse model of the familial form of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109400288314422<>ScoreDetail__5468|IGFALS|0.000604077523282155__11179|SOD1|0.00109400288314422__ 0 0 0 0 0 207533 12614931 278063 14042 7625 NA NAC NAC 5 0.0 Treatment with N -acetyl--cysteine (NAC), NAC a precursor of GSH improved survival 14 in a mouse 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 207534 12614931 278067 18723 10261 ROS1 ROS ROS 15 0.6 appears to be a factor in motor neuron death and ROS formation and a decrease in mitochondrial membrane potential (MMP) MMP 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207535 12614931 278075 7361 20442 FBRS FBS FBS 18 0.0 (DMEM, DMEM Biochrom Berlin Germany supplemented with 5% heat-inactivated defined FBS (defined defined FBS Hyclone Logan UT 1 mM glutamine and 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 207536 12614931 278075 7361 20442 FBRS FBS FBS 20 0.0 Berlin Germany supplemented with 5% heat-inactivated defined FBS (defined defined FBS Hyclone Logan UT 1 mM glutamine and antibiotics (100 100 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 207537 12614931 278090 19573 10691 SDS SDS SDS 9 0.0 Then an equal volume of 20% sodium dodecyl sulphate (SDS) SDS in 50% dimethylformamide was added to each well and the 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000278596972932662<>ScoreDetail__10691|SDS|0.000112815884476534__19440|SBDS|0.000278596972932662__ 0 0 0 0 0 207538 12614931 278094 18312 670 RHOD Rho Rho 17 0.0 measured by uptake of the lipophilic cation rhodamine 123 (Rho Rho 123 Fluka Chemie CH into mitochondria 1 JUMiner_v2.2 1 1 ras 0 0 0 0 0 0 0 0 207539 12614931 278098 18312 670 RHOD Rho Rho 9 0.0 The cells were then resuspended in 1 ml of Rho 123 (10 10 _amp_#x3bc;g/ml) _amp_#x3bc g ml for 30 min 1 JUMiner_v2.2 1 1 ras 0 0 0 0 0 0 0 0 207540 12614931 278102 18723 10261 ROS1 ROS ROS 0 0.6 ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207541 12614931 278103 18723 10261 ROS1 ROS ROS 4 0.6 For determination of intracellular ROS control and EA-treated cells were exposed during the last 30 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207542 12614931 278105 18723 10261 ROS1 ROS ROS 11 0.6 the fluorescence intensity is proportional to the level of intracellular ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207543 12614931 278109 9462 5013 HMOX1 HO-1 HO-1 0 3.4 HO-1 mRNA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207544 12614931 278110 9462 5013 HMOX1 HO-1 HO-1 3 3.4 The heme oxygenase-1 (HO-1) HO-1 mRNA level was measured by Northern Blot analysis as previously 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207545 12614931 278117 6054 2983 DNTT TDT TdT 13 0.3 by the TUNEL technique which uses terminal deoxynucleotidyl transferase (TdT) TdT to catalyse the binding of FITC-conjugated dUTP to DNA strand 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207546 12614931 278121 6054 2983 DNTT TDT TdT 20 0.3 mixture (Roche Roche Molecular Biochemicals Monza Italy containing dUTP-FITC and TdT and incubated for 60 min at 37 _amp_#xb0 C in 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207547 12614931 278140 18312 670 RHOD Rho Rho 24 0.0 NSC-34 motor neurons by selective uptake of the lipophilic cation Rho 123 into mitochondria ( Fig 3 1 JUMiner_v2.2 1 1 ras 0 0 0 0 0 0 0 0 207548 12614931 278143 18312 670 RHOD Rho Rho 10 0.0 The histograms of relative MMP measured by fluorescent emission from Rho 123 taken up by mitochondria in control and EA-exposed NSC-34 1 JUMiner_v2.2 1 1 ras 0 0 0 0 0 0 0 0 207549 12614931 278144 18723 10261 ROS1 ROS ROS 8 0.6 Since GSH depletion leads to the generation of ROS in different experimental conditions we measured the level of ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207550 12614931 278144 18723 10261 ROS1 ROS ROS 18 0.6 ROS in different experimental conditions we measured the level of ROS by adding the probe DCFH-DA to the cultures 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207551 12614931 278145 18723 10261 ROS1 ROS ROS 0 0.6 ROS were rapidly raised by 100 _amp_#x3bc M EA_amp_#x2014 about twice 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207552 12614931 278146 18723 10261 ROS1 ROS ROS 3 0.6 The increase in ROS formation after 90 min of exposure to EA was concentration-dependent 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207553 12614931 278150 9462 5013 HMOX1 HO-1 HO-1 12 3.4 marker of oxidative stress we also measured the induction of HO-1 mRNA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207554 12614931 278151 9462 5013 HMOX1 HO-1 HO-1 7 3.4 Exposure to 100 _amp_#x3bc M EA promptly increased HO-1 mRNA with a massive rise 3 h after treatment (respectively 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207555 12614931 278166 18723 10261 ROS1 ROS ROS 23 0.6 of almost 80% in GSH was accompanied by mitochondrial impairment ROS formation and a limited decrease of MMP 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207556 12614931 278168 18723 10261 ROS1 ROS ROS 16 0.6 a steady drop in mitochondrial function and MMP while increased ROS formation remains a burst limited to the initial phase 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207557 12614931 278170 18723 10261 ROS1 ROS ROS 9 0.6 Impaired mitochondrial respiration was probably the major source of ROS since Wullner et al 23 showed that ROS formation after 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207558 12614931 278170 18723 10261 ROS1 ROS ROS 19 0.6 source of ROS since Wullner et al 23 showed that ROS formation after EA exposure of cerebellar granule cells was almost 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207559 12614931 278171 18723 10261 ROS1 ROS ROS 2 0.6 In mitochondria ROS derive from the conversion of oxygen to superoxide and hydrogen 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207560 12614931 278178 20996 11179 SOD1 ALS ALS 11 0.9 treatment with catalase was beneficial in a mouse model of ALS 28 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109400288314422<>ScoreDetail__5468|IGFALS|0.000604077523282155__11179|SOD1|0.00109400288314422__ 0 0 0 0 0 207561 12614931 278181 18723 10261 ROS1 ROS ROS 4 0.6 The increase of intracellular ROS was accompanied by a decrease in MMP indicating the opening 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207562 12614931 278182 18723 10261 ROS1 ROS ROS 6 0.6 This phenomenon can be induced by ROS electron transport chain inhibition and oxidation of GSH 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207563 12614931 278184 18723 10261 ROS1 ROS ROS 12 0.6 support this since only the initial depolarization was concomitant with ROS formation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207564 12614931 278185 18723 10261 ROS1 ROS ROS 0 0.6 ROS could cause the initial opening of the MPTP while later 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207565 12614931 278191 20996 11179 SOD1 ALS ALS 16 0.9 levels were found in the motor nerve terminals of sporadic ALS patients 35 and in motor neurons of transgenic mouse models 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109400288314422<>ScoreDetail__5468|IGFALS|0.000604077523282155__11179|SOD1|0.00109400288314422__ 0 0 0 0 0 207566 12614931 278191 20996 11179 SOD1 ALS ALS 30 0.9 35 and in motor neurons of transgenic mouse models of ALS at the early stages of the disease 36 37 and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109400288314422<>ScoreDetail__5468|IGFALS|0.000604077523282155__11179|SOD1|0.00109400288314422__ 0 0 0 0 0 207567 12614931 278194 20996 11179 SOD1 ALS ALS 13 0.9 evidence that motor neurons die by an apoptotic pathway in ALS (for for a review see 40 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109400288314422<>ScoreDetail__5468|IGFALS|0.000604077523282155__11179|SOD1|0.00109400288314422__ 0 0 0 0 0 207568 12614931 278197 9462 5013 HMOX1 HO-1 HO-1 7 3.4 GSH depletion by EA induced expression of HO-1 which has been reported to be protective in different models 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207569 12614931 278198 9462 5013 HMOX1 HO-1 HO-1 4 3.4 The end products of HO-1 enzymatic activity potentially act as antioxidants 45 and can thus 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207570 12614931 278198 12337 6871 MAPK1 p38 p38 36 1.7 manner as an anti-apoptotic messenger possibly through activation of the p38 mitogen-activated protein kinase (MAPK) MAPK signal transduction pathway 46 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.000789849615733871<>ScoreDetail__1189|AHSA1|0.000120336943441637__6878|MAPK4|0.000528623001547189__6871|MAPK1|0.000789849615733871__6876|MAPK14|0.000634195101121851__ 0 0 0 0 0 207571 12614931 278198 12337 6871 MAPK1 MAPK MAPK 40 1.7 possibly through activation of the p38 mitogen-activated protein kinase (MAPK) MAPK signal transduction pathway 46 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207572 12614931 278199 9462 5013 HMOX1 HO-1 HO-1 4 3.4 However the role of HO-1 in our model requires further investigation since proapoptotic signals prevailed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207573 12614931 278200 9462 5013 HMOX1 HO-1 HO-1 4 3.4 Interestingly increased immunoreactivity for HO-1 and p38MAPK were detected in human and mouse ALS 47 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207574 12614931 278200 20996 11179 SOD1 ALS ALS 13 0.9 for HO-1 and p38MAPK were detected in human and mouse ALS 47 48 and 49 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109400288314422<>ScoreDetail__5468|IGFALS|0.000604077523282155__11179|SOD1|0.00109400288314422__ 0 0 0 0 0 207575 12614931 278202 20996 11179 SOD1 ALS ALS 1 0.9 In ALS there is evidence of oxidative stress coupled to mitochondrial damage 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109400288314422<>ScoreDetail__5468|IGFALS|0.000604077523282155__11179|SOD1|0.00109400288314422__ 0 0 0 0 0 207576 12614931 278220 18723 10261 ROS1 ROS ROS 8 0.6 Effect of ethacrynic acid on the generation of ROS in NSC-34 cells 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207577 12614931 278221 18723 10261 ROS1 ROS ROS 26 0.6 different EA concentrations for 90 min (panel panel B and ROS generation of was measured from the conversion of DCFH-DA to 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 207578 12614931 278226 9462 5013 HMOX1 HO-1 HO-1 3 3.4 The heme oxygenase-1 (HO-1) HO-1 mRNA signal is shown 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 207986 12618129 278644 20996 11179 SOD1 ALS ALS 3 1.8 Amyotrophic lateral sclerosis (ALS) ALS is a devastating neurodegenerative disease which affects the anterior horn 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 207987 12618129 278645 20996 11179 SOD1 ALS ALS 19 1.8 on the finding that cybrids obtained from mitochondria of sporadic ALS patients exhibited impaired respiratory chain activities increased free radical scavenging 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 207988 12618129 278646 20996 11179 SOD1 ALS ALS 9 1.8 To date however no distinct mtDNA alterations associated with ALS have been reported 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 207989 12618129 278647 20996 11179 SOD1 ALS ALS 10 1.8 Therefore we reexamined the hypotheses that mtDNA mutations accumulate in ALS and that cybrids generated from ALS patients_amp_#x2019 blood have impaired 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 207990 12618129 278647 20996 11179 SOD1 ALS ALS 16 1.8 mtDNA mutations accumulate in ALS and that cybrids generated from ALS patients_amp_#x2019 blood have impaired mitochondrial respiration 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 207991 12618129 278648 20996 11179 SOD1 ALS ALS 16 1.8 143B osteosarcoma _amp_#x3c1 0 cells and platelet mitochondria of sporadic ALS patients or age-matched controls 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 207992 12618129 278649 20996 11179 SOD1 ALS ALS 10 1.8 We found no statistically significant differences in mitochondrial respiration between ALS and control cybrids even when the electron transport chain was 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 207993 12618129 278650 20996 11179 SOD1 ALS ALS 9 1.8 Mitochondrial respiratory chain enzyme activities were also normal in ALS cybrids and there was no increase in free radical production 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 207994 12618129 278651 20996 11179 SOD1 ALS ALS 8 1.8 Therefore we showed that mtDNA from platelets of ALS patients was able to restore normal respiratory function in _amp_#x3c1 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 207995 12618129 278653 20996 11179 SOD1 ALS ALS 3 1.8 Amyotrophic lateral sclerosis (ALS) ALS is a devastating neurodegenerative disease that affects the anterior horn 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 207996 12618129 278654 20996 11179 SOD1 ALS ALS 4 1.8 The annual incidence of ALS is 1 in 100 000 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 207997 12618129 278656 20996 11179 SOD1 ALS ALS 16 1.8 a potential role of mitochondrial dysfunction in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 207998 12618129 278657 20996 11179 SOD1 ALS ALS 7 1.8 In anterior horn cells of patients with ALS accumulations of abnormal mitochondria were observed 16 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 207999 12618129 278658 20996 11179 SOD1 ALS ALS 24 1.8 and 25 and in spinal cord 4 and 24 from ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208000 12618129 278659 20996 11179 SOD1 ALS ALS 21 1.8 a mutant form of superoxide dismutase 1 associated with familial ALS 15 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208001 12618129 278660 20996 11179 SOD1 ALS ALS 20 1.8 on biochemical studies of cybrids obtained from mitochondria of sporadic ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208002 12618129 278662 20996 11179 SOD1 ALS ALS 9 1.8 To date however no distinct mtDNA alterations associated with ALS have been reported 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208003 12618129 278663 20996 11179 SOD1 ALS ALS 14 1.8 of mtDNA mutations and their role in the pathogenesis of ALS remains the subject of debate 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208004 12618129 278664 20996 11179 SOD1 ALS ALS 13 1.8 work we reexamine the hypothesis that mtDNA mutations accumulate in ALS and seek confirmation that cybrids generated from ALS patients_amp_#x2019 blood 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208005 12618129 278664 20996 11179 SOD1 ALS ALS 21 1.8 accumulate in ALS and seek confirmation that cybrids generated from ALS patients_amp_#x2019 blood exhibit impaired mitochondrial respiration 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208006 12618129 278667 20996 11179 SOD1 ALS ALS 8 1.8 The patient cohort consisted of 23 subjects 13 ALS patients (mean mean age 59.7 _amp_#xb1 15.3 SD and 10 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208007 12618129 278669 20996 11179 SOD1 ALS ALS 16 1.8 and El Escorial electrophysiological 5 criteria for the diagnosis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208008 12618129 278684 4829 2294 COX8A COX COX 16 1.2 (succinate_amp_#x2013;cytochrome succinate_amp_#x2013 cytochrome c reductase IV (cytochrome cytochrome c oxidase COX and the mitochondrial matrix enzyme citrate synthase (CS) CS were 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 208009 12618129 278694 20996 11179 SOD1 ALS ALS 3 1.8 For each assay ALS and control cybrids were compared using unpaired Student_amp_#x2019 s t 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208010 12618129 278696 20996 11179 SOD1 ALS ALS 0 1.8 ALS cybrids have normal mitochondrial respiration 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208011 12618129 278701 20996 11179 SOD1 ALS ALS 3 1.8 Under basal conditions ALS and control cybrid mass cultures showed no differences in respiration 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208012 12618129 278702 20996 11179 SOD1 ALS ALS 14 1.8 a statistically significant deficit in oxygen consumption under basal conditions ALS cybrids might still harbor deleterious mutations present at low levels 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208013 12618129 278703 4829 2294 COX8A COX COX 5 1.2 For example in 143B-derived cybrids COX excess capacity is such that even a stop codon mutation 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 208014 12618129 278703 4829 2294 COX8A COX COX 18 1.2 is such that even a stop codon mutation in a COX subunit can be tolerated up to 40% heteroplasmy before an 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 208015 12618129 278705 4829 2294 COX8A COX COX 8 1.2 Accordingly 5 _amp_#x3bc M KCN a specific inhibitor of COX was added either at the beginning of the assay ( 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 208016 12618129 278708 4829 2294 COX8A COX COX 10 1.2 Because KCN competes with oxygen for the catalytic site on COX KCN inhibition increased to approximately 20% at O 2-50%RA 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 208017 12618129 278709 20996 11179 SOD1 ALS ALS 9 1.8 Even with this degree of respiratory inhibition by KCN ALS and control cybrid mass cultures showed no differences in respiration 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208018 12618129 278710 20996 11179 SOD1 ALS ALS 29 1.8 increased proportion of cybrid cells with reduced respiration within the ALS group hidden among cells with normal respiration 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208019 12618129 278712 20996 11179 SOD1 ALS ALS 14 1.8 was no statistically significant difference in the average respiration of ALS cybrid clones ( n = 130 and control clones ( 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208020 12618129 278713 20996 11179 SOD1 ALS ALS 23 1.8 5 _amp_#x3bc M KCN induced a decrease in respiration in ALS cybrid clones 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208021 12618129 278716 20996 11179 SOD1 ALS ALS 9 1.8 Therefore we compared the number of low-respiring clones in ALS subjects to the number found in control subjects 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208022 12618129 278719 20996 11179 SOD1 ALS ALS 5 1.8 We found no difference between ALS and controls in the number of low-respiring clones with or 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208023 12618129 278720 20996 11179 SOD1 ALS ALS 28 1.8 of the occurrence of these clones was the same in ALS and control cybrids 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208024 12618129 278721 20996 11179 SOD1 ALS ALS 6 1.8 Finally to determine whether any individual ALS subject had defective mitochondrial respiration we compared the average of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208025 12618129 278721 20996 11179 SOD1 ALS ALS 21 1.8 respiration we compared the average of 10 clones from each ALS subject to the average of 100 control clones 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208026 12618129 278722 20996 11179 SOD1 ALS ALS 16 1.8 in cell respiration in any of the individual groups of ALS clones (data data not shown 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208027 12618129 278723 20996 11179 SOD1 ALS ALS 0 1.8 ALS cybrids have normal respiratory chain activities 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208028 12618129 278724 4829 2294 COX8A COX COX 10 1.2 of the mitochondrial respiratory chain complexes I III II III COX and of the nuclear encoded mitochondrial matrix enzyme citrate synthase 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 208029 12618129 278725 20996 11179 SOD1 ALS ALS 24 1.8 mitochondrial content the activities of mitochondrial respiratory chain enzymes in ALS cybrids were the same as those of controls in both 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208030 12618129 278726 20996 11179 SOD1 ALS ALS 7 1.8 In addition no differences were found between ALS and controls when activities were normalized by those of 143B 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208031 12618129 278727 20996 11179 SOD1 ALS ALS 30 1.8 1 SD of the average of 100 control clones between ALS and control clones (data data not shown 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208032 12618129 278728 20996 11179 SOD1 ALS ALS 7 1.8 Reactive oxygen species production is unchanged in ALS cybrids 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208033 12618129 278729 20996 11179 SOD1 ALS ALS 9 1.8 Intracellular reactive oxygen species (ROS) ROS production was measured in ALS and control cybrid mass cultures loaded with H 2 DCFDA 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208034 12618129 278729 4829 2294 COX8A COX COX 29 1.2 DCFDA and incubated in medium containing increasing concentrations of the COX inhibitor KCN from 0 to 10 _amp_#x3bc M 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 208035 12618129 278729 18723 10261 ROS1 ROS ROS 4 0.0 Intracellular reactive oxygen species (ROS) ROS production was measured in ALS and control cybrid mass cultures 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 208036 12618129 278730 18723 10261 ROS1 ROS ROS 5 0.0 As expected the levels of ROS detected increased with time ( Fig 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 208037 12618129 278731 20996 11179 SOD1 ALS ALS 6 1.8 However no statistically significant differences between ALS and control cybrids were evident in medium without inhibitors 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208038 12618129 278734 20996 11179 SOD1 ALS ALS 20 1.8 of KCN was very small and did not differ between ALS and control cybrids further confirming that ALS cybrids did not 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208039 12618129 278734 20996 11179 SOD1 ALS ALS 27 1.8 not differ between ALS and control cybrids further confirming that ALS cybrids did not harbor respiration defects predisposing to enhanced oxidative 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208040 12618129 278734 18723 10261 ROS1 ROS ROS 5 0.0 As expected the increase in ROS production in the presence of KCN was very small and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 208041 12618129 278736 20996 11179 SOD1 ALS ALS 35 1.8 disease 10 19 and 20 Alzheimer_amp_#x2019 s disease 9 and ALS 18 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208042 12618129 278738 20996 11179 SOD1 ALS ALS 20 1.8 _amp_#x3c1 0 cells repopulated with mtDNA from platelets of sporadic ALS patients had reduced electron transfer chain activities increased free radical 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208043 12618129 278739 20996 11179 SOD1 ALS ALS 17 1.8 putative mtDNA mutations responsible for the defective biochemical phenotypes in ALS cybrids as well as in cybrids from other diseases has 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208044 12618129 278740 20996 11179 SOD1 ALS ALS 19 1.8 mtDNA genomes in blood from an independent series of sporadic ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208045 12618129 278749 20996 11179 SOD1 ALS ALS 15 1.8 to detect any statistically significant decrease in respiratory function in ALS cybrids compared to controls 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208046 12618129 278751 20996 11179 SOD1 ALS ALS 10 1.8 the frequency of _amp_#x201c defective_amp_#x201d clones was the same in ALS and control cybrids 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208047 12618129 278752 20996 11179 SOD1 ALS ALS 8 1.8 These results suggested that the mtDNA derived from ALS platelets did not contain enough pathogenic mutations to prevent the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208048 12618129 278753 20996 11179 SOD1 ALS ALS 16 1.8 cause of the occurrence of low respiring clones in both ALS and control groups 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208049 12618129 278756 20996 11179 SOD1 ALS ALS 20 1.8 found approximately a 20% defect in complex I activity of ALS cybrids compared to controls 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208050 12618129 278757 20996 11179 SOD1 ALS ALS 2 1.8 Obviously the ALS patients who participated in our study were different 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208051 12618129 278758 20996 11179 SOD1 ALS ALS 5 1.8 However the size of the ALS groups in the two studies (11 11 and 13 in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208052 12618129 278763 20996 11179 SOD1 ALS ALS 15 1.8 functions are impaired in muscle and spinal cord from sporadic ALS patients 4 Vielhaber et al. 2000 25 and 24 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208053 12618129 278764 20996 11179 SOD1 ALS ALS 22 1.8 abundant although at very low levels in spinal cord from ALS patients 24 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208054 12618129 278768 20996 11179 SOD1 ALS ALS 29 1.8 affected tissues may play a role in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208055 12618129 278769 20996 11179 SOD1 ALS ALS 20 1.8 that pathogenic mtDNA mutations are more abundant in platelets from ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208056 12618129 278775 20996 11179 SOD1 ALS ALS 24 1.8 the hypothesis that there are pathogenically significant mtDNA mutations in ALS as well as other neurodegenerative diseases 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208057 12618129 278778 20996 11179 SOD1 ALS ALS 3 1.8 Isolated platelets from ALS patients and controls were fused to mtDNA-less osteosarcoma 143B _amp_#x3c1 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208058 12618129 278781 20996 11179 SOD1 ALS ALS 4 1.8 (A) A Cybrid mass culture (ALS ALS n = 13 controls n = 10 and clone (ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208059 12618129 278781 20996 11179 SOD1 ALS ALS 14 1.8 n = 13 controls n = 10 and clone (ALS ALS n = 130 controls n = 100 respiration rates in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208060 12618129 278784 20996 11179 SOD1 ALS ALS 4 1.8 (C) C Cybrid mass culture (ALS ALS n = 13 controls n = 10 and clone (ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208061 12618129 278784 20996 11179 SOD1 ALS ALS 14 1.8 n = 13 controls n = 10 and clone (ALS ALS n = 130 controls n = 100 respiration rates with 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208062 12618129 278790 20996 11179 SOD1 ALS ALS 8 1.8 (A) A Respiratory chain activities in cybrid mass cultures (ALS ALS n = 13 controls n = 10 normalized by the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208063 12618129 278791 20996 11179 SOD1 ALS ALS 7 1.8 (B) B Respiratory chain activities in cybrid clones (ALS ALS n = 130 controls n = 100 normalized by the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000636756930857386<>ScoreDetail__5468|IGFALS|0.000422082241807246__11179|SOD1|0.000636756930857386__ 0 0 0 0 0 208064 12618129 278794 4829 2294 COX8A COX COX 10 1.2 NADH cytochrome c reductase II III succinate cytochrome c reductase COX cytochrome c oxidase 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 209620 12654515 280252 20996 11179 SOD1 SOD1 SOD1 7 3.7 The increased oxidative stress induced by mutant SOD1 is associated with motor neuron degeneration in both human ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209621 12654515 280252 20996 11179 SOD1 ALS ALS 17 1.7 SOD1 is associated with motor neuron degeneration in both human ALS and transgenic mice expressing mutant SOD1 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00211663176525962<>ScoreDetail__5468|IGFALS|0.000441164674741317__11179|SOD1|0.00211663176525962__ 0 0 0 0 0 209622 12654515 280252 20996 11179 SOD1 SOD1 SOD1 23 3.7 degeneration in both human ALS and transgenic mice expressing mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209623 12654515 280253 23910 12680 VEGFA VEGF VEGF 4 4.3 Vascular endothelial growth factor (VEGF) VEGF is neurotrophic and also protects from hypoxia-induced neuronal injury 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209624 12654515 280254 23910 12680 VEGFA VEGF VEGF 4 4.3 The potential role of VEGF in preventing mutant SOD1-mediated motor neuron cell death was examined 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209625 12654515 280254 20996 11179 SOD1 SOD1 SOD1-mediated 8 1.7 The potential role of VEGF in preventing mutant SOD1-mediated motor neuron cell death was examined using a mouse NSC34 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209626 12654515 280255 20996 11179 SOD1 SOD1 SOD1 12 3.7 adenovirus containing mutant G93A-SOD1 but not vector control or wild-type SOD1 increased cellular oxidative stress and motor neuron-like cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209627 12654515 280256 23910 12680 VEGFA VEGF VEGF 5 4.3 However NSC34 cells pretreated with VEGF displayed a dose-dependent resistance to oxidative damage from hydrogen peroxide 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209628 12654515 280256 22551 11892 TNF TNF TNF-A 16 1.2 displayed a dose-dependent resistance to oxidative damage from hydrogen peroxide TNF-_amp_#x3b1 and mutant G93A-SOD1 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209629 12654515 280257 23910 12680 VEGFA VEGF VEGF 0 4.3 VEGF activated both PI3-K and MAPK activities in mouse NSC34 motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209630 12654515 280257 16616 8978 PIK3CG PI3K PI3-K 3 2.6 VEGF activated both PI3-K and MAPK activities in mouse NSC34 motor neuron-like cells 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209631 12654515 280257 12337 6871 MAPK1 MAPK MAPK 5 2.2 VEGF activated both PI3-K and MAPK activities in mouse NSC34 motor neuron-like cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209632 12654515 280258 12337 6871 MAPK1 MAPK MAPK 12 2.2 and constitutively active as well as dominant negative mutants of MAPK and PI3-K revealed that the protective effects of VEGF were 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209633 12654515 280258 16616 8978 PIK3CG PI3K PI3-K 14 2.6 active as well as dominant negative mutants of MAPK and PI3-K revealed that the protective effects of VEGF were mediated via 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209634 12654515 280258 23910 12680 VEGFA VEGF VEGF 21 4.3 of MAPK and PI3-K revealed that the protective effects of VEGF were mediated via the PI3-K activity and that MAPK activation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209635 12654515 280258 16616 8978 PIK3CG PI3K PI3-K 26 2.6 that the protective effects of VEGF were mediated via the PI3-K activity and that MAPK activation was not associated with NSC34 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209636 12654515 280258 12337 6871 MAPK1 MAPK MAPK 30 2.2 of VEGF were mediated via the PI3-K activity and that MAPK activation was not associated with NSC34 cell survival 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209637 12654515 280259 23910 12680 VEGFA VEGF VEGF-induced 1 3.8 Furthermore VEGF-induced downstream Akt activation promoted motor neuron-like NSC34 cell survival in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209638 12654515 280259 543 391 AKT1 AKT Akt 3 0.1 Furthermore VEGF-induced downstream Akt activation promoted motor neuron-like NSC34 cell survival in the presence 6 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209639 12654515 280260 23910 12680 VEGFA VEGF VEGF 1 4.3 Thus VEGF protected mouse NSC34 motor neuron-like cell death from mutant G93A-SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209640 12654515 280260 16616 8978 PIK3CG PI3K PI3-K 14 2.6 motor neuron-like cell death from mutant G93A-SOD1 effects via PI3-K/Akt PI3-K Akt activation 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209641 12654515 280260 543 391 AKT1 AKT Akt 14 0.3 neuron-like cell death from mutant G93A-SOD1 effects via PI3-K/Akt PI3-K Akt activation 4 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209642 12654515 280264 20996 11179 SOD1 ALS ALS 3 1.7 Amyotrophic lateral sclerosis (ALS), ALS commonly known as Lou Gehrig_amp_#x2019 s disease is a progressive 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00211663176525962<>ScoreDetail__5468|IGFALS|0.000441164674741317__11179|SOD1|0.00211663176525962__ 0 0 0 0 0 209643 12654515 280265 20996 11179 SOD1 ALS ALS 11 1.7 etiological and pathological factors causing motor neuron degeneration in the ALS have not been identified and there is no effective treatment 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00211663176525962<>ScoreDetail__5468|IGFALS|0.000441164674741317__11179|SOD1|0.00211663176525962__ 0 0 0 0 0 209644 12654515 280266 20996 11179 SOD1 SOD1 SOD1 10 3.7 discovery that mutations of the copper_amp_#x2013 zinc superoxide dismutase (SOD1) SOD1 gene cause a portion of human familial ALS and that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209645 12654515 280266 20996 11179 SOD1 ALS ALS 18 1.7 dismutase (SOD1) SOD1 gene cause a portion of human familial ALS and that transgenic animal models expressing mutant SOD1 mimic human 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00211663176525962<>ScoreDetail__5468|IGFALS|0.000441164674741317__11179|SOD1|0.00211663176525962__ 0 0 0 0 0 209646 12654515 280266 20996 11179 SOD1 SOD1 SOD1 26 3.7 human familial ALS and that transgenic animal models expressing mutant SOD1 mimic human ALS have contributed significantly to our understanding of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209647 12654515 280266 20996 11179 SOD1 ALS ALS 29 1.7 and that transgenic animal models expressing mutant SOD1 mimic human ALS have contributed significantly to our understanding of human ALS 5 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00211663176525962<>ScoreDetail__5468|IGFALS|0.000441164674741317__11179|SOD1|0.00211663176525962__ 0 0 0 0 0 209648 12654515 280266 20996 11179 SOD1 ALS ALS 38 1.7 human ALS have contributed significantly to our understanding of human ALS 5 18 37 41 and 51 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00211663176525962<>ScoreDetail__5468|IGFALS|0.000441164674741317__11179|SOD1|0.00211663176525962__ 0 0 0 0 0 209649 12654515 280267 20996 11179 SOD1 SOD1 SOD1 4 3.7 The G93A mutation in SOD1 (G93A-SOD1) G93A-SOD1 is one of the 90 currently known mutations 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209650 12654515 280267 20996 11179 SOD1 ALS ALS 17 1.7 one of the 90 currently known mutations that cause human ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00211663176525962<>ScoreDetail__5468|IGFALS|0.000441164674741317__11179|SOD1|0.00211663176525962__ 0 0 0 0 0 209651 12654515 280268 20996 11179 SOD1 SOD1 SOD1-mediated 6 1.7 Nevertheless effective approaches to prevent mutant SOD1-mediated motor neuron death remain largely unidentified 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209652 12654515 280269 23910 12680 VEGFA VEGF VEGF 5 4.3 Recently vascular endothelial growth factor (VEGF) VEGF has been demonstrated to have neurotrophic effects by promoting neuronal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209653 12654515 280270 23910 12680 VEGFA VEGF VEGF 9 4.3 Knockout mice with deleted hypoxic response elements in the VEGF promoter region develop a motor neuron-like disease mimicking human ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209654 12654515 280270 20996 11179 SOD1 ALS ALS 19 1.7 VEGF promoter region develop a motor neuron-like disease mimicking human ALS 40 suggesting that hypoxia-mediated VEGF expression may be associated with 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00211663176525962<>ScoreDetail__5468|IGFALS|0.000441164674741317__11179|SOD1|0.00211663176525962__ 0 0 0 0 0 209655 12654515 280270 23910 12680 VEGFA VEGF VEGF 26 4.3 motor neuron-like disease mimicking human ALS 40 suggesting that hypoxia-mediated VEGF expression may be associated with motor neuron degeneration 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209656 12654515 280271 23910 12680 VEGFA VEGF VEGF 0 4.3 VEGF also known as vascular permeability factor is a dimeric glycoprotein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209657 12654515 280271 7629 3763 FLT1 FLT1 Flt-1 21 0.6 binds to endothelial cell specific receptors fms-like tyrosine kinase (Flt-1) Flt-1 and fetal liver kinase (Flk-1) Flk-1 16 and 36 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209658 12654515 280271 10981 6307 KDR FLK1 Flk-1 26 0.3 fms-like tyrosine kinase (Flt-1) Flt-1 and fetal liver kinase (Flk-1) Flk-1 16 and 36 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209659 12654515 280271 5009 2433 CSF1R FMS fms-like 18 0.0 a dimeric glycoprotein that binds to endothelial cell specific receptors fms-like tyrosine kinase (Flt-1) Flt-1 and fetal liver kinase (Flk-1) Flk-1 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209660 12654515 280272 23910 12680 VEGFA VEGF VEGF 4 4.3 Acting through these receptors VEGF is believed to initiate several intracellular signal transduction systems including 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209661 12654515 280272 16616 8978 PIK3CG PI3K PI3-K 17 2.6 initiate several intracellular signal transduction systems including phosphatidylinositol 3-kinase (PI3-K) PI3-K and mitogen-activated protein kinase (MAPK) MAPK 42 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209662 12654515 280272 12337 6871 MAPK1 MAPK MAPK 22 2.2 including phosphatidylinositol 3-kinase (PI3-K) PI3-K and mitogen-activated protein kinase (MAPK) MAPK 42 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209663 12654515 280273 23910 12680 VEGFA VEGF VEGF 10 4.3 Hypoxia and spinal cord injury have been demonstrated to increase VEGF expression 19 20 and 35 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209664 12654515 280274 23910 12680 VEGFA VEGF VEGF 6 4.3 Neuronal or neuronal-like cells pretreated with VEGF prevent glutamate- and hypoxia/ischemia-mediated hypoxia ischemia-mediated cell death in vitro 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209665 12654515 280275 23910 12680 VEGFA VEGF VEGF 5 4.3 More importantly topical application of VEGF reduces ischemia-mediated brain damage in vivo 19 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209666 12654515 280276 23910 12680 VEGFA VEGF VEGF 9 4.3 Although some studies have focused on the effects of VEGF on the central nervous system (CNS), CNS the potential role 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209667 12654515 280276 23910 12680 VEGFA VEGF VEGF 20 4.3 the central nervous system (CNS), CNS the potential role of VEGF in motor neuron survival by mutant SOD1 effects remains largely 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209668 12654515 280276 20996 11179 SOD1 SOD1 SOD1 27 3.7 potential role of VEGF in motor neuron survival by mutant SOD1 effects remains largely unknown 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209669 12654515 280277 23910 12680 VEGFA VEGF VEGF 13 4.3 the NSC34 motor neuron-like cell culture model to test whether VEGF can prevent mutant SOD1-mediated motor neuron degeneration 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209670 12654515 280277 20996 11179 SOD1 SOD1 SOD1-mediated 17 1.7 cell culture model to test whether VEGF can prevent mutant SOD1-mediated motor neuron degeneration 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209671 12654515 280278 20996 11179 SOD1 ALS ALS 9 1.7 The G93A-SOD1 mutation that occurs frequently in the human ALS population and causes severe disease onset and progression was used 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00211663176525962<>ScoreDetail__5468|IGFALS|0.000441164674741317__11179|SOD1|0.00211663176525962__ 0 0 0 0 0 209672 12654515 280278 23910 12680 VEGFA VEGF VEGF 22 4.3 causes severe disease onset and progression was used to analyze VEGF effects on motor neuron degeneration 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209673 12654515 280279 23910 12680 VEGFA VEGF VEGF 7 4.3 We demonstrate that NSC34 cells pretreated with VEGF reduces mutant G93A-SOD1- TNF-_amp_#x3b1;- and hydrogen peroxide-mediated motor neuron-like cell 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209674 12654515 280280 23910 12680 VEGFA VEGF VEGF 0 4.3 VEGF activates both PI3-K and MAPK activities in NSC34 motor neuron-like 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209675 12654515 280280 16616 8978 PIK3CG PI3K PI3-K 3 2.6 VEGF activates both PI3-K and MAPK activities in NSC34 motor neuron-like cells 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209676 12654515 280280 12337 6871 MAPK1 MAPK MAPK 5 2.2 VEGF activates both PI3-K and MAPK activities in NSC34 motor neuron-like cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209677 12654515 280281 12337 6871 MAPK1 MAPK MAPK 12 2.2 pharmacological inhibitors and constitutively active and dominant negative mutants of MAPK and PI3-K we further demonstrate that PI3-K activity but not 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209678 12654515 280281 16616 8978 PIK3CG PI3K PI3-K 14 2.6 and constitutively active and dominant negative mutants of MAPK and PI3-K we further demonstrate that PI3-K activity but not MAPK activity 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209679 12654515 280281 16616 8978 PIK3CG PI3K PI3-K 19 2.6 negative mutants of MAPK and PI3-K we further demonstrate that PI3-K activity but not MAPK activity protects mouse NSC34 cells from 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209680 12654515 280281 12337 6871 MAPK1 MAPK MAPK 23 2.2 and PI3-K we further demonstrate that PI3-K activity but not MAPK activity protects mouse NSC34 cells from mutant G93A-SOD1 effects 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209681 12654515 280282 543 391 AKT1 AKT Akt 5 0.0 In addition we show that Akt activation promotes NSC34 motor neuron-like cell survival in the presence 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209682 12654515 280283 23910 12680 VEGFA VEGF VEGF 8 4.3 Thus we propose that the neurotrophic-like activity of VEGF on mouse NSC34 motor neuron-like cell survival is mediated by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209683 12654515 280283 16616 8978 PIK3CG PI3K PI3-K 22 2.6 neuron-like cell survival is mediated by activation of the PI3-K/Akt PI3-K Akt pathway 2 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209684 12654515 280283 543 391 AKT1 AKT Akt 22 0.3 cell survival is mediated by activation of the PI3-K/Akt PI3-K Akt pathway 2 4 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209685 12654515 280286 23910 12680 VEGFA VEGF VEGF 0 4.3 VEGF was purchased from Calbiochem (San San Diego CA USA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209686 12654515 280287 22551 11892 TNF TNF TNF-A 0 1.2 TNF-_amp_#x3b1 N -acetyl-cysteine (N-AC), N-AC 5_amp_#x2032 5_amp_#x2032 -dimethylpryrroline-N -oxide (DMPO), DMPO 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209687 12654515 280287 14042 7625 NA NAC N-AC 3 0.0 TNF-_amp_#x3b1 N -acetyl-cysteine (N-AC), N-AC 5_amp_#x2032 5_amp_#x2032 -dimethylpryrroline-N -oxide (DMPO), DMPO PD98059 LY294002 Wortmannin and 11 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 209688 12654515 280289 20996 11179 SOD1 SOD1 SOD1 3 3.7 Polyclonal antibody against SOD1 was purchased from Chemicon International (Temecula, Temecula CA USA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209689 12654515 280292 7361 20442 FBRS FBS FBS 47 0.0 (DMEM) DMEM supplemented with 10% heat-inactivated fetal bovine serum (FBS), FBS 100 units/ml units ml penicillin and 100 _amp_#x3bc;g/ml _amp_#x3bc g 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 209690 12654515 280297 16616 8978 PIK3CG PI3K PI3-K 4 2.6 Wild-type and constitutively active PI3-K catalytic subunit p110 (myristoylated) myristoylated and dominant negative PI3-K regulatory 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209691 12654515 280297 19369 16860 SART3 p110 p110 7 1.3 Wild-type and constitutively active PI3-K catalytic subunit p110 (myristoylated) myristoylated and dominant negative PI3-K regulatory subunit p85 were 1 JUMiner_v2.2 1 0 0 2 2557 TotalCon:2<>2557|CUX1|1523|Complete__16860|SART3|9733|Complete__<>AvaiableGeneRif=2<>BEST:2557|CUX1|0.00106563676060789<>ScoreDetail__16860|SART3|0.000284861985968147__2557|CUX1|0.00106563676060789__ 0 0 0 0 0 209692 12654515 280297 16616 8978 PIK3CG PI3K PI3-K 12 2.6 active PI3-K catalytic subunit p110 (myristoylated) myristoylated and dominant negative PI3-K regulatory subunit p85 were purchased from Upstate Biochemical (Lake Lake 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209693 12654515 280297 16618 8979 PIK3R1 p85 p85 15 0.6 subunit p110 (myristoylated) myristoylated and dominant negative PI3-K regulatory subunit p85 were purchased from Upstate Biochemical (Lake Lake Placid NY USA 1 JUMiner_v2.2 1 0 0 2 8979 TotalCon:3<>8979|PIK3R1|5295|Complete__8980|PIK3R2|5296|Complete__14950|PPP1R13B|23368|Complete__<>AvaiableGeneRif=3<>BEST:8979|PIK3R1|0.000988827623103241<>ScoreDetail__8980|PIK3R2|0.000960689045936396__14950|PPP1R13B|0.000437680693864439__8979|PIK3R1|0.000988827623103241__ 0 0 0 0 0 209694 12654515 280298 543 391 AKT1 AKT Akt 6 0.0 Constitutively active (myristoylated) myristoylated and dominant negative Akt (K179M-Akt) K179M-Akt were kindly provided by Dr Alfonso Bellacosa Fox 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209695 12654515 280300 1759 1102 BRD1 BRL BRL 21 0.3 vector containing target gene in 0.4 ml Opti-MEM (Gibco Gibco BRL at room temperature for 10 min then cells were electroporated 1 JUMiner_v2.2 1 2 gibco brl 0 0 0 0 0 0 0 0 209696 12654515 280306 23910 12680 VEGFA VEGF VEGF 6 4.3 Mouse NSC34 cells were pretreated with VEGF for 30 min and then infected with 2_amp_#xd7 10 6 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209697 12654515 280307 23910 12680 VEGFA VEGF VEGF 25 4.3 with complete medium either in the presence or absence of VEGF for various lengths of time before analysis 32 2.5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209698 12654515 280326 3778 10620 CCL21 ECL ECL 9 0.0 The immunoreactive protein was then detected by enhanced chemiluminescence (ECL) ECL 2.9 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209699 12654515 280327 12337 6871 MAPK1 MAP MAP 0 2.2 MAP kinase activation assay 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209700 12654515 280328 12337 6871 MAPK1 MAP MAP 0 2.2 MAP kinase activation was measured by the phosphorylation of ERK1/2 ERK1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209701 12654515 280328 12339 6877 MAPK3 ERK1 ERK1 9 2.7 MAP kinase activation was measured by the phosphorylation of ERK1/2 ERK1 2 using anti-phospho-ERK1/2 anti-phospho-ERK1 2 antibody (Cell Cell Signaling 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209702 12654515 280329 23910 12680 VEGFA VEGF VEGF-stimulated 3 3.8 Briefly control and VEGF-stimulated NSC34 cells were washed twice with ice-cold PBS and lysed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209703 12654515 280330 12337 6871 MAPK1 ERK ERK 30 2.2 membrane and probed with anti-phospho-ERK1/2 anti-phospho-ERK1 2 antibody that recognizes ERK only when it is phosphorylated at Thr202 and Tyr204 (Cell 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.00125947265897189<>ScoreDetail__3393|EPHB2|0.000713962991934831__6871|MAPK1|0.00125947265897189__ 0 0 0 0 0 209704 12654515 280332 16561 8947 PI3 PI3 PI3-kinase 0 0.3 PI3-kinase activity assay 11 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 209705 12654515 280333 16618 8979 PIK3R1 p85 p85 5 0.6 Cell lysates were immunoprecipitated with p85 antibody and were subsequently used for PI3-K activity assay 1 JUMiner_v2.2 1 0 0 2 8979 TotalCon:3<>8979|PIK3R1|5295|Complete__8980|PIK3R2|5296|Complete__14950|PPP1R13B|23368|Complete__<>AvaiableGeneRif=3<>BEST:8979|PIK3R1|0.000988827623103241<>ScoreDetail__8980|PIK3R2|0.000960689045936396__14950|PPP1R13B|0.000437680693864439__8979|PIK3R1|0.000988827623103241__ 0 0 0 0 0 209706 12654515 280333 16616 8978 PIK3CG PI3K PI3-K 12 2.6 were immunoprecipitated with p85 antibody and were subsequently used for PI3-K activity assay 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209707 12654515 280336 3870 1706 CD8A p32 p32 22 0.3 kinase reaction was initiated by adding 10 _amp_#x3bc Ci of p32 ATP (6000 6000 Ci/mmol, Ci mmol DuPont-NEN Boston MA USA 1 JUMiner_v2.2 1 0 0 2 1243 TotalCon:2<>1243|C1QBP|708|Complete__1706|CD8A|925|Complete__<>AvaiableGeneRif=2<>BEST:1243|C1QBP|0.00110424028268551<>ScoreDetail__1706|CD8A|0.00105025520219867__1243|C1QBP|0.00110424028268551__ 0 0 0 0 0 209708 12654515 280342 543 391 AKT1 AKT Akt 0 0.0 Akt activation assay 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209709 12654515 280343 543 391 AKT1 AKT Akt 0 0.0 Akt activation was examined by Western blotting with phosphorylation specific Akt 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209710 12654515 280343 543 391 AKT1 AKT Akt 10 0.0 Akt activation was examined by Western blotting with phosphorylation specific Akt antibody (Cell Cell Signaling 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209711 12654515 280344 23910 12680 VEGFA VEGF VEGF-treated 5 3.8 Briefly lysates from vehicle- and VEGF-treated cells were separated by SDS_amp_#x2013 PAGE transferred probed with anti-phospho-Akt 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 209712 12654515 280344 3778 10620 CCL21 ECL ECL 19 0.0 SDS_amp_#x2013 PAGE transferred probed with anti-phospho-Akt antibody and detected with ECL 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209713 12654515 280347 23910 12680 VEGFA VEGF VEGF-treated 11 3.8 expressed as mean_amp_#xb1 S.E.M and the differences between vehicle- and VEGF-treated mouse NSC34 motor neuron-like cells were analyzed using two-tailed Student 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209714 12654515 280351 20996 11179 SOD1 SOD1 SOD1-mediated 11 1.7 oxidative stress appears to be an early event of mutant SOD1-mediated motor neuron degeneration although the causal relationships between mutant SOD1-mediated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209715 12654515 280351 20996 11179 SOD1 SOD1 SOD1-mediated 21 1.7 SOD1-mediated motor neuron degeneration although the causal relationships between mutant SOD1-mediated oxidative stress and mutant SOD1-mediated motor neuron death are not 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209716 12654515 280351 20996 11179 SOD1 SOD1 SOD1-mediated 26 1.7 the causal relationships between mutant SOD1-mediated oxidative stress and mutant SOD1-mediated motor neuron death are not fully elucidated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209717 12654515 280352 20996 11179 SOD1 SOD1 SOD1 6 3.7 Infection with adenovirus containing human wild-type SOD1 (WT-SOD1) WT-SOD1 and human mutant G93A-SOD1 (G93A-SOD1) G93A-SOD1 increased target 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209718 12654515 280354 14042 7625 NA NAC N-AC 12 0.0 previous study showing that the anti-oxidants catalase N -acetyl-cysteine (N-AC) N-AC and the spin trapping molecule 5_amp_#x2032 5_amp_#x2032 -dimethylpryrroline-N -oxide (DMPO) 11 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 209719 12654515 280355 22551 11892 TNF TNF TNF-A 19 1.2 neuron-like cell death similar to that of hydrogen peroxide and TNF-_amp_#x3b1 ( Fig 1D 3.2 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209720 12654515 280356 23910 12680 VEGFA VEGF VEGF 0 4.3 VEGF protects from mutant SOD1- TNF-_amp_#x3b1;- and H 2 O 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209721 12654515 280356 20996 11179 SOD1 SOD1 SOD1- 4 1.7 VEGF protects from mutant SOD1- TNF-_amp_#x3b1;- and H 2 O 2 -mediated mouse NSC34 motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209722 12654515 280357 23910 12680 VEGFA VEGF VEGF 0 4.3 VEGF and vehicle pretreated mouse NSC34 cells were infected with adenovirus 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209723 12654515 280357 22551 11892 TNF TNF TNF-A 17 1.2 were infected with adenovirus containing mutant G93A-SOD1 and exposed to TNF-_amp_#x3b1 and hydrogen peroxide respectively 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209724 12654515 280358 23910 12680 VEGFA VEGF VEGF 0 4.3 VEGF treatment was associated with significant increases in cell survival in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209725 12654515 280358 20996 11179 SOD1 SOD1 mSOD1 14 1.7 with significant increases in cell survival in the presence of mSOD1 TNF-_amp_#x3b1 and hydrogen peroxide ( Fig 2 3.3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209726 12654515 280358 22551 11892 TNF TNF TNF-A 15 1.2 significant increases in cell survival in the presence of mSOD1 TNF-_amp_#x3b1 and hydrogen peroxide ( Fig 2 3.3 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209727 12654515 280359 23910 12680 VEGFA VEGF VEGF 0 4.3 VEGF transiently activates PI3-K and MAPK activities 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209728 12654515 280359 16616 8978 PIK3CG PI3K PI3-K 3 2.6 VEGF transiently activates PI3-K and MAPK activities 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209729 12654515 280359 12337 6871 MAPK1 MAPK MAPK 5 2.2 VEGF transiently activates PI3-K and MAPK activities 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209730 12654515 280360 16616 8978 PIK3CG PI3K PI3-K 0 2.6 PI3-K and/or and or MAPK signaling pathways underlie critical components of 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209731 12654515 280360 12337 6871 MAPK1 MAPK MAPK 2 2.2 PI3-K and/or and or MAPK signaling pathways underlie critical components of the survival-related activity of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209732 12654515 280361 23910 12680 VEGFA VEGF VEGF 4 4.3 Thus we tested whether VEGF regulates PI3-K and/or and or MAPK activation in NSC34 cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209733 12654515 280361 16616 8978 PIK3CG PI3K PI3-K 6 2.6 Thus we tested whether VEGF regulates PI3-K and/or and or MAPK activation in NSC34 cells 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209734 12654515 280361 12337 6871 MAPK1 MAPK MAPK 8 2.2 Thus we tested whether VEGF regulates PI3-K and/or and or MAPK activation in NSC34 cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209735 12654515 280362 23910 12680 VEGFA VEGF VEGF 0 4.3 VEGF induced concentration- and time-dependent increases in PI3-K and MAPK activities 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209736 12654515 280362 16616 8978 PIK3CG PI3K PI3-K 7 2.6 VEGF induced concentration- and time-dependent increases in PI3-K and MAPK activities ( Fig 3 and Fig 4 suggesting 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209737 12654515 280362 12337 6871 MAPK1 MAPK MAPK 9 2.2 VEGF induced concentration- and time-dependent increases in PI3-K and MAPK activities ( Fig 3 and Fig 4 suggesting that these 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209738 12654515 280362 23910 12680 VEGFA VEGF VEGF-associated 25 3.8 and Fig 4 suggesting that these pathways may potentially mediate VEGF-associated motor neuron-like cell protection 3.4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209739 12654515 280363 23910 12680 VEGFA VEGF VEGF-mediated 0 3.8 VEGF-mediated PI3-K activity not MAPK activity promotes mouse NSC34 motor neuron-like 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209740 12654515 280363 16616 8978 PIK3CG PI3K PI3-K 1 2.6 VEGF-mediated PI3-K activity not MAPK activity promotes mouse NSC34 motor neuron-like cell 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209741 12654515 280363 12337 6871 MAPK1 MAPK MAPK 4 2.2 VEGF-mediated PI3-K activity not MAPK activity promotes mouse NSC34 motor neuron-like cell survival in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209742 12654515 280363 20996 11179 SOD1 SOD1 SOD1 18 3.7 NSC34 motor neuron-like cell survival in the presence of mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209743 12654515 280364 16616 8978 PIK3CG PI3K PI3-K 8 2.6 To further examine the respective contributions of the PI3-K and MAPK signaling pathways to VEGF-induced cell survival the PI3-K 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209744 12654515 280364 12337 6871 MAPK1 MAPK MAPK 10 2.2 To further examine the respective contributions of the PI3-K and MAPK signaling pathways to VEGF-induced cell survival the PI3-K inhibitors LY294002 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209745 12654515 280364 23910 12680 VEGFA VEGF VEGF-induced 14 3.8 respective contributions of the PI3-K and MAPK signaling pathways to VEGF-induced cell survival the PI3-K inhibitors LY294002 at 50 _amp_#x3bc M 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209746 12654515 280364 16616 8978 PIK3CG PI3K PI3-K 18 2.6 PI3-K and MAPK signaling pathways to VEGF-induced cell survival the PI3-K inhibitors LY294002 at 50 _amp_#x3bc M or Wortmannin at 20 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209747 12654515 280364 12337 6871 MAPK1 MAPK MAPK 34 2.2 at 20 _amp_#x3bc M (data data not shown and the MAPK inhibitor PD98059 at 20 _amp_#x3bc M were administered to the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209748 12654515 280365 16616 8978 PIK3CG PI3K PI3-K 0 2.6 PI3-K blockers reduced NSC34 cell viability even in the presence of 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209749 12654515 280365 23910 12680 VEGFA VEGF VEGF 11 4.3 blockers reduced NSC34 cell viability even in the presence of VEGF ( Fig 5A while PD98059 did not modify cell survival 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209750 12654515 280366 16616 8978 PIK3CG PI3K PI3-K 10 2.6 In addition transfection with the constitutively active catalytic subunit of PI3-K P110 but not with the constitutively active MEK1 the upstream 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209751 12654515 280366 19369 16860 SART3 P110 P110 11 1.3 addition transfection with the constitutively active catalytic subunit of PI3-K P110 but not with the constitutively active MEK1 the upstream activating 1 JUMiner_v2.2 1 0 0 2 2557 TotalCon:2<>2557|CUX1|1523|Complete__16860|SART3|9733|Complete__<>AvaiableGeneRif=2<>BEST:2557|CUX1|0.00106563676060789<>ScoreDetail__16860|SART3|0.000284861985968147__2557|CUX1|0.00106563676060789__ 0 0 0 0 0 209752 12654515 280366 12297 6840 MAP2K1 MEK1 MEK1 18 2.2 subunit of PI3-K P110 but not with the constitutively active MEK1 the upstream activating kinase of ERK prevented mutant G93A-SOD1-mediated NSC34 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209753 12654515 280366 12337 6871 MAPK1 ERK ERK 24 2.2 with the constitutively active MEK1 the upstream activating kinase of ERK prevented mutant G93A-SOD1-mediated NSC34 cell death ( Fig 5B 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.00125947265897189<>ScoreDetail__3393|EPHB2|0.000713962991934831__6871|MAPK1|0.00125947265897189__ 0 0 0 0 0 209754 12654515 280367 16616 8978 PIK3CG PI3K PI3-K 9 2.6 Conversely transfections with the dominant negative regulatory subunit of PI3-K P85 promoted cell death even in the presence of VEGF 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209755 12654515 280367 16618 8979 PIK3R1 P85 P85 10 0.6 Conversely transfections with the dominant negative regulatory subunit of PI3-K P85 promoted cell death even in the presence of VEGF while 1 JUMiner_v2.2 1 0 0 2 8979 TotalCon:3<>8979|PIK3R1|5295|Complete__8980|PIK3R2|5296|Complete__14950|PPP1R13B|23368|Complete__<>AvaiableGeneRif=3<>BEST:8979|PIK3R1|0.000988827623103241<>ScoreDetail__8980|PIK3R2|0.000960689045936396__14950|PPP1R13B|0.000437680693864439__8979|PIK3R1|0.000988827623103241__ 0 0 0 0 0 209756 12654515 280367 23910 12680 VEGFA VEGF VEGF 19 4.3 PI3-K P85 promoted cell death even in the presence of VEGF while transfection with dominant negative MEK1 was void of any 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209757 12654515 280367 12297 6840 MAP2K1 MEK1 MEK1 25 2.2 in the presence of VEGF while transfection with dominant negative MEK1 was void of any effect on NSC34 cell viability after 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209758 12654515 280368 23910 12680 VEGFA VEGF VEGF 4 4.3 Activation of Akt by VEGF contributes to the protection from mutant SOD1-mediated motor neuron-like cell 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209759 12654515 280368 20996 11179 SOD1 SOD1 SOD1-mediated 11 1.7 of Akt by VEGF contributes to the protection from mutant SOD1-mediated motor neuron-like cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209760 12654515 280368 543 391 AKT1 AKT Akt 2 0.1 Activation of Akt by VEGF contributes to the protection from mutant SOD1-mediated motor 6 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209761 12654515 280369 16616 8978 PIK3CG PI3K PI3-K 6 2.6 One of the downstream effectors of PI3-K is Akt activation 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209762 12654515 280369 543 391 AKT1 AKT Akt 8 0.1 One of the downstream effectors of PI3-K is Akt activation 6 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209763 12654515 280370 23910 12680 VEGFA VEGF VEGF 5 4.3 We therefore initially examined whether VEGF treatment of NSC34 cells was associated with Akt phosphorylation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209764 12654515 280370 543 391 AKT1 AKT Akt 13 0.0 examined whether VEGF treatment of NSC34 cells was associated with Akt phosphorylation 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209765 12654515 280371 23910 12680 VEGFA VEGF VEGF 4 4.3 Indeed cells exposed to VEGF displayed concentration- and time-dependent Akt activation ( Fig 5D and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209766 12654515 280371 543 391 AKT1 AKT Akt 9 0.0 Indeed cells exposed to VEGF displayed concentration- and time-dependent Akt activation ( Fig 5D and E 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209767 12654515 280372 23910 12680 VEGFA VEGF VEGF 18 4.3 resulted in a significant reduction in the protective effect by VEGF on survival of NSC34 cells infected with mutant G93A-SOD1 ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209768 12654515 280372 543 391 AKT1 AKT Akt 7 0.0 Overexpression of the dominant negative mutant of Akt resulted in a significant reduction in the protective effect by 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209769 12654515 280373 543 391 AKT1 AKT Akt 6 0.0 In contrast expression of constitutively active Akt increased cell survival despite the presence of mutant G93A-SOD1 ( 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209770 12654515 280374 23910 12680 VEGFA VEGF VEGF 10 4.3 Taken together the data indicate that activation of Akt by VEGF contributes to the protection from NSC34 motor neuron-like cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209771 12654515 280374 20996 11179 SOD1 SOD1 SOD1 26 3.7 NSC34 motor neuron-like cell death associated with expression of mutant SOD1 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209772 12654515 280374 543 391 AKT1 AKT Akt 8 0.1 Taken together the data indicate that activation of Akt by VEGF contributes to the protection from NSC34 motor neuron-like 6 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209773 12654515 280376 23910 12680 VEGFA VEGF VEGF 6 4.3 In this study we show that VEGF administration significantly protects from the decreased cell viability induced by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209774 12654515 280377 23910 12680 VEGFA VEGF VEGF 8 4.3 We further demonstrate that the protective effects of VEGF are critically dependent on the activation of the PI3-K-Akt pathway 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209775 12654515 280377 12337 6871 MAPK1 MAPK MAPK 22 2.2 on the activation of the PI3-K-Akt pathway and independent of MAPK activation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209776 12654515 280378 23910 12680 VEGFA VEGF VEGF 11 4.3 lines of evidence prompted us to examine the effects of VEGF on mutant SOD1-mediated motor neuron-like cell death (i) i VEGF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209777 12654515 280378 20996 11179 SOD1 SOD1 SOD1-mediated 14 1.7 prompted us to examine the effects of VEGF on mutant SOD1-mediated motor neuron-like cell death (i) i VEGF acts as a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209778 12654515 280378 23910 12680 VEGFA VEGF VEGF 20 4.3 VEGF on mutant SOD1-mediated motor neuron-like cell death (i) i VEGF acts as a neurotrophic factor preventing hypoxia (ischemia)-mediated ischemia -mediated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209779 12654515 280378 23910 12680 VEGFA VEGF VEGF 62 4.3 (iii) iii disruption of the hypoxic response elements in the VEGF promoter region of transgenic mice elicits a pattern of motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209780 12654515 280378 20996 11179 SOD1 ALS ALS 81 1.7 of motor neuron degeneration that markedly resembles that of human ALS in a mouse model 40 and (iv) iv mutations of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00211663176525962<>ScoreDetail__5468|IGFALS|0.000441164674741317__11179|SOD1|0.00211663176525962__ 0 0 0 0 0 209781 12654515 280378 20996 11179 SOD1 SOD1 SOD1 93 3.7 in a mouse model 40 and (iv) iv mutations of SOD1 result in enhanced oxidative stress and contribute at least partially 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209782 12654515 280379 23910 12680 VEGFA VEGF VEGF 7 4.3 Thus one of the beneficial effects of VEGF on cell survival could theoretically be ascribed to a protective 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209783 12654515 280380 23910 12680 VEGFA VEGF VEGF 7 4.3 Our findings confirm such an hypothesis whereby VEGF is effective in preventing mutant SOD1-induced mouse NSC34 motor neuron-like 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209784 12654515 280380 20996 11179 SOD1 SOD1 SOD1-induced 13 1.7 such an hypothesis whereby VEGF is effective in preventing mutant SOD1-induced mouse NSC34 motor neuron-like cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209785 12654515 280381 23910 12680 VEGFA VEGF VEGF 0 4.3 VEGF was initially identified as an angiogenic factor that stimulates endothelial 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209786 12654515 280382 23910 12680 VEGFA VEGF VEGF 2 4.3 More recently VEGF was shown to induce neuroprotective functions both in vitro and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209787 12654515 280383 23910 12680 VEGFA VEGF VEGF 2 4.3 For example VEGF rescues HN33 and hippocampal neuronal cells from the apoptosis induced 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209788 12654515 280384 23910 12680 VEGFA VEGF VEGF 1 4.3 Furthermore VEGF exerts direct neurotrophic effects on axonal outgrowth and neuronal survival 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209789 12654515 280385 23910 12680 VEGFA VEGF VEGF 5 4.3 Our current findings indicate that VEGF promotes motor neuron-like cell survival in the presence of mutant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209790 12654515 280385 20996 11179 SOD1 SOD1 SOD1 16 3.7 promotes motor neuron-like cell survival in the presence of mutant SOD1 thereby supporting the notion that deficits in VEGF protein induction 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209791 12654515 280385 23910 12680 VEGFA VEGF VEGF 24 4.3 of mutant SOD1 thereby supporting the notion that deficits in VEGF protein induction or release may contribute to motor neuron degeneration 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209792 12654515 280386 23910 12680 VEGFA VEGF VEGF 5 4.3 These results also suggest that VEGF may have beneficial therapeutic effects in the prevention of motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209793 12654515 280386 20996 11179 SOD1 ALS ALS 20 1.7 effects in the prevention of motor neuron degeneration in human ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00211663176525962<>ScoreDetail__5468|IGFALS|0.000441164674741317__11179|SOD1|0.00211663176525962__ 0 0 0 0 0 209794 12654515 280387 23910 12680 VEGFA VEGF VEGF 5 4.3 It is well established that VEGF can activate both PI3-K and MAPK (MEK/ERK) MEK ERK pathways 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209795 12654515 280387 16616 8978 PIK3CG PI3K PI3-K 9 2.6 It is well established that VEGF can activate both PI3-K and MAPK (MEK/ERK) MEK ERK pathways yet the protective effect 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209796 12654515 280387 12337 6871 MAPK1 MAPK MAPK 11 2.2 is well established that VEGF can activate both PI3-K and MAPK (MEK/ERK) MEK ERK pathways yet the protective effect of VEGF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209797 12654515 280387 12337 6871 MAPK1 ERK ERK 12 2.2 that VEGF can activate both PI3-K and MAPK (MEK/ERK) MEK ERK pathways yet the protective effect of VEGF on motor neuron-like 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.00125947265897189<>ScoreDetail__3393|EPHB2|0.000713962991934831__6871|MAPK1|0.00125947265897189__ 0 0 0 0 0 209798 12654515 280387 23910 12680 VEGFA VEGF VEGF 19 4.3 MAPK (MEK/ERK) MEK ERK pathways yet the protective effect of VEGF on motor neuron-like cell survival upon the expression of mutant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209799 12654515 280388 12337 6871 MAPK1 MAPK MAPK 8 2.2 While the specific functional roles played by the MAPK pathway are unclear it is likely that this pathway may 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209800 12654515 280388 12297 6840 MAP2K1 MEK1 MEK1-treated 32 2.2 proliferation of motor neuron-like cells because PD98059 and dominant negative MEK1-treated cells reduced cell proliferation (data data not shown 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 209801 12654515 280389 16616 8978 PIK3CG PI3K PI3-K 18 2.6 of Matsuzaki et al 34 who showed that both the PI3-K and MAPK pathways participate in neuronal cell protection by VEGF 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209802 12654515 280389 12337 6871 MAPK1 MAPK MAPK 20 2.2 et al 34 who showed that both the PI3-K and MAPK pathways participate in neuronal cell protection by VEGF against glutamate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209803 12654515 280389 23910 12680 VEGFA VEGF VEGF 28 4.3 PI3-K and MAPK pathways participate in neuronal cell protection by VEGF against glutamate excitotoxicity in primary rat hippocampal neuronal cultures 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209804 12654515 280390 20996 11179 SOD1 SOD1 SOD1 49 3.7 intrinsic characteristics of the neurotoxic initiators (glutamate glutamate vs mutant SOD1 leading to heterogeneities in downstream kinase recruitment and regulation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209805 12654515 280391 16616 8978 PIK3CG PI3K PI3-K 10 2.6 It has become apparent that activation of kinases such as PI3-K or MAPK does not constitute an isolated event but rather 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209806 12654515 280391 12337 6871 MAPK1 MAPK MAPK 12 2.2 become apparent that activation of kinases such as PI3-K or MAPK does not constitute an isolated event but rather represents a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209807 12654515 280393 16616 8978 PIK3CG PI3K PI3-K 6 2.6 Thus it is possible that the PI3-K/Akt PI3-K Akt signaling module recruited by VEGF in our experiments is 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209808 12654515 280393 23910 12680 VEGFA VEGF VEGF 11 4.3 possible that the PI3-K/Akt PI3-K Akt signaling module recruited by VEGF in our experiments is associated with survival and the activation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209809 12654515 280393 12337 6871 MAPK1 MAPK MAPK-related 23 2.2 our experiments is associated with survival and the activation of MAPK-related signaling pathways is primarily related to proliferation in mouse NSC34 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209810 12654515 280393 543 391 AKT1 AKT Akt 6 0.3 Thus it is possible that the PI3-K/Akt PI3-K Akt signaling module recruited by VEGF in our experiments is associated 4 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209811 12654515 280394 16616 8978 PIK3CG PI3K PI3-K 16 2.6 activation is essential for implementation of the protective effect by PI3-K on mutant G93A-SOD1-mediated motor neuron-like cell survival 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209812 12654515 280394 543 391 AKT1 AKT Akt 5 0.0 Our experiments further revealed that Akt activation is essential for implementation of the protective effect by 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209813 12654515 280395 23910 12680 VEGFA VEGF VEGF 11 4.3 expression of dominant negative Akt blocked the protective function of VEGF while the expression of constitutively active Akt partially prevented mutant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209814 12654515 280395 20996 11179 SOD1 SOD1 SOD1-mediated 22 1.7 while the expression of constitutively active Akt partially prevented mutant SOD1-mediated motor neuron-like cell death even in the absence of VEGF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209815 12654515 280395 23910 12680 VEGFA VEGF VEGF 32 4.3 SOD1-mediated motor neuron-like cell death even in the absence of VEGF ( Fig 5F 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209816 12654515 280395 543 391 AKT1 AKT Akt 5 0.0 Indeed expression of dominant negative Akt blocked the protective function of VEGF while the expression of 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209817 12654515 280395 543 391 AKT1 AKT Akt 18 0.0 protective function of VEGF while the expression of constitutively active Akt partially prevented mutant SOD1-mediated motor neuron-like cell death even in 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209818 12654515 280396 16616 8978 PIK3CG PI3K PI3-K 17 2.6 is now well established as a critical protein activated by PI3-K governing the balance between survival and apoptosis 7 and 13 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209819 12654515 280396 543 391 AKT1 AKT Akt 6 0.0 These findings are not surprising since Akt is now well established as a critical protein activated by 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209820 12654515 280397 543 391 AKT1 AKT Akt 2 0.0 Once phosphorylated Akt has been demonstrated to promote cell survival by inactivation of 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209821 12654515 280398 23910 12680 VEGFA VEGF VEGF 10 4.3 It is unclear what apoptosis-related targets are specifically repressed by VEGF in the mutant SOD1-infected NSC34 motor neuron-like system 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209822 12654515 280398 20996 11179 SOD1 SOD1 SOD1-infected 14 1.7 apoptosis-related targets are specifically repressed by VEGF in the mutant SOD1-infected NSC34 motor neuron-like system 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209823 12654515 280399 23910 12680 VEGFA VEGF VEGF 8 4.3 However several lines of evidence suggest that the VEGF/Akt VEGF Akt pathway is particularly important to neuronal survival 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209824 12654515 280399 543 391 AKT1 AKT Akt 8 0.3 However several lines of evidence suggest that the VEGF/Akt VEGF Akt pathway is particularly important to neuronal survival 4 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209825 12654515 280400 23910 12680 VEGFA VEGF VEGF 12 4.3 exposed to a pre-conditioning hypoxic stimulus up-regulated the expression of VEGF and Akt and the activity of the latter was critical 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209826 12654515 280400 543 391 AKT1 AKT Akt 14 0.1 a pre-conditioning hypoxic stimulus up-regulated the expression of VEGF and Akt and the activity of the latter was critical to increased 6 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209827 12654515 280401 543 391 AKT1 AKT Akt 4 0.0 Similarly expression of active Akt suppressed mouse hippocampal neuronal death induced by hypoxia glutamate or 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209828 12654515 280402 543 391 AKT1 AKT Akt 4 0.0 In addition activation of Akt was tightly linked to neuronal cell survival after traumatic brain 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209829 12654515 280404 23910 12680 VEGFA VEGF VEGF 9 4.3 Taken together these results suggest that hypoxia modulation of VEGF expression (activity) activity is essential to motor neuron survival 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209830 12654515 280405 16616 8978 PIK3CG PI3K PI3-K 7 2.6 We now demonstrate that the activation of PI3-K/Akt PI3-K Akt signaling pathways by VEGF can promote motor neuron-like cell 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209831 12654515 280405 23910 12680 VEGFA VEGF VEGF 11 4.3 that the activation of PI3-K/Akt PI3-K Akt signaling pathways by VEGF can promote motor neuron-like cell survival in the presence of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209832 12654515 280405 20996 11179 SOD1 SOD1 SOD1 23 3.7 promote motor neuron-like cell survival in the presence of mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209833 12654515 280405 543 391 AKT1 AKT Akt 7 0.3 We now demonstrate that the activation of PI3-K/Akt PI3-K Akt signaling pathways by VEGF can promote motor neuron-like cell survival 4 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209834 12654515 280406 16616 8978 PIK3CG PI3K PI3-K 5 2.6 However since the activation of PI3-K/Akt PI3-K Akt is a transient event ( Fig 4 the long-lasting 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209835 12654515 280406 23910 12680 VEGFA VEGF VEGF 19 4.3 transient event ( Fig 4 the long-lasting protective function of VEGF on mutant SOD1-mediated motor neuron-like cell death may be due 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209836 12654515 280406 20996 11179 SOD1 SOD1 SOD1-mediated 22 1.7 Fig 4 the long-lasting protective function of VEGF on mutant SOD1-mediated motor neuron-like cell death may be due to the modulation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209837 12654515 280406 543 391 AKT1 AKT Akt 5 0.3 However since the activation of PI3-K/Akt PI3-K Akt is a transient event ( Fig 4 the long-lasting protective 4 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209838 12654515 280407 23910 12680 VEGFA VEGF VEGF 6 4.3 In summary we have shown that VEGF can protect from mutant SOD1- and oxidative stress-mediated motor neuron-like 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209839 12654515 280407 20996 11179 SOD1 SOD1 SOD1- 11 1.7 summary we have shown that VEGF can protect from mutant SOD1- and oxidative stress-mediated motor neuron-like cell death in a cell 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209840 12654515 280408 16616 8978 PIK3CG PI3K PI3-K 13 2.6 pharmacological and molecular genetic approaches we have demonstrated that PI3-K/Akt PI3-K Akt activation is the primary contributor to the neuroprotective function 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209841 12654515 280408 23910 12680 VEGFA VEGF VEGF 24 4.3 activation is the primary contributor to the neuroprotective function of VEGF in mouse NSC34 motor neuron-like cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209842 12654515 280408 543 391 AKT1 AKT Akt 13 0.3 and molecular genetic approaches we have demonstrated that PI3-K/Akt PI3-K Akt activation is the primary contributor to the neuroprotective function of 4 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209843 12654515 280409 20996 11179 SOD1 ALS ALS 20 1.7 interventional strategies aiming to alleviate motor neuron degeneration in human ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00211663176525962<>ScoreDetail__5468|IGFALS|0.000441164674741317__11179|SOD1|0.00211663176525962__ 0 0 0 0 0 209844 12654515 280411 20996 11179 SOD1 SOD1 mSOD1 4 1.7 Expression of mutant G93A-SOD1 (mSOD1) mSOD1 increased NSC34 motor neuron-like cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209845 12654515 280412 20996 11179 SOD1 SOD1 SOD1 4 3.7 (A) A Western analysis of SOD1 expression in NSC34 motor neuron-like cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209846 12654515 280413 3778 10620 CCL21 ECL ECL 26 0.0 a nitrocellulose membrane immunoreacted with anti-SOD1 antibody and detected by ECL 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209847 12654515 280414 20996 11179 SOD1 SOD1 mSOD1 5 1.7 (B) B Expression of mutant G93A-SOD1 (mSOD1) mSOD1 increased cellular production of reactive oxygen species 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209848 12654515 280415 18723 10261 ROS1 ROS ROS 3 0.3 DCF assay of ROS production in NSC34 cells infected with vector control WT-SOD1 or 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 209849 12654515 280419 22551 11892 TNF TNF TNF-A 19 1.2 with WT-SOD1 mutant G93A-SOD1 or treated with hydrogen peroxide or TNF-_amp_#x3b1 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209850 12654515 280422 23910 12680 VEGFA VEGF VEGF 0 4.3 VEGF reduced hydrogen peroxide- TNF-_amp_#x3b1;- and mutant SOD1-mediated NSC34 motor neuron-like 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209851 12654515 280422 20996 11179 SOD1 SOD1 SOD1-mediated 7 1.7 VEGF reduced hydrogen peroxide- TNF-_amp_#x3b1;- and mutant SOD1-mediated NSC34 motor neuron-like cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209852 12654515 280423 23910 12680 VEGFA VEGF VEGF 1 4.3 (A) A VEGF reduced hydrogen peroxide-mediated NSC34 motor neuron-like cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209853 12654515 280424 23910 12680 VEGFA VEGF VEGF 8 4.3 NSC34 cells were pretreated with 100 ng/ml ng ml of VEGF or vehicle control for 30 min and then exposed to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209854 12654515 280426 22551 11892 TNF TNF TNF-A 13 1.2 A except that cells were treated with different concentrations of TNF-_amp_#x3b1 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209855 12654515 280429 23910 12680 VEGFA VEGF VEGF 0 4.3 VEGF activated MAPK activity in mouse NSC34 motor neuron-like cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209856 12654515 280429 12337 6871 MAPK1 MAPK MAPK 2 2.2 VEGF activated MAPK activity in mouse NSC34 motor neuron-like cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209857 12654515 280430 23910 12680 VEGFA VEGF VEGF 11 4.3 with different doses (25_amp_#x2013;200 25_amp_#x2013 200 ng/ml) ng ml of VEGF and then assayed for ERK1/2 ERK1 2 phosphorylation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209858 12654515 280430 12339 6877 MAPK3 ERK1 ERK1 16 2.7 ng/ml) ng ml of VEGF and then assayed for ERK1/2 ERK1 2 phosphorylation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209859 12654515 280431 12337 6871 MAPK1 MAPK MAPK 4 2.2 (B) B The increase of MAPK activity in three independent experiments compared to that of vector 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209860 12654515 280431 12339 6877 MAPK3 ERK1 Erk1 18 2.7 independent experiments compared to that of vector control calibrated by Erk1 expression (mean_amp_#xb1;S.E.M.; mean_amp_#xb1 S.E.M. n =3 *statistically significant compared to 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209861 12654515 280432 23910 12680 VEGFA VEGF VEGF 9 4.3 NSC34 cells were treated with 100 ng/ml ng ml of VEGF for different lengths of time (30_amp_#x2013;180 30_amp_#x2013 180 min and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209862 12654515 280432 12339 6877 MAPK3 ERK1 ERK1 21 2.7 time (30_amp_#x2013;180 30_amp_#x2013 180 min and then assayed for ERK1/2 ERK1 2 phosphorylation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209863 12654515 280433 12337 6871 MAPK1 MAPK MAPK 4 2.2 (D) D The increase of MAPK activity in three independent experiments compared to that of vector 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209864 12654515 280433 12339 6877 MAPK3 ERK1 Erk1 18 2.7 independent experiments compared to that of vector control calibrated by Erk1 expression (mean_amp_#xb1;S.E.M.; mean_amp_#xb1 S.E.M. n =3 *statistically significant compared to 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209865 12654515 280435 23910 12680 VEGFA VEGF VEGF 0 4.3 VEGF activated PI3-K activity in mouse NSC34 motor neuron-like cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209866 12654515 280435 16616 8978 PIK3CG PI3K PI3-K 2 2.6 VEGF activated PI3-K activity in mouse NSC34 motor neuron-like cells 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209867 12654515 280436 23910 12680 VEGFA VEGF VEGF 9 4.3 (A) A NSC34 cells were treated with different doses of VEGF (25_amp_#x2013;200 25_amp_#x2013 200 ng/ml) ng ml and then assayed for 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209868 12654515 280436 16616 8978 PIK3CG PI3K PI3-K 16 2.6 (25_amp_#x2013;200 25_amp_#x2013 200 ng/ml) ng ml and then assayed for PI3-K activity as described in Materials and methods 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209869 12654515 280437 16616 8978 PIK3CG PI3K PI3-K 4 2.6 (B) B The increase of PI3-K activity in three independent experiments compared to that of vector 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209870 12654515 280438 23910 12680 VEGFA VEGF VEGF 9 4.3 NSC34 cells were treated with 100 ng/ml ng ml of VEGF for different lengths of time (30_amp_#x2013;180 30_amp_#x2013 180 min and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209871 12654515 280438 16616 8978 PIK3CG PI3K PI3-K 21 2.6 of time (30_amp_#x2013;180 30_amp_#x2013 180 min and then assayed for PI3-K activity as described in Materials and methods 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209872 12654515 280439 16616 8978 PIK3CG PI3K PI3-K 4 2.6 (D) D The increase of PI3-K activity in three independent experiments compared to that of vector 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209873 12654515 280441 16616 8978 PIK3CG PI3K PI3-K 2 2.6 Activation of PI3-K/Akt PI3-K Akt pathways by VEGF contributed to the protection from mutant 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209874 12654515 280441 23910 12680 VEGFA VEGF VEGF 5 4.3 Activation of PI3-K/Akt PI3-K Akt pathways by VEGF contributed to the protection from mutant G93A-SOD1-mediated NSC34 motor neuron-like 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209875 12654515 280441 543 391 AKT1 AKT Akt 2 0.3 Activation of PI3-K/Akt PI3-K Akt pathways by VEGF contributed to the protection from mutant G93A-SOD1-mediated 4 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209876 12654515 280442 16616 8978 PIK3CG PI3K PI3-K 1 2.6 (A) A PI3-K activity inhibitor LY294002 not MAPK activity inhibitor PD98059 contributed to 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209877 12654515 280442 12337 6871 MAPK1 MAPK MAPK 6 2.2 (A) A PI3-K activity inhibitor LY294002 not MAPK activity inhibitor PD98059 contributed to the loss of the protection 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209878 12654515 280443 16616 8978 PIK3CG PI3K PI3-K 3 2.6 (B) B Constitutively active PI3-K catalytic subunit (p110), p110 not constitutively active MEK1 contributed to 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209879 12654515 280443 19369 16860 SART3 p110 p110 6 1.3 (B) B Constitutively active PI3-K catalytic subunit (p110), p110 not constitutively active MEK1 contributed to the protection from NSC34 1 JUMiner_v2.2 1 0 0 2 2557 TotalCon:2<>2557|CUX1|1523|Complete__16860|SART3|9733|Complete__<>AvaiableGeneRif=2<>BEST:2557|CUX1|0.00106563676060789<>ScoreDetail__16860|SART3|0.000284861985968147__2557|CUX1|0.00106563676060789__ 0 0 0 0 0 209880 12654515 280443 12297 6840 MAP2K1 MEK1 MEK1 10 2.2 Constitutively active PI3-K catalytic subunit (p110), p110 not constitutively active MEK1 contributed to the protection from NSC34 cell death from mutant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209881 12654515 280444 16618 8979 PIK3R1 p85 p85 3 0.6 (C) C Dominant negative p85 of PI3-K regulatory subunit not dominant negative MEK1 contributed to 1 JUMiner_v2.2 1 0 0 2 8979 TotalCon:3<>8979|PIK3R1|5295|Complete__8980|PIK3R2|5296|Complete__14950|PPP1R13B|23368|Complete__<>AvaiableGeneRif=3<>BEST:8979|PIK3R1|0.000988827623103241<>ScoreDetail__8980|PIK3R2|0.000960689045936396__14950|PPP1R13B|0.000437680693864439__8979|PIK3R1|0.000988827623103241__ 0 0 0 0 0 209882 12654515 280444 16616 8978 PIK3CG PI3K PI3-K 5 2.6 (C) C Dominant negative p85 of PI3-K regulatory subunit not dominant negative MEK1 contributed to the loss 11 JUMiner_v2.2 1 0 0 2 8978 TotalCon:3<>8975|PIK3CA|5290|Complete__8976|PIK3CB|5291|Complete__8978|PIK3CG|5294|Complete__<>AvaiableGeneRif=3<>BEST:8978|PIK3CG|0.00112435358630161<>ScoreDetail__8976|PIK3CB|0.000793446835849663__8978|PIK3CG|0.00112435358630161__8975|PIK3CA|0.000955397649064189__ 0 0 0 0 0 209883 12654515 280444 12297 6840 MAP2K1 MEK1 MEK1 11 2.2 Dominant negative p85 of PI3-K regulatory subunit not dominant negative MEK1 contributed to the loss of the protection from NSC34 cell 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209884 12654515 280445 23910 12680 VEGFA VEGF VEGF 9 4.3 NSC34 cells were treated with 100 ng/ml ng ml of VEGF for different lengths of time (30_amp_#x2013;180 30_amp_#x2013 180 min and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209885 12654515 280445 543 391 AKT1 AKT Akt 21 0.0 of time (30_amp_#x2013;180 30_amp_#x2013 180 min and then assayed for Akt activation as described in Materials and methods 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209886 12654515 280446 543 391 AKT1 AKT Akt 4 0.0 (E) E The increase of Akt activation in three independent experiments compared to that of vector 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209887 12654515 280447 23910 12680 VEGFA VEGF VEGF 15 4.3 while dominant negative Akt partially abolished the protective function of VEGF on NSC34 motor neuron survival upon expression of mutant G93A-SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 209888 12654515 280447 543 391 AKT1 AKT Akt 3 0.0 (F) F Constitutively active Akt enhanced while dominant negative Akt partially abolished the protective function 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 209889 12654515 280447 543 391 AKT1 AKT Akt 8 0.0 (F) F Constitutively active Akt enhanced while dominant negative Akt partially abolished the protective function of VEGF on NSC34 motor 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 211262 12663085 281718 1607 1014 BCR CML CML 7 0.9 characterized major AGE are N -(carboxymethyl)lysine - carboxymethyl lysine (CML) CML 18 pentosidine 16 pyrraline 57 and imidazolon 63 ( Fig 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211263 12663085 281724 20996 11179 SOD1 ALS ALS 36 1.4 AD Parkinson_amp_#x2019 s disease 10 and amyotrophic lateral sclerosis (ALS) ALS 15 and 88 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211264 12663085 281727 20996 11179 SOD1 ALS ALS 21 1.4 product an early compound in the glycation reaction in the ALS spinal cord 39 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211265 12663085 281728 20996 11179 SOD1 ALS ALS 11 1.4 number of other reports indicate an association of glycation with ALS 15 and 88 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211266 12663085 281738 20996 11179 SOD1 ALS ALS 8 1.4 Finally we review the evidence of glycation in ALS spinal cords and then discuss its neurotoxicity on cultured spinal 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211267 12663085 281765 1607 1014 BCR CML CML 5 0.9 Structure-identified AGE include N -(carboxymethyl)lysine - carboxymethyl lysine (CML) CML 18 pentosidine 16 and 23 pyrraline 57 imidazolon 63 crosslin 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211268 12663085 281766 1607 1014 BCR CML CML 0 0.9 CML is formed from fructose lysine (one one of the Amadori 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211269 12663085 281767 1607 1014 BCR CML CML 7 0.9 In addition to glucose other sources of CML include unsaturated fatty acids such as oleic acid and linoleic 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211270 12663085 281768 1607 1014 BCR CML CML 3 0.9 The idea that CML is a marker of oxidation rather than of glycation is 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211271 12663085 281770 4682 2197 COL1A1 collagen collagen 4 0.3 Pentosidine increases in skin collagen and lens crystallin rectilinearly with age 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211272 12663085 281777 1607 1014 BCR CML CML 0 0.9 CML and pyrraline in contrast do not provide cross-linkage 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211273 12663085 281788 20996 11179 SOD1 ALS ALS 5 1.4 A common pathological finding in ALS is the presence of an abnormal accumulation of neurofilaments (hyaline 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211274 12663085 281789 14282 7739 NEFL NF-L NF-L 10 1.6 have three isoforms which are referred to as light (NF-L), NF-L medium (NF-M), NF-M and heavy chains (NF-H) NF-H 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211275 12663085 281789 14285 7734 NEFM NF-M NF-M 12 1.6 which are referred to as light (NF-L), NF-L medium (NF-M), NF-M and heavy chains (NF-H) NF-H 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211276 12663085 281789 14280 7737 NEFH NFH NF-H 16 0.6 light (NF-L), NF-L medium (NF-M), NF-M and heavy chains (NF-H) NF-H 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211277 12663085 281790 14280 7737 NEFH NFH NF-H 4 0.6 The tail domain of NF-H has multiple repeats of Lys_amp_#x2013 Ser_amp_#x2013 Pro (KSP), KSP accounting 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211278 12663085 281796 12369 6893 MAPT tau tau 7 0.9 Inclusion bodies and intracellular deposits associated with tau are implicated in AD and other neurodegenerative diseases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211279 12663085 281797 12369 6893 MAPT tau tau 3 0.9 The glycation of tau has also been extensively studied with regard to AD 49 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211280 12663085 281798 12369 6893 MAPT tau tau 10 0.9 probed in soluble and insoluble PHF (paired paired helical filaments -tau from AD brains using anti-CML antibody 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211281 12663085 281799 12369 6893 MAPT tau tau 4 0.9 The results demonstrated that tau becomes glycated in PHF-tau and that the glycation may play 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211282 12663085 281800 12369 6893 MAPT tau tau 1 0.9 Glycated tau exhibited a loss of capacity in the promotion of microtubule 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211283 12663085 281801 20996 11179 SOD1 SOD1 SOD-1 6 2.7 Since mutations of the superoxide dismutase-1 (SOD-1) SOD-1 gene were first identified in 1993 it has been considered 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211284 12663085 281801 20996 11179 SOD1 ALS ALS 22 1.4 1993 it has been considered a possible cause of familial ALS (FALS) FALS 76 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211285 12663085 281802 20996 11179 SOD1 SOD1 SOD-1 5 2.7 Bredesen advocated the possibility that SOD-1 even plays a role in sporadic ALS 7 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211286 12663085 281802 20996 11179 SOD1 ALS ALS 12 1.4 the possibility that SOD-1 even plays a role in sporadic ALS 7 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211287 12663085 281803 20996 11179 SOD1 SOD1 SOD-1 3 2.7 The glycation of SOD-1 under diabetic conditions has been studied extensively by Taniguchi et 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211288 12663085 281804 20996 11179 SOD1 SOD1 SOD-1 5 2.7 Glycation prompts the degradation of SOD-1 70 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211289 12663085 281805 20996 11179 SOD1 SOD1 SOD-1 11 2.7 the lens of diabetic rats glycation and the degradation of SOD-1 were clearly recognized 104 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211290 12663085 281806 20996 11179 SOD1 SOD1 SOD-1 1 2.7 Mutant SOD-1 is more easily glycated than normal SOD-1 and would therefore 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211291 12663085 281806 20996 11179 SOD1 SOD1 SOD-1 8 2.7 Mutant SOD-1 is more easily glycated than normal SOD-1 and would therefore be more rapidly degraded 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211292 12663085 281807 20996 11179 SOD1 SOD1 SOD-1 3 2.7 In addition mutant SOD-1 has a low affinity for copper 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211293 12663085 281808 20996 11179 SOD1 SOD1 SOD-1 6 2.7 Copper released from mutant or glycated SOD-1 would promote the generation of hydroxyl radicals by the Fenton 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211294 12663085 281812 5546 2728 DDOST AGE-R1 AGE-R1 19 3.3 receptor function three proteins have been reported as AGE-binding proteins AGE-R1 (oligosaccharyl oligosaccharyl transferase complex protein 48 (OST48)), OST48 AGE-R2 (80K-H 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211295 12663085 281812 5546 2728 DDOST OST48 OST48 25 3.0 AGE-binding proteins AGE-R1 (oligosaccharyl oligosaccharyl transferase complex protein 48 (OST48)), OST48 AGE-R2 (80K-H 80K-H protein and AGE-R3 (galectin-3) galectin-3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211296 12663085 281812 17314 9411 PRKCSH AGE-R2 AGE-R2 26 3.5 proteins AGE-R1 (oligosaccharyl oligosaccharyl transferase complex protein 48 (OST48)), OST48 AGE-R2 (80K-H 80K-H protein and AGE-R3 (galectin-3) galectin-3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211297 12663085 281813 926 620 APP amyloid amyloid 12 1.0 al demonstrated that RAGE and SR mediate cell adhesion to amyloid _amp_#x3b2 protein (A_amp_#x3b2;) A_amp_#x3b2 and induction of oxidative stress 118 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 211298 12663085 281830 9462 5013 HMOX1 HO-1 HO-1 4 1.0 AGE coexisted with hemeoxygenase-1 (HO-1) HO-1 on neurofibrillary tangles 119 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211299 12663085 281831 9462 5013 HMOX1 HO-1 HO-1 1 1.0 Since HO-1 is induced under oxidative stress it was speculated that reactive 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211300 12663085 281831 12369 6893 MAPT tau tau 17 0.9 it was speculated that reactive oxygen species were produced by tau modified with AGE leading to the induction of HO-1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211301 12663085 281831 9462 5013 HMOX1 HO-1 HO-1 26 1.0 by tau modified with AGE leading to the induction of HO-1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211302 12663085 281834 12369 6893 MAPT tau tau 5 0.9 In vitro glycation of A_amp_#x3b2 tau and apoprotein E (apoE), apoE and their effects were investigated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211303 12663085 281834 912 613 APOE apoprotein apoprotein 7 1.0 In vitro glycation of A_amp_#x3b2 tau and apoprotein E (apoE), apoE and their effects were investigated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211304 12663085 281834 912 613 APOE APOE apoE 9 1.0 In vitro glycation of A_amp_#x3b2 tau and apoprotein E (apoE), apoE and their effects were investigated 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211305 12663085 281836 12369 6893 MAPT tau tau 7 0.9 In addition to hyperphosphorylation the glycation of tau leads to the formation of paired helical filaments in AD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211306 12663085 281837 912 613 APOE APOE apoE 3 1.0 The glycation of apoE impairs its binding to heparin 93 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211307 12663085 281838 12369 6893 MAPT tau tau 1 0.9 AGE-modified tau produced reactive oxygen species in cultured cells and also caused 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211308 12663085 281845 18723 10261 ROS1 ROS ROS 13 0.0 A_amp_#x3b2 can form aggregates and produce reactive oxygen species (ROS) ROS even if it is not modified by AGE 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211309 12663085 281853 1607 1014 BCR CML CML 0 0.9 CML is reported to increase with aging in the pyramidal neurons 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211310 12663085 281857 1607 1014 BCR CML CML 6 0.9 In AD brains the presence of CML was confirmed both inside and outside the cytoplasm of neurons 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211311 12663085 281858 1607 1014 BCR CML CML 1 0.9 However CML is also present in the cytoplasm of neurons of healthy 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211312 12663085 281859 1607 1014 BCR CML CML 3 0.9 In addition the CML outside the cytoplasm of neurons was not related to senile 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211313 12663085 281860 1607 1014 BCR CML CML 3 0.9 AGE (pentosidine pentosidine and CML are co-localized with lipofuscin outside the cytoplasm of neurons 26 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211314 12663085 281862 1607 1014 BCR CML CML 6 0.9 The presence of extraneuroperikaryal pentosidine and CML was finally confirmed in astrocytes and microglias and this was 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211315 12663085 281863 1607 1014 BCR CML CML 0 0.9 CML and pentosidine have recently become to be considered as markers 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211316 12663085 281864 3355 1374 CA3 CA3 CA3 20 0.0 identified in the perikaryon of hippocampal neurons (especially especially forms CA3 and CA4 in all subjects (AD AD and diabetes mellitus 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211317 12663085 281864 3356 1375 CA4 CA4 CA4 20 0.0 identified in the perikaryon of hippocampal neurons (especially especially forms CA3 and CA4 in all subjects (AD AD and diabetes mellitus 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211318 12663085 281864 3356 1375 CA4 CA4 CA4 22 0.0 the perikaryon of hippocampal neurons (especially especially forms CA3 and CA4 in all subjects (AD AD and diabetes mellitus (DM) DM 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211319 12663085 281876 14535 7873 NOS2A iNOS iNOS 10 2.7 Wong et al reported that AGE-positive astrocytes and microglia expressing iNOS were found in AD brains and concluded that the activation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211320 12663085 281880 1607 1014 BCR CML CML 7 0.9 This antibody does not recognize pyrraline pentosidine CML FFP 2-furoyl-4 5 - 2-furanyl -1-H -imidazole or AFGP (1-alkyl-2-formyl-3,4-diglycosyl-pyrroles) 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211321 12663085 281884 1607 1014 BCR CML CML 15 0.9 Castellani et al 11 concerned in situ techniques to assess CML the predominant advanced glycation end-product that accumulates in vivo along 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211322 12663085 281885 1607 1014 BCR CML CML 4 0.9 The levels of both CML and hexitol-lysine increased in the neurons especially in those cases 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211323 12663085 281886 1607 1014 BCR CML CML 10 0.9 findings of concurrent increases in both the end-stage modification (CML) CML and the initial Amadori products of sugar adduction provide evidence 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211324 12663085 281887 1607 1014 BCR CML CML 3 0.9 In addition because CML can result from either lipid peroxidation or advanced glycation whereas 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211325 12663085 281887 6554 3309 ELA2 HNE HNE 31 0.3 study together with studies demonstrating the presence of 4-hydroxy-2-nonenal (HNE) HNE adducts and pentosidine provides evidence of two distinct processes acting 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 211326 12663085 281889 926 620 APP amyloid amyloid 6 1.0 In this study most of the amyloid core of a subset of senile plaques showed no staining 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 211327 12663085 281889 1607 1014 BCR CML CML 22 0.9 senile plaques showed no staining or only faint immunoreactivity for CML 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211328 12663085 281890 1607 1014 BCR CML CML 16 0.9 both AD cases and in the controls with antibodies to CML and hexigtol-lysine 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211329 12663085 281892 1607 1014 BCR CML CML 18 0.9 control subject also showed strong labeling with the antibodies to CML and hexitol-lysine supporting the hypothesis that glycation is an early 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211330 12663085 281895 1607 1014 BCR CML CML 11 0.9 other studies the distribution of neuronal and glial deposits of CML did not correspond with the distribution of AD pathology causing 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211331 12663085 281895 1607 1014 BCR CML CML 27 0.9 distribution of AD pathology causing those authors to conclude that CML does not directly cause the formation of neurofibrillary tangles or 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211332 12663085 281900 11629 6493 LAMC2 CSF CSF 0 1.6 CSF studies 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211333 12663085 281901 11629 6493 LAMC2 CSF CSF 19 1.6 early glycation product an Amadori product in cerebrospinal fluid (CSF) CSF in aging and late-onset AD 93 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211334 12663085 281902 11629 6493 LAMC2 CSF CSF 7 1.6 The concentration of the Amadori product in CSF correlated with the CSF glucose concentration but did not change 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211335 12663085 281902 11629 6493 LAMC2 CSF CSF 11 1.6 concentration of the Amadori product in CSF correlated with the CSF glucose concentration but did not change with age ( n 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211336 12663085 281903 11629 6493 LAMC2 CSF CSF 5 1.6 In contrast the level of CSF Amadori product was 1.7 times greater in AD patients ( 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211337 12663085 281904 11629 6493 LAMC2 CSF CSF 14 1.6 Amadori products was found in all major proteins of the CSF of AD patients including albumin apoE and transthyretin 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211338 12663085 281904 912 613 APOE APOE apoE 20 1.0 major proteins of the CSF of AD patients including albumin apoE and transthyretin 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211339 12663085 281905 11629 6493 LAMC2 CSF CSF 19 1.6 times greater in AD patients than in controls (total total CSF glycation of the samples was 8.9 and 3.1 arbitrary units/_amp_#x3bc;g 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211340 12663085 281906 11629 6493 LAMC2 CSF CSF 4 1.6 This demonstrated that increased CSF glycation in AD is not due to a specific protein 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211341 12663085 281906 11629 6493 LAMC2 CSF CSF 19 1.6 not due to a specific protein modification because all major CSF proteins of different origin are involved in the process (albumin 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211342 12663085 281906 912 613 APOE APOE apoE 40 1.0 from plasma 90% of transthyretin synthesized by choroid plexus and apoE derived from astrocytes 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211343 12663085 281908 11629 6493 LAMC2 CSF CSF 1 1.6 The CSF is likely to be at least one of the sites 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211344 12663085 281908 11629 6493 LAMC2 CSF CSF 24 1.6 glycation based on the hypothesis of the involvement of impaired CSF circulation in AD 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211345 12663085 281909 912 613 APOE APOE apoE 29 1.0 to in vitro glycation than does normal apoE3 while glycated apoE maintains its high binding affinity to A_amp_#x3b2 -peptide 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211346 12663085 281910 11629 6493 LAMC2 CSF CSF 10 1.6 Shuvaev et al proposed that the increased early glycation of CSF proteins in AD patients might stimulate the formation and subsequent 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211347 12663085 281919 1607 1014 BCR CML CML 14 0.9 such as _amp_#x2018 glycoxidation_amp_#x2019 and _amp_#x2018 glycoxidation products_amp_#x2019 (pentosidine, pentosidine CML etc. is also used 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211348 12663085 281939 1607 1014 BCR CML CML 59 0.9 of AGE 16 and 62 3-DG-derived AGE are imidazolone pyrraline CML and pentosidine of which imidazolone is the most specific AGE 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211349 12663085 281948 1607 1014 BCR CML CML 11 0.9 cultured dorsal root ganglion (DRG) DRG cells the generation of CML was detected after exposure to 3-DG and glyoxal 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211350 12663085 281953 14535 7873 NOS2A NOS NOS 14 2.7 by antioxidants aminoguanidine and inhibitors of nitric oxide synthase (NOS) NOS 1 JUMiner_v2.2 1 0 0 2 7873 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7873|NOS2A|0.000427726166974101<>ScoreDetail__7873|NOS2A|0.000427726166974101__7872|NOS1|0.000401885518748567__ 0 0 0 0 0 211351 12663085 281954 18723 10261 ROS1 ROS ROS 5 0.0 This suggests that not only ROS but also reactive nitrogen species contribute to AGE-mediated cytotoxicity ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211352 12663085 281955 4682 2197 COL1A1 collagen collagen 15 0.3 survival of cultured DRG neurons were significantly reduced on glycated collagen IV and laminin 54 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211353 12663085 281966 14452 14374 NLRP1 NAC NAC 11 0.3 of MG and 3-DG was attenuated by N -acetylcysteine (NAC) NAC 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 211354 12663085 281967 14452 14374 NLRP1 NAC NAC 0 0.3 NAC can raise intracellular GSH levels and thereby provide cells with 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 211355 12663085 281967 18723 10261 ROS1 ROS ROS 21 0.0 the co-substrate required to eliminate hydroperoxides resulting in protection from ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211356 12663085 281968 14452 14374 NLRP1 NAC NAC 2 0.3 In addition NAC also reacts with MG directly and reversibly to form the 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 211357 12663085 281971 14535 7873 NOS2A NOS NOS 19 2.7 glycation AG has antioxidant properties 81 and also inhibits inducible NOS (iNOS) iNOS 100 1 JUMiner_v2.2 1 0 0 2 7873 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7873|NOS2A|0.000427726166974101<>ScoreDetail__7873|NOS2A|0.000427726166974101__7872|NOS1|0.000401885518748567__ 0 0 0 0 0 211358 12663085 281971 14535 7873 NOS2A iNOS iNOS 20 2.7 has antioxidant properties 81 and also inhibits inducible NOS (iNOS) iNOS 100 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211359 12663085 281972 1607 1014 BCR CML CML 12 0.9 al reported that 3-DG and glyoxal accelerated the formation of CML in explant-cultured neurons in explant of dorsal root ganglia 62 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211360 12663085 281973 1607 1014 BCR CML CML 15 0.9 fully explain the involvement of glycation in their system since CML is produced by lipid peroxidation under conditions of oxidative stress 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211361 12663085 281973 1607 1014 BCR CML CML 33 0.9 of oxidative stress and the direct pathway from 3-DG to CML is a minor pathway 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211362 12663085 281974 1607 1014 BCR CML CML 8 0.9 Even though glyoxal is a known precursor of CML glyoxal itself is also formed during lipid peroxidation 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211363 12663085 281978 1607 1014 BCR CML CML 4 0.9 Does this mean that CML is not sufficiently toxic to cause neuronal death 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211364 12663085 281992 14535 7873 NOS2A iNOS iNOS 22 2.7 properties 81 and also inhibits inducible nitric oxide synthase (iNOS) iNOS 100 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211365 12663085 281995 17575 9583 PTBP1 PTB PTB 3 0.3 N -Phenacylthiazolium bromide (PTB) PTB and ALT711 are known as AGE cross-link breakers 111 1 JUMiner_v2.2 1 2 phenacylthiazolium bromide 0 2 9583 TotalCon:2<>9583|PTBP1|5725|Complete__17662|PTBP2|58155|Complete__<>AvaiableGeneRif=2<>BEST:9583|PTBP1|0.000413367179834246<>ScoreDetail__9583|PTBP1|0.000413367179834246__17662|PTBP2|0.000234977031384217__ 0 0 0 0 0 211366 12663085 281996 926 620 APP amyloid amyloid 12 1.0 al reported preliminary findings suggesting that cross-link breakers can disaggregate amyloid deposits 111 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 211367 12663085 282006 20996 11179 SOD1 ALS ALS 5 1.4 Glycation in amyotrophic lateral sclerosis (ALS) ALS 12.1 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211368 12663085 282007 20996 11179 SOD1 ALS ALS 1 1.4 Familial ALS 12.1.1 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211369 12663085 282008 20996 11179 SOD1 ALS ALS 1 1.4 Familial ALS and SOD-1 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211370 12663085 282008 20996 11179 SOD1 SOD1 SOD-1 3 2.7 Familial ALS and SOD-1 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211371 12663085 282009 20996 11179 SOD1 ALS ALS 3 1.4 Amyotrophic lateral sclerosis (ALS) ALS is a progressive fatal neurodegenerative disorder that involves the motor 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211372 12663085 282010 20996 11179 SOD1 ALS ALS 3 1.4 Approximately 10% of ALS cases (familial familial ALS or FALS are inherited the other 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211373 12663085 282010 20996 11179 SOD1 ALS ALS 6 1.4 Approximately 10% of ALS cases (familial familial ALS or FALS are inherited the other 90% are sporadic 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211374 12663085 282011 20996 11179 SOD1 SOD1 SOD-1 14 2.7 evidence that more than 50 mutations in the gene for SOD-1 the cytosolic copper/zinc-binding copper zinc-binding dimeric form of a protective 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211375 12663085 282012 20996 11179 SOD1 SOD1 SOD-1 5 2.7 A discussion of FALS with SOD-1 mutations is complicated because transgenic expression of different SOD-1 mutants 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211376 12663085 282012 20996 11179 SOD1 SOD1 SOD-1 14 2.7 with SOD-1 mutations is complicated because transgenic expression of different SOD-1 mutants in both mice and rats causes an ALS-like syndrome 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211377 12663085 282012 20996 11179 SOD1 ALS ALS-like 23 1.4 different SOD-1 mutants in both mice and rats causes an ALS-like syndrome independently of whether SOD-1 catalytic activity is changed 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211378 12663085 282012 20996 11179 SOD1 SOD1 SOD-1 28 2.7 mice and rats causes an ALS-like syndrome independently of whether SOD-1 catalytic activity is changed 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211379 12663085 282013 20996 11179 SOD1 SOD1 SOD-1 10 2.7 These observations suggest that a novel gain-of-function effect of mutant SOD-1 may have a pathogenic role in FALS 33 and 85 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211380 12663085 282014 20996 11179 SOD1 SOD1 SOD-1 9 2.7 First an increase in the peroxidase activity of mutant SOD-1 leading to hydroxyl radical production was assumed while several authors 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211381 12663085 282016 20996 11179 SOD1 SOD1 SOD-1 15 2.7 argued against the copper-mediated theory of motor neuron degeneration in SOD-1 mutant mice 101 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211382 12663085 282017 20996 11179 SOD1 SOD1 SOD-1 2 2.7 Finally mutant SOD-1 has a tendency to form aggregates spontaneously 31 and 89 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211383 12663085 282019 20996 11179 SOD1 SOD1 SOD-1 36 2.7 phosphorylated neurofilament protein are the characteristic markers of FALS with SOD-1 mutations 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211384 12663085 282020 20996 11179 SOD1 SOD1 SOD-1 11 2.7 Shibata et al 83 demonstrated the presence of intense SOD-1 immunoreactivity in the NHIs of FALS patients with a heterozygous 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211385 12663085 282020 20996 11179 SOD1 SOD1 SOD-1 32 2.7 to Val substitution at codon 4 (Ala4Val) Ala4Val in the SOD-1 gene 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211386 12663085 282021 20996 11179 SOD1 ALS ALS 6 1.4 Similar findings were observed in other ALS families with different mutations and a two base-pair deletion 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211387 12663085 282022 20996 11179 SOD1 SOD1 SOD-1 9 2.7 Of added interest is a recent report that mutant SOD-1 expressed in cultured cells abnormally aggregates in the cytoplasm 12.1.3 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211388 12663085 282024 1607 1014 BCR CML CML 8 0.9 Shibata et al investigated the immunohistochemical localization of CML one of the major AGE structures in spinal cords from 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211389 12663085 282024 20996 11179 SOD1 SOD1 SOD-1 34 2.7 heterozygous Ala to Val substitution at codon 4 in the SOD-1 gene 83 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211390 12663085 282025 1607 1014 BCR CML CML 18 0.9 NHIs were intensely stained by a monoclonal antibody specific for CML 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211391 12663085 282026 1607 1014 BCR CML CML 5 0.9 Immunoelectron microscopy revealed that the CML determinants were restricted to the granule-associated thick linear structures that 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211392 12663085 282027 1607 1014 BCR CML CML 5 0.9 No focal collection of either CML or SOD-1 was found in neurons of the controls 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211393 12663085 282027 20996 11179 SOD1 SOD1 SOD-1 7 2.7 No focal collection of either CML or SOD-1 was found in neurons of the controls 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211394 12663085 282028 20996 11179 SOD1 SOD1 SOD-1 6 2.7 In the light of evidence that SOD-1 is a protein that is susceptible to the Maillard reaction 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211395 12663085 282028 1607 1014 BCR CML CML 23 0.9 to the Maillard reaction the finding of the coexistence of CML and SOD-1 in NHIs points to the possibility that CML-modified 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211396 12663085 282028 20996 11179 SOD1 SOD1 SOD-1 25 2.7 Maillard reaction the finding of the coexistence of CML and SOD-1 in NHIs points to the possibility that CML-modified SOD-1 is 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211397 12663085 282028 1607 1014 BCR CML CML-modified 33 0.3 CML and SOD-1 in NHIs points to the possibility that CML-modified SOD-1 is deposited in NHIs 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211398 12663085 282028 20996 11179 SOD1 SOD1 SOD-1 34 2.7 and SOD-1 in NHIs points to the possibility that CML-modified SOD-1 is deposited in NHIs 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211399 12663085 282029 1607 1014 BCR CML CML 5 0.9 However the target protein of CML modification in NHIs remains unclear because NHIs seen in patients 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211400 12663085 282029 20996 11179 SOD1 ALS ALS 18 1.4 NHIs remains unclear because NHIs seen in patients with familial ALS have been shown to contain not only SOD-1 but also 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211401 12663085 282029 20996 11179 SOD1 SOD1 SOD-1 26 2.7 with familial ALS have been shown to contain not only SOD-1 but also phosphorylated NFP and ubiquitin 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211402 12663085 282031 20996 11179 SOD1 SOD1 SOD-1 4 2.7 The decreased activity of SOD-1 by glycation is not necessarily considered to be the sole 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211403 12663085 282033 20996 11179 SOD1 SOD SOD-1-positive 9 1.4 Kato et al 35 and 37 found SOD-1-positive inclusions in astrocytes (astrocytic astrocytic hyaline inclusions or AHIs as 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211404 12663085 282033 20996 11179 SOD1 SOD1 SOD-1 29 2.7 as in neurons (NHIs) NHIs in patients with FALS with SOD-1 mutations and in transgenic mice expressing human SOD-1 with the 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211405 12663085 282033 20996 11179 SOD1 SOD1 SOD-1 37 2.7 FALS with SOD-1 mutations and in transgenic mice expressing human SOD-1 with the G85R mutation 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211406 12663085 282034 1607 1014 BCR CML CML 9 0.9 AHIs were also immunoreactive for insoluble AGE such as CML pyrraline and pentosidine and similar to NHIs were ultrastructurally composed 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211407 12663085 282034 1607 1014 BCR CML CML 27 0.9 were ultrastructurally composed of granule-coated fibrils that exhibited immunoreactivity to CML and pyrraline 12.2 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211408 12663085 282035 20996 11179 SOD1 ALS ALS 1 1.4 Sporadic ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211409 12663085 282036 20996 11179 SOD1 ALS ALS 4 1.4 In cases of sporadic ALS as well as FALS Chou et al 15 demonstrated the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211410 12663085 282040 20996 11179 SOD1 ALS ALS 14 1.4 Chou et al. no staining was detected in NHIs in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211411 12663085 282041 1607 1014 BCR CML CML 44 0.9 antibodies used those of Chou et al do not recognize CML and the AGE detected by Shibata et al consisted of 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211412 12663085 282041 1607 1014 BCR CML CML 55 0.9 and the AGE detected by Shibata et al consisted of CML 12.3 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211413 12663085 282042 20996 11179 SOD1 ALS ALS 3 1.4 Familial vs sporadic ALS/non-oxidative ALS non-oxidative vs oxidative glycation 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211414 12663085 282043 1607 1014 BCR CML CML 0 0.9 CML is thought to be a major epitope for many of 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211415 12663085 282044 1607 1014 BCR CML CML 10 0.9 However recent findings have indicated that a major source of CML may be derived from pathways other than glycation 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211416 12663085 282045 1607 1014 BCR CML CML 10 0.9 Fu et al clearly demonstrated that the major source of CML was lipid peroxidation not glycation 18 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211417 12663085 282046 1607 1014 BCR CML CML 0 0.9 CML does not contain the reactive groups involved in cross-linking and 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211418 12663085 282047 1607 1014 BCR CML CML 1 0.9 Thus CML is considered to be a marker of oxidation rather than 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211419 12663085 282048 1607 1014 BCR CML CML 4 0.9 Accordingly the existence of CML is not decisive evidence of the involvement of glycation in 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211420 12663085 282048 20996 11179 SOD1 ALS ALS 18 1.4 evidence of the involvement of glycation in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211421 12663085 282051 20996 11179 SOD1 ALS ALS 7 1.4 To clarify the involvement of glycation in ALS and the interplay between glycation and oxidative stress several studies 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211422 12663085 282052 1607 1014 BCR CML CML 8 0.9 Shibata et al analyzed the immunohistochemical localization of CML as a lipid peroxidation or protein glycoxidation product pentosidine as 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211423 12663085 282054 20996 11179 SOD1 SOD1 SOD-1 13 2.7 conducted in the spinal cords of FALS patients with the SOD-1 mutation (A4V) A4V in sporadic ALS patients and in age-matched 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211424 12663085 282054 20996 11179 SOD1 ALS ALS 18 1.4 FALS patients with the SOD-1 mutation (A4V) A4V in sporadic ALS patients and in age-matched control individuals 86 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211425 12663085 282055 1607 1014 BCR CML CML 9 0.9 In the FALS cases intense immunoreactivities for pyrraline and CML were confined to the characteristic NHIs and imidazolone immunoreactivity was 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211426 12663085 282057 20996 11179 SOD1 ALS ALS 3 1.4 In the sporadic ALS cases intense immunoreactivities for pentosidine CML and the HNE_amp_#x2013 protein 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211427 12663085 282057 1607 1014 BCR CML CML 9 0.9 In the sporadic ALS cases intense immunoreactivities for pentosidine CML and the HNE_amp_#x2013 protein adduct were found in the cytoplasm 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211428 12663085 282058 6554 3309 ELA2 HNE HNE 15 0.3 markers of oxidation and/or and or glycoxidation (adducts adducts of HNE crotoaldehyde CML and pentosidine were localized in the gray matter 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 211429 12663085 282058 1607 1014 BCR CML CML 17 0.9 oxidation and/or and or glycoxidation (adducts adducts of HNE crotoaldehyde CML and pentosidine were localized in the gray matter neuropil of 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211430 12663085 282059 1607 1014 BCR CML CML 10 0.9 In addition Kato et al found that AHIs immunoreactive for CML pyrraline and pentosidine were negative for stress-response proteins (SRPs), SRPs 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211431 12663085 282059 6554 3309 ELA2 HNE HNE 20 0.3 pyrraline and pentosidine were negative for stress-response proteins (SRPs), SRPs HNE acrolein NOSs and nitrotyrosine as representative markers of oxidative stress 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 211432 12663085 282059 14535 7873 NOS2A NOS NOSs 22 2.7 pentosidine were negative for stress-response proteins (SRPs), SRPs HNE acrolein NOSs and nitrotyrosine as representative markers of oxidative stress 35 1 JUMiner_v2.2 1 0 0 2 7873 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7873|NOS2A|0.000427726166974101<>ScoreDetail__7873|NOS2A|0.000427726166974101__7872|NOS1|0.000401885518748567__ 0 0 0 0 0 211433 12663085 282059 23630 18414 UCN2 SRP SRPs 19 0.2 CML pyrraline and pentosidine were negative for stress-response proteins (SRPs), SRPs HNE acrolein NOSs and nitrotyrosine as representative markers of oxidative 5 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211434 12663085 282060 20996 11179 SOD1 ALS ALS 14 1.4 oxidative reactions are involved in the disease processes of sporadic ALS while there is no evidence for increased oxidative damage except 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211435 12663085 282060 1607 1014 BCR CML CML 26 0.9 there is no evidence for increased oxidative damage except for CML deposition in the FALS spinal cord 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211436 12663085 282061 20996 11179 SOD1 SOD SOD-1-related 17 1.4 of pyrraline and imidazolone supports the non-oxidative mechanism in the SOD-1-related degeneration of motor neurons 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211437 12663085 282064 20996 11179 SOD1 ALS ALS 15 1.4 we first confirmed the initial stage of glycation in sporadic ALS spinal cords 12.4 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211438 12663085 282065 20996 11179 SOD1 ALS ALS 6 1.4 An Amadori product 1-hexitol-lysine in sporadic ALS spinal cord 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211439 12663085 282066 20996 11179 SOD1 ALS ALS 16 1.4 Amadori product the initial reaction product of glycation in the ALS spinal cord by the presence of an anti-1-hexitol-lysine (1-HL) 1-HL 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211440 12663085 282067 20996 11179 SOD1 ALS ALS 20 1.4 Amadori compound was detected in axonal spheroids of the sporadic ALS spinal cord 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211441 12663085 282068 20996 11179 SOD1 ALS ALS 24 1.4 not merely correlate with physiological aging but is specific to ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211442 12663085 282072 20996 11179 SOD1 ALS ALS 25 1.4 motoneurons our cases of BSMA as well as of sporadic ALS showed no impairment of glucose tolerance 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211443 12663085 282073 20996 11179 SOD1 ALS ALS 12 1.4 showed the presence of an Amadori product 1-hexitol-lysine in the ALS and BSMA spinal cord 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211444 12663085 282075 20996 11179 SOD1 ALS ALS 15 1.4 as a modulator of the death pathway of motoneurons in ALS and BSMA because glycation of essential components such as antioxidative 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211445 12663085 282076 20996 11179 SOD1 ALS ALS 5 1.4 Late-stage glycation reaction in sporadic ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211446 12663085 282077 20996 11179 SOD1 ALS ALS 23 1.4 the production of AGE following the early reaction in sporadic ALS spinal cords the presence of CML and non-CML AGE was 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211447 12663085 282077 1607 1014 BCR CML CML 29 0.9 early reaction in sporadic ALS spinal cords the presence of CML and non-CML AGE was examined 41 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211448 12663085 282078 1607 1014 BCR CML CML 13 0.9 research we elicited antibodies that clearly distinguished non-CML AGE from CML 108 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211449 12663085 282079 1607 1014 BCR CML CML 6 0.9 Anti-non-CML antibody does not react with CML pyrraline pentosidine or Amadori compounds but possibly recognizes all other 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211450 12663085 282080 1607 1014 BCR CML CML 0 0.9 CML is thought to be a major epitope for many of 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211451 12663085 282081 1607 1014 BCR CML CML 10 0.9 However recent findings have indicated that a major source of CML may be derived from pathways other than glycation 18 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211452 12663085 282086 20996 11179 SOD1 ALS ALS 12 1.4 anti-non-CML AGE antibodies faintly stained vascular endothelial cells from both ALS and age-matched control subjects 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211453 12663085 282088 20996 11179 SOD1 ALS ALS 12 1.4 of non-CML AGE was evident in the anterior horn of ALS spinal cords demonstrating the existence of the late stage of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211454 12663085 282088 20996 11179 SOD1 ALS ALS 27 1.4 existence of the late stage of the glycation reaction in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211455 12663085 282089 1607 1014 BCR CML CML 3 0.9 The existence of CML was also confirmed suggesting that augmented oxidative stress was also 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211456 12663085 282090 20996 11179 SOD1 ALS ALS 3 1.4 AGE receptors in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211457 12663085 282091 5546 2728 DDOST AGE-R1 AGE-R1 15 3.3 receptors (other other than RAGE reported in the human brain AGE-R1 (oligosaccharyltransferase oligosaccharyltransferase family and AGE-R2 (substrate substrate of protein kinase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211458 12663085 282091 17314 9411 PRKCSH AGE-R2 AGE-R2 19 3.5 reported in the human brain AGE-R1 (oligosaccharyltransferase oligosaccharyltransferase family and AGE-R2 (substrate substrate of protein kinase C have been found in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211459 12663085 282092 20996 11179 SOD1 ALS ALS 17 1.4 these receptors in conglomerates of cortical motor neurons in eight ALS brains (five five sporadic ALS and three FALS and three 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211460 12663085 282092 20996 11179 SOD1 ALS ALS 21 1.4 cortical motor neurons in eight ALS brains (five five sporadic ALS and three FALS and three control brains with antibodies against 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211461 12663085 282092 5546 2728 DDOST AGE-R1 AGE-R1 32 3.3 and three FALS and three control brains with antibodies against AGE-R1 and AGE-R2 13 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211462 12663085 282092 17314 9411 PRKCSH AGE-R2 AGE-R2 32 3.5 and three FALS and three control brains with antibodies against AGE-R1 and AGE-R2 13 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211463 12663085 282092 17314 9411 PRKCSH AGE-R2 AGE-R2 34 3.5 FALS and three control brains with antibodies against AGE-R1 and AGE-R2 13 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211464 12663085 282093 5546 2728 DDOST AGE-R1 AGE-R1 3 3.3 They found that AGE-R1 immunoreactivity was co-localized with those of AGE SOD-1 and neurofilaments 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211465 12663085 282093 20996 11179 SOD1 SOD1 SOD-1 11 2.7 found that AGE-R1 immunoreactivity was co-localized with those of AGE SOD-1 and neurofilaments 12.7 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211466 12663085 282094 20996 11179 SOD1 ALS ALS 6 1.4 AGE in an animal model of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211467 12663085 282100 20996 11179 SOD1 ALS ALS 22 1.4 activity in the brain region (precentral precentral gyrus affected in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211468 12663085 282101 20996 11179 SOD1 SOD SOD 0 1.7 SOD and catalase activities were not changed suggesting that specific defects 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211469 12663085 282101 20996 11179 SOD1 ALS ALS 19 1.4 specific defects of the GSH system are more important in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211470 12663085 282103 14452 14374 NLRP1 NAC NAC 10 0.3 To test this possibility we added glutathione-augmenting agents such as NAC and glutathione ethyl ester (GEE) GEE 24 h before MG 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 211471 12663085 282109 20996 11179 SOD1 ALS ALS 8 1.4 Since AGE accumulate in the spinal cords of ALS patients 14 and 84 further studies are needed to address 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211472 12663085 282117 20996 11179 SOD1 ALS ALS 4 1.4 After reviewing glycation in ALS spinal cords its neurotoxicity to cultured spinal motor neurons was 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000730585365101325<>ScoreDetail__5468|IGFALS|0.000325134524409474__11179|SOD1|0.000730585365101325__ 0 0 0 0 0 211473 12663085 282126 18723 10261 ROS1 ROS ROS 3 0.0 Reactive oxygen species (ROS) ROS are produced via a glycation reaction 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 211474 12663085 282133 1607 1014 BCR CML CML 5 0.9 Chemical structures of various AGE CML N -(carboxymethyl)lysine; - carboxymethyl lysine CEL N -(carboxyethyl)lysine; - carboxyethyl 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 211475 12663085 282136 18723 10261 ROS1 ROS ROS 0 0.0 ROS reactive oxygen species NO nitric oxide RNOS reactive NO species 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212169 12684448 283316 20996 11179 SOD1 ALS ALS 9 2.2 Observations of elevated CSF glutamate in amyotrophic lateral sclerosis (ALS), ALS together with findings that motor neurons are selectively vulnerable to 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212170 12684448 283316 11629 6493 LAMC2 CSF CSF 3 0.0 Observations of elevated CSF glutamate in amyotrophic lateral sclerosis (ALS), ALS together with findings 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212171 12684448 283318 18723 10261 ROS1 ROS ROS 11 0.0 find that glutamate induces far greater reactive oxygen species (ROS) ROS generation in cultured motor neurons than in other spinal neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212172 12684448 283319 18723 10261 ROS1 ROS ROS 6 0.0 In addition we found that the ROS seem to be able to leave the motor neurons and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212173 12684448 283320 20996 11179 SOD1 ALS ALS 7 2.2 Correspondingly in a transgenic mouse model of ALS protein oxidation was increased in regions immediately surrounding motor neurons 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212174 12684448 283322 20996 11179 SOD1 ALS ALS 23 2.2 motor neurons and glia which may prove useful in understanding ALS pathogenesis 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212175 12684448 283323 20996 11179 SOD1 SOD SOD 16 2.2 sclerosis ROS glutamate excitotoxicity glutamate transport cell culture free radicals SOD nitrotyrosine AMPA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212176 12684448 283323 18723 10261 ROS1 ROS ROS 7 0.0 Key words motor neuron amyotrophic lateral sclerosis ROS glutamate excitotoxicity glutamate transport cell culture free radicals SOD nitrotyrosine 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212177 12684448 283324 20996 11179 SOD1 ALS ALS 3 2.2 Amyotrophic lateral sclerosis (ALS) ALS is a devastating neurodegenerative disease characterized by the selective loss 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212178 12684448 283326 20996 11179 SOD1 SOD1 SOD1 18 2.2 linked to mutations in the enzyme superoxide dismutase 1 (SOD1) SOD1 (Rosen Rosen et al. 1993 the vast majority (90-95%) 90-95% 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212179 12684448 283328 20996 11179 SOD1 ALS ALS 53 2.2 glutamate transport in spinal cord and motor cortex of sporadic ALS patients (Rothstein Rothstein et al. 1992 1996 Shaw et al. 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212180 12684448 283328 11629 6493 LAMC2 CSF CSF 20 0.0 in acute conditions of ischemia or epilepsy observations of elevated CSF glutamate levels (Rothstein Rothstein et al. 1990 Shaw et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212181 12684448 283332 18723 10261 ROS1 ROS ROS 39 0.0 intracellular Ca increases and consequent mitochondrial reactive oxygen species (ROS) ROS generation (Carriedo Carriedo et al. 1998 2000 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212182 12684448 283333 20996 11179 SOD1 ALS ALS 41 2.2 may limit mitochondrial Ca uptake seem to be spared in ALS (Alexianu Alexianu et al. 1994 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212183 12684448 283336 20996 11179 SOD1 ALS ALS 10 2.2 Although this astrocytic dysfunction can explain excitotoxic MN injury in ALS and thus might be considered to be the primary defect 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212184 12684448 283337 18723 10261 ROS1 ROS ROS 10 0.0 The present study aims to explore the connection between MN ROS generation and astroglial transport 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212185 12684448 283338 18723 10261 ROS1 ROS ROS 44 0.0 that exposure to AMPA or kainate induced strong and selective ROS generation in cultured MNs (Carriedo Carriedo et al. 2000 the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212186 12684448 283339 18723 10261 ROS1 ROS ROS 9 0.0 The first is to determine whether MNs produce more ROS than other spinal neurons during activation with the endogenous excitatory 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212187 12684448 283340 18723 10261 ROS1 ROS ROS 10 0.0 In addition we sought to examine the hypothesis that such ROS generated within MNs in response to excitotoxic activation can pass 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212188 12684448 283343 20996 11179 SOD1 SOD1 SOD1 5 2.2 For spinal cord immunohistochemical studies SOD1 G93A transgenic mice (The The Jackson Laboratory Bar Harbor ME 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212189 12684448 283351 8254 4235 GFAP GFAP GFAP 10 2.5 studies using the astrocyte-specific marker glial fibrillary acidic protein (GFAP) GFAP confirmed the identity of cells with these morphological characteristics (see 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212190 12684448 283353 8254 4235 GFAP GFAP GFAP 15 2.5 blocked and exposed to primary antibody SMI-32 1 5000 and GFAP 1 400 (Dako, Dako Glostrup Denmark glutamate transporter GLT-1 (also 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212191 12684448 283353 20017 10940 SLC1A2 GLT-1 GLT-1 22 2.5 and GFAP 1 400 (Dako, Dako Glostrup Denmark glutamate transporter GLT-1 (also also known as EAAT2 0.17 microg/ml microg ml (kindly 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212192 12684448 283353 20017 10940 SLC1A2 EAAT2 EAAT2 26 2.5 Dako Glostrup Denmark glutamate transporter GLT-1 (also also known as EAAT2 0.17 microg/ml microg ml (kindly kindly supplied by Jeff Rothstein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212193 12684448 283357 20996 11179 SOD1 SOD1 SOD1 1 2.2 For SOD1 G93A transgenic mouse studies spinal cords were removed from 90- 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212194 12684448 283360 21063 14524 SPAG9 HSS HSS 30 0.3 in a static bath consisting of HEPES-buffered salt solution (HSS) HSS (in in m M 120 NaCl 5.4 KCl 1.8 CaCl 1 JUMiner_v2.2 1 2 UserEdit 0 2 4236 TotalCon:4<>4236|GFER|2671|Complete__15894|PANK2|80025|Complete__10818|SGSH|6448|Complete__14524|SPAG9|9043|Complete__<>AvaiableGeneRif=4<>BEST:4236|GFER|0.000310135303327289<>ScoreDetail__4236|GFER|0.000310135303327289__14524|SPAG9|0.000243143357323478__10818|SGSH|0.000185467491167676__15894|PANK2|0.0002572409200608__ 1 1 0 0 0 212195 12684448 283360 20247 20116 SLC25A29 CACL CaCl 40 1.0 HSS (in in m M 120 NaCl 5.4 KCl 1.8 CaCl 2 0.8 MgCl 2 20 HEPES 15 glucose and 10 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 212196 12684448 283361 19254 10472 RUNX2 CCD CCD 30 0.0 and fluorescence signals were collected using a 12-bit cooled digital CCD camera (Orca-100; Orca-100 Hamamatsu Bridgewater NJ and analyzed after background 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212197 12684448 283362 17497 9543 PSMB6 Delta Delta 15 1.0 of the oxidation-sensitive dyes HEt (Bindokas Bindokas et al. 1996 Delta F was monitored only in mitochondria-rich perinuclear regions of the 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 212198 12684448 283362 18723 10261 ROS1 ROS ROS 0 0.0 ROS generation was monitored by use of the oxidation-sensitive dyes HEt 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212199 12684448 283363 17497 9543 PSMB6 Delta Delta 3 1.0 In HEt experiments Delta F was measured in the soma and nucleus of neurons 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 212200 12684448 283363 17497 9543 PSMB6 Delta Delta 16 1.0 measured in the soma and nucleus of neurons whereas astrocytic Delta F was measured only over nuclei because nuclear HEt signals 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 212201 12684448 283365 20996 11179 SOD1 SOD SOD 28 2.2 (MK-801)] MK-801 alone or in the presence of antioxidants (SOD, SOD 100 U/ml; U ml catalase 400 U/ml), U ml followed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212202 12684448 283365 21063 14524 SPAG9 HSS HSS 47 0.3 incubation in H glutamate (2 2 microCi/ml) microCi ml in HSS for 5 min 1 JUMiner_v2.2 1 2 UserEdit 0 2 4236 TotalCon:4<>4236|GFER|2671|Complete__15894|PANK2|80025|Complete__10818|SGSH|6448|Complete__14524|SPAG9|9043|Complete__<>AvaiableGeneRif=4<>BEST:4236|GFER|0.000310135303327289<>ScoreDetail__4236|GFER|0.000310135303327289__14524|SPAG9|0.000243143357323478__10818|SGSH|0.000185467491167676__15894|PANK2|0.0002572409200608__ 1 1 0 0 0 212203 12684448 283366 21063 14524 SPAG9 HSS HSS 16 0.3 was terminated by washes (three three times in Na -free HSS with excess unlabeled glutamate 1 JUMiner_v2.2 1 2 UserEdit 0 2 4236 TotalCon:4<>4236|GFER|2671|Complete__15894|PANK2|80025|Complete__10818|SGSH|6448|Complete__14524|SPAG9|9043|Complete__<>AvaiableGeneRif=4<>BEST:4236|GFER|0.000310135303327289<>ScoreDetail__4236|GFER|0.000310135303327289__14524|SPAG9|0.000243143357323478__10818|SGSH|0.000185467491167676__15894|PANK2|0.0002572409200608__ 1 1 0 0 0 212204 12684448 283371 18723 10261 ROS1 ROS ROS 2 0.0 Glutamate triggered ROS generation in cultured motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212205 12684448 283372 18723 10261 ROS1 ROS ROS 1 0.0 MN ROS generation was examined in a dissociated cell culture model 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212206 12684448 283379 20996 11179 SOD1 ALS ALS 13 2.2 builds on and integrates clues to possible mechanisms involved in ALS pathogenesis suggested by a number of previous studies 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212207 12684448 283380 18723 10261 ROS1 ROS ROS 15 0.0 excitotoxic exposures (generally generally mediated through NMDA receptors can induce ROS generation in central neurons (Lafon-Cazal Lafon-Cazal et al. 1993 Dugan 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212208 12684448 283380 18723 10261 ROS1 ROS ROS 51 0.0 to indicate that the nonselective endogenous excitatory transmitter glutamate induces ROS quite selectively with strong generation in MNs and minimal ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212209 12684448 283380 18723 10261 ROS1 ROS ROS 61 0.0 ROS quite selectively with strong generation in MNs and minimal ROS production in other spinal neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212210 12684448 283381 18723 10261 ROS1 ROS ROS 16 0.0 that glutamate transporters are sensitive to inhibition by exogenously applied ROS (Trotti Trotti et al. 1998 this is the first to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212211 12684448 283381 18723 10261 ROS1 ROS ROS 29 0.0 et al. 1998 this is the first to demonstrate that ROS generated within MNs (or or within any neuron in fact 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212212 12684448 283382 20996 11179 SOD1 ALS ALS 16 2.2 oxidative changes in MNs and in spinal cord astrocytes in ALS (Abe Abe et al. 1995 Beal et al. 1997 Ferrante 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212213 12684448 283383 20996 11179 SOD1 SOD SOD 18 2.2 seen in an annular pattern immediately surrounding MNs in the SOD mouse model of ALS is novel and lends support to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212214 12684448 283383 20996 11179 SOD1 ALS ALS 22 2.2 pattern immediately surrounding MNs in the SOD mouse model of ALS is novel and lends support to the hypothesis that the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212215 12684448 283383 18723 10261 ROS1 ROS ROS 36 0.0 lends support to the hypothesis that the oxidation results from ROS emanating directly out of MNs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212216 12684448 283384 18723 10261 ROS1 ROS ROS 18 0.0 the feasibility of a previously untested mechanism in which MN ROS contributes directly to transporter dysfunction in surrounding astrocytes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212217 12684448 283388 18723 10261 ROS1 ROS ROS 18 0.0 in intact spinal cord it is not possible to isolate ROS emanation to individual neurons or to assess its effects on 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212218 12684448 283391 18723 10261 ROS1 ROS ROS 4 0.0 Thus the relatively selective ROS generation we observe in cultured MNs in response to glutamate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212219 12684448 283391 18723 10261 ROS1 ROS ROS 22 0.0 response to glutamate receptor activation and the ability of this ROS to escape the cell and affect the surrounding microenvironment is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212220 12684448 283392 18723 10261 ROS1 ROS ROS 11 0.0 we reported previously that AMPA or kainate exposures cause selective ROS generation in MNs it is striking that such a high 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212221 12684448 283393 18723 10261 ROS1 ROS ROS 27 0.0 might be expected to induce a more uniform pattern of ROS production 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212222 12684448 283394 18723 10261 ROS1 ROS ROS 12 0.0 the case of AMPA or kainate exposures this highly selective ROS generation is probably best explained by rapid Ca entry through 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212223 12684448 283395 18723 10261 ROS1 ROS ROS 10 0.0 In addition as with AMPA or kainate exposures the glutamate-triggered ROS generation appears to require Ca influx and is inhibited by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212224 12684448 283396 18723 10261 ROS1 ROS ROS-sensitive 4 0.0 Subsequent experiments using the ROS-sensitive dye HEt revealed that excitotoxic exposures causing strong ROS generation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212225 12684448 283396 18723 10261 ROS1 ROS ROS 13 0.0 the ROS-sensitive dye HEt revealed that excitotoxic exposures causing strong ROS generation within MNs also induce increases in fluorescence of astrocyte 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212226 12684448 283397 18723 10261 ROS1 ROS ROS 23 0.0 (Aeschbacher Aeschbacher et al. 1986 this observation suggests that the ROS passes across two plasma membranes both exiting the MN and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212227 12684448 283398 20996 11179 SOD1 SOD SOD 11 2.2 observed block of this oxidation by an extracellular antioxidant (SOD) SOD provides strong support for the idea that the ROS passes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212228 12684448 283398 18723 10261 ROS1 ROS ROS 20 0.0 (SOD) SOD provides strong support for the idea that the ROS passes through the extracellular space in which it can be 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212229 12684448 283399 18723 10261 ROS1 ROS ROS 6 0.0 Additional experiments examined the ability of ROS generated in MNs to affect the function of nearby glutamate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212230 12684448 283401 18723 10261 ROS1 ROS ROS 6 0.0 Indeed beyond being selective producers of ROS the present observations suggest that MNs if stimulated strongly can 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212231 12684448 283401 18723 10261 ROS1 ROS ROS 18 0.0 present observations suggest that MNs if stimulated strongly can produce ROS in sufficient quantities to induce a rapid disruption of glutamate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212232 12684448 283402 20996 11179 SOD1 ALS ALS 6 2.2 In studies of glutamate transporters in ALS and SOD mutant mouse models there has been discussion as 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212233 12684448 283402 20996 11179 SOD1 SOD SOD 8 2.2 In studies of glutamate transporters in ALS and SOD mutant mouse models there has been discussion as to whether 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212234 12684448 283403 20996 11179 SOD1 ALS ALS 38 2.2 that similar oxidative dysfunction might contribute to transport loss in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212235 12684448 283404 18723 10261 ROS1 ROS ROS 7 0.0 Although determination of the precise forms of ROS that may mediate disruption of glutamate transport is beyond the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212236 12684448 283406 20996 11179 SOD1 ALS ALS 13 2.2 increased nitrotyrosine labeling in motor neurons and ventral horn in ALS and/or and or SOD mutant mouse models (Abe Abe et 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212237 12684448 283406 20996 11179 SOD1 SOD SOD 15 2.2 motor neurons and ventral horn in ALS and/or and or SOD mutant mouse models (Abe Abe et al. 1995 Beal et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212238 12684448 283406 20996 11179 SOD1 SOD SOD 48 2.2 increased nitrotyrosine staining in an annular pattern around MNs in SOD mutant mice suggest that this species may be involved 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212239 12684448 283407 20996 11179 SOD1 ALS ALS 8 2.2 Novel support for a feedforward mechanism contributing to ALS pathogenesis 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212240 12684448 283408 20996 11179 SOD1 ALS ALS 19 2.2 has been suggested to underlie excitotoxic damage to MNs in ALS could reflect a primary astrocytic deficit 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212241 12684448 283409 18723 10261 ROS1 ROS ROS 14 0.0 suggesting that disruption of astrocytic transport is induced specifically by ROS generated within MNs provides support for an alternative model in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212242 12684448 283411 20996 11179 SOD1 ALS ALS 15 2.2 local changes predicted by the present model and observed in ALS a primary global loss of astrocytic glutamate transport capacity induces 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212243 12684448 283412 20996 11179 SOD1 SOD1 SOD1 12 2.2 a critical involvement of both cell types in the mutant SOD1 mouse models of ALS development of disease seems to require 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212244 12684448 283412 20996 11179 SOD1 ALS ALS 16 2.2 both cell types in the mutant SOD1 mouse models of ALS development of disease seems to require the mutant enzyme to 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212245 12684448 283413 20996 11179 SOD1 ALS ALS 16 2.2 for the close association of affected MNs and astrocytes in ALS the present model presents a mechanistic framework that can explain 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212246 12684448 283414 20996 11179 SOD1 ALS ALS 26 2.2 with the pronounced oxidative damage and mitochondrial abnormalities seen in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212247 12684448 283414 18723 10261 ROS1 ROS ROS 10 0.0 First the apparent ability of glutamate to cause selective mitochondrial ROS generation in MNs is compatible with the pronounced oxidative damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212248 12684448 283415 20017 10940 SLC1A2 GLT-1 GLT-1 25 2.5 an explanation for previous reports of oxidative modifications of the GLT-1 transporter in ALS (Pedersen Pedersen et al. 1998 Trotti et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212249 12684448 283415 20996 11179 SOD1 ALS ALS 28 2.2 previous reports of oxidative modifications of the GLT-1 transporter in ALS (Pedersen Pedersen et al. 1998 Trotti et al. 1999 Deitch 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212250 12684448 283415 18723 10261 ROS1 ROS ROS 6 0.0 In addition the suggestion that the ROS can exit MNs and affect surrounding astrocytes provides an explanation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212251 12684448 283416 18723 10261 ROS1 ROS ROS 25 0.0 al. 2000 and thus should be readily accessible to MN ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212252 12684448 283417 18723 10261 ROS1 ROS ROS-induced 2 0.0 Finally because ROS-induced disruption of glutamate transport would be expected to cause additional 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212253 12684448 283417 18723 10261 ROS1 ROS ROS 28 0.0 which in turn would result in increased excitotoxic activation and ROS generation in the local population of MNs the present observations 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212254 12684448 283418 20996 11179 SOD1 SOD SOD 24 2.2 compatible with a multiplicity of inciting mechanisms (e.g., e.g. mutant SOD leading into a common self-propagating disease pathway 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212255 12684448 283419 20996 11179 SOD1 ALS ALS 13 2.2 the nature of reciprocal interactions between MNs and astrocytes in ALS could powerfully impact the development of new therapeutic strategies 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212256 12684448 283427 18723 10261 ROS1 ROS ROS 4 0.0 Glutamate exposure causes preferential ROS generation in cultured MNs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212257 12684448 283436 18723 10261 ROS1 ROS ROS 3 0.0 Mechanisms of MN ROS generation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212258 12684448 283438 18723 10261 ROS1 ROS ROS 6 0.0 A Ca dependence of MN ROS generation ( circles was examined by exposing cultures to glutamate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212259 12684448 283439 18723 10261 ROS1 ROS ROS 8 0.0 B The role of mitochondria in MN ROS generation was tested by addition of the electron transport blocker 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212260 12684448 283443 18723 10261 ROS1 ROS ROS 1 0.0 MN ROS generation induces oxidation in neighboring astrocytes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212261 12684448 283444 20996 11179 SOD1 SOD SOD 35 2.2 MK-801 alone ( left or with addition of the antioxidant SOD (100 100 U/ml) U ml to the bath (+ AO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212262 12684448 283449 20996 11179 SOD1 SOD SOD 22 2.2 both the absence ( black or presence ( white of SOD with minimal response in other neurons ( squares 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212263 12684448 283450 20996 11179 SOD1 SOD SOD 45 2.2 ( bottom left or presence ( bottom right of extracellular SOD (+ AO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212264 12684448 283454 18723 10261 ROS1 ROS ROS 1 0.0 MN ROS can disrupt glutamate uptake in surrounding astrocytes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212265 12684448 283455 20996 11179 SOD1 SOD SOD 30 2.2 micro M MK-801 alone or with addition of the antioxidants SOD (100 100 U/ml) U ml and catalase (400 400 U/ml) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212266 12684448 283465 20996 11179 SOD1 SOD1 SOD1 6 2.2 Lumbar spinal cord sections from 3-month-old SOD1 transgenic mice ( G93A and nontransgenic controls ( non-TG ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212267 12684448 283472 17497 9543 PSMB6 Delta Delta 29 1.0 was highly selective for MNs (Carriedo Carriedo et al. 2000 Delta F in MNs (most most evident over the nuclei than 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 212268 12684448 283472 18723 10261 ROS1 ROS ROS 11 0.0 our previous studies using these cultures we found that the ROS generation induced by exposure to AMPA or kainate was highly 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212269 12684448 283473 17497 9543 PSMB6 Delta Delta 13 1.0 mitochondrially sequestered oxidation-sensitive fluorophore DHR (Dugan Dugan et al. 1995 Delta F was most notable in the perinuclear mitochondria-rich regions of 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 212270 12684448 283474 18723 10261 ROS1 ROS ROS 12 0.0 using HEt-loaded cultures were performed to examine the mechanisms of ROS generation in MNs (Fig Fig 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212271 12684448 283475 17497 9543 PSMB6 Delta Delta 2 1.0 The glutamate-induced Delta F was dependent on the presence of Ca in the 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 212272 12684448 283475 18723 10261 ROS1 ROS ROS 24 0.0 medium and suggesting a central role for mitochondria in the ROS generation it was blocked by addition of the electron transport 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212273 12684448 283476 18723 10261 ROS1 ROS ROS 2 0.0 Motor neuron ROS generation induces oxidation in neighboring astrocytes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212274 12684448 283477 18723 10261 ROS1 ROS ROS 6 0.0 We next sought to determine whether ROS generated in MNs was capable of inducing oxidation in surrounding 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212275 12684448 283479 17497 9543 PSMB6 Delta Delta 26 1.0 response in other spinal neurons (Carriedo Carriedo et al. 2000 Delta F in astrocytic nuclei permits highly sensitive ROS detection Before 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 212276 12684448 283479 18723 10261 ROS1 ROS ROS 10 0.0 This exposure paradigm which we found previously to cause strong ROS generation in MNs with virtually no response in other spinal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212277 12684448 283479 18723 10261 ROS1 ROS ROS 34 0.0 al. 2000 Delta F in astrocytic nuclei permits highly sensitive ROS detection Before imaging a microscope field (400_amp_#215;) 400_amp_#215 was selected 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212278 12684448 283480 17497 9543 PSMB6 Delta Delta 12 1.0 kainate (100 100 micro M plus 10 micro M MK-801 Delta F was measured in astrocytes at various distances from the 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 212279 12684448 283481 17497 9543 PSMB6 Delta Delta 35 1.0 results initially only from regions surrounding strongly responding MNs ( Delta F >3 a level of response seen in one-half of 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 212280 12684448 283481 18723 10261 ROS1 ROS ROS 17 0.0 oxidation in astrocytes would be proportionate to the intensity of ROS generation in the central MN we compiled results initially only 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212281 12684448 283482 17497 9543 PSMB6 Delta Delta 18 1.0 50 microm of the strongly responding MNs showed significantly greater Delta F than those farther away ( p _lt_ 0.001 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 212282 12684448 283483 20996 11179 SOD1 SOD SOD 8 2.2 With the addition of a cell-impermeant antioxidant enzyme (SOD, SOD 100 U/ml), U ml despite closely matched MN Delta F 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212283 12684448 283483 17497 9543 PSMB6 Delta Delta 15 1.0 (SOD, SOD 100 U/ml), U ml despite closely matched MN Delta F the astrocytic response was eliminated 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>9543|PSMB6|5694|No_GeneRif__12856|YY1|7528|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 212284 12684448 283484 20996 11179 SOD1 SOD SOD 5 2.2 This selective effect of extracellular SOD on astrocytic responses suggests strongly that the ROS generated in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212285 12684448 283484 20996 11179 SOD1 SOD SOD 29 2.2 extracellular bath (in in which it can be quenched by SOD before inducing oxidation in neighboring glia 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212286 12684448 283484 18723 10261 ROS1 ROS ROS 13 0.0 of extracellular SOD on astrocytic responses suggests strongly that the ROS generated in MNs passes into the extracellular bath (in in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212287 12684448 283486 18723 10261 ROS1 ROS ROS 2 0.0 Motor neuron ROS can disrupt glutamate uptake in surrounding astrocytes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212288 12684448 283487 18723 10261 ROS1 ROS ROS 4 0.0 The ability of this ROS to affect glutamate transport in nearby glia was assessed using 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212289 12684448 283495 20996 11179 SOD1 SOD SOD 14 2.2 uptake was prevented by addition of cell-impermeant antioxidant enzymes (SOD, SOD 100 U/ml; U ml catalase 400 U/ml) U ml to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212290 12684448 283497 18723 10261 ROS1 ROS ROS 14 0.0 simplified culture system enabled us to perform real-time examination of ROS generated in MNs and their effects in local glia 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212291 12684448 283498 20996 11179 SOD1 SOD1 SOD1 28 2.2 use of transgenic mice expressing the G93A mutant form of SOD1 associated with familial forms of ALS (Gurney Gurney et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 212292 12684448 283498 20996 11179 SOD1 ALS ALS 34 2.2 G93A mutant form of SOD1 associated with familial forms of ALS (Gurney Gurney et al. 1994 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 212293 12684448 283500 20996 11179 SOD1 ALS ALS 1 2.2 In ALS MNs protein oxidative damage has been well documented by 3-nitrotyrosine 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000873395958961213<>ScoreDetail__5468|IGFALS|0.000354695988201691__11179|SOD1|0.000873395958961213__ 0 0 0 0 0 203906 12718737 273319 20996 11179 SOD1 ALS ALS 23 1.4 stroke Parkinson's disease (PD) PD and amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113487316397057<>ScoreDetail__5468|IGFALS|0.000151280208766688__11179|SOD1|0.00113487316397057__ 0 0 0 0 0 203907 12718737 273323 20996 11179 SOD1 SOD SOD 6 1.7 Antioxidant enzymes such as superoxide dismutase (SOD), SOD catalase and glutathione peroxidase (GPx) GPx have demonstrated therapeutic efficacy 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 203908 12718737 273325 20996 11179 SOD1 SOD SOD 2 1.7 Most recently SOD mimetics small molecules which mimic the activity of endogenous superoxide 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 203909 12718737 273326 20996 11179 SOD1 ALS ALS 25 1.4 in treating some neurodegenerative diseases such as stroke PD and ALS but also the pitfalls that have met antioxidant molecules in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113487316397057<>ScoreDetail__5468|IGFALS|0.000151280208766688__11179|SOD1|0.00113487316397057__ 0 0 0 0 0 205107 12753090 274886 14533 7872 NOS1 nNOS nNOS 3 2.7 Proteasome activation and nNOS down-regulation in neuroblastoma cells expressing a Cu Zn superoxide dismutase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 205108 12753090 274886 20996 11179 SOD1 ALS ALS 17 1.9 expressing a Cu Zn superoxide dismutase mutant involved in familial ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00168801999439831<>ScoreDetail__5468|IGFALS|0.000488654063463946__11179|SOD1|0.00168801999439831__ 0 0 0 0 0 205109 12753090 274891 14533 7872 NOS1 nNOS nNOS 24 2.7 oxide production and down-regulation of neuronal nitric oxide synthase (nNOS) nNOS level were detected 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 205110 12753090 274892 14533 7872 NOS1 nNOS nNOS 1 2.7 The nNOS down-regulation was correlated to increased proteolytic degradation by proteasome because 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 205111 12753090 274892 14533 7872 NOS1 nNOS nNOS 15 2.7 to increased proteolytic degradation by proteasome because comparable levels of nNOS were detected in G93A and parental cells upon treatment with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 205112 12753090 274893 14533 7872 NOS1 nNOS nNOS 12 2.7 rate of proteolysis observed in G93A cells was specific for nNOS as Cu Zn superoxide dismutase (Cu,Zn Cu Zn SOD degradation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 205113 12753090 274893 20996 11179 SOD1 SOD SOD 18 1.9 for nNOS as Cu Zn superoxide dismutase (Cu,Zn Cu Zn SOD degradation by proteasome was influenced neither by its mutation nor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 205114 12753090 274895 20996 11179 SOD1 SOD SOD 10 1.9 these results confirm the pro-oxidant activity of G93A Cu Zn SOD mutant and at the same time suggest a cross-talk between 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 205385 12769802 275504 20996 11179 SOD1 ALS ALS 20 0.0 AD Parkinson's disease (PD), PD and amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000785712250190322<>ScoreDetail__5468|IGFALS|0.000463445718920171__11179|SOD1|0.000785712250190322__ 0 0 0 0 0 205386 12769802 275505 18723 10261 ROS1 ROS ROS 7 0.0 An unbalanced overproduction of reactive oxygen species (ROS) ROS may give rise to oxidative stress which can induce neuronal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 205387 12769802 275506 20996 11179 SOD1 ALS ALS 18 0.0 stress is involved in the pathogenesis of AD PD and ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000785712250190322<>ScoreDetail__5468|IGFALS|0.000463445718920171__11179|SOD1|0.000785712250190322__ 0 0 0 0 0 205388 12769802 275507 20996 11179 SOD1 ALS ALS 33 0.0 in animal models of neurodegenerative diseases including AD PD and ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000785712250190322<>ScoreDetail__5468|IGFALS|0.000463445718920171__11179|SOD1|0.000785712250190322__ 0 0 0 0 0 205389 12769802 275508 20996 11179 SOD1 ALS ALS 16 0.0 antioxidants might exert some protective effect against AD PD and ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000785712250190322<>ScoreDetail__5468|IGFALS|0.000463445718920171__11179|SOD1|0.000785712250190322__ 0 0 0 0 0 205390 12769802 275510 14352 7794 NFKB1 NF-kB NF-kB 15 0.3 the role played by the nuclear transcription factor -kB (NF-kB) NF-kB in apoptosis and in the pathogenesis of neurodegenerative disorders such 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 205391 12769802 275510 20996 11179 SOD1 ALS ALS 30 0.0 the pathogenesis of neurodegenerative disorders such as AD PD and ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000785712250190322<>ScoreDetail__5468|IGFALS|0.000463445718920171__11179|SOD1|0.000785712250190322__ 0 0 0 0 0 205392 12769802 275511 14352 7794 NFKB1 NF-kB NF-kB 7 0.3 The effects of ROS and antioxidants on NF-kB function and their relevance in the pathophysiology of neurodegenerative diseases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 205393 12769802 275511 18723 10261 ROS1 ROS ROS 3 0.0 The effects of ROS and antioxidants on NF-kB function and their relevance in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 200564 12873154 268347 20996 11179 SOD1 ALS ALS 7 0.0 Biomedical researchers interested in amyotrophic lateral sclerosis (ALS) ALS must invoke newly developing technologies if we are to discover 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000806067489832558<>ScoreDetail__5468|IGFALS|0.000401058795219379__11179|SOD1|0.000806067489832558__ 0 0 0 0 0 200565 12873154 268348 20996 11179 SOD1 ALS ALS 3 0.0 The focus of ALS research over the last 10 years has been on reactive 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000806067489832558<>ScoreDetail__5468|IGFALS|0.000401058795219379__11179|SOD1|0.000806067489832558__ 0 0 0 0 0 200566 12873154 268348 18723 10261 ROS1 ROS ROS 16 0.0 last 10 years has been on reactive oxygen species (ROS) ROS and glutamate excitotoxicity resulting in several clinical trials and the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 200567 12873154 268348 20996 11179 SOD1 ALS ALS 38 0.0 of the only drug currently available for the treatment of ALS riluzole 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000806067489832558<>ScoreDetail__5468|IGFALS|0.000401058795219379__11179|SOD1|0.000806067489832558__ 0 0 0 0 0 200568 12873154 268349 20996 11179 SOD1 ALS ALS 15 0.0 been minimal at best and the prognosis for patients with ALS has not improved beyond very modest retardation of the disease 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000806067489832558<>ScoreDetail__5468|IGFALS|0.000401058795219379__11179|SOD1|0.000806067489832558__ 0 0 0 0 0 200569 12873154 268350 18723 10261 ROS1 ROS ROS 2 0.0 By emphasising ROS and glutamate excitotoxicity current ALS research has only partially been 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 200570 12873154 268350 20996 11179 SOD1 ALS ALS 7 0.0 By emphasising ROS and glutamate excitotoxicity current ALS research has only partially been able to attenuate the rate 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000806067489832558<>ScoreDetail__5468|IGFALS|0.000401058795219379__11179|SOD1|0.000806067489832558__ 0 0 0 0 0 200571 12873154 268354 20996 11179 SOD1 ALS ALS 10 0.0 Oxidative stress seen in both familial and sporadic forms of ALS may be only one post-translational mechanism likely to affect specific 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000806067489832558<>ScoreDetail__5468|IGFALS|0.000401058795219379__11179|SOD1|0.000806067489832558__ 0 0 0 0 0 200572 12873154 268356 20996 11179 SOD1 ALS ALS 18 0.0 specific cells represent the kinds of advances needed to combat ALS in the third millennium 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000806067489832558<>ScoreDetail__5468|IGFALS|0.000401058795219379__11179|SOD1|0.000806067489832558__ 0 0 0 0 0 201128 12893007 269197 18723 10261 ROS1 ROS ROS 13 0.3 stress in which production of highly reactive oxygen species (ROS) ROS overwhelms antioxidant defenses is a feature of many neurological diseases 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201129 12893007 269198 20996 11179 SOD1 ALS ALS 40 2.9 s disease Lewy bodies related diseases amyotrophic lateral sclerosis (ALS), ALS and Huntington disease 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00118312467196082<>ScoreDetail__5468|IGFALS|0.000361573749745768__11179|SOD1|0.00118312467196082__ 0 0 0 0 0 201130 12893007 269200 20996 11179 SOD1 ALS ALS 5 2.9 In some familiar cases of ALS mutation in the gene for Cu/Zn Cu Zn superoxide dismutase 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00118312467196082<>ScoreDetail__5468|IGFALS|0.000361573749745768__11179|SOD1|0.00118312467196082__ 0 0 0 0 0 201131 12893007 269200 20996 11179 SOD1 SOD1 SOD1 14 2.9 in the gene for Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 can be identified 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201132 12893007 269201 18723 10261 ROS1 ROS ROS 4 0.3 In other neurodegenerative diseases ROS have some usually not clear role in early pathogenesis or 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201133 12893007 269203 6554 3309 ELA2 HNE HNE 21 0.8 aldehydes among which one of most important is 4-hydroxynonenal (HNE) HNE 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201134 12893007 269204 6554 3309 ELA2 HNE HNE 3 0.8 The presence of HNE is increased in brain tissue and cerebrospinal fluid of AD 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201135 12893007 269204 20996 11179 SOD1 ALS ALS 20 2.9 cerebrospinal fluid of AD patients and in spinal cord of ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00118312467196082<>ScoreDetail__5468|IGFALS|0.000361573749745768__11179|SOD1|0.00118312467196082__ 0 0 0 0 0 201136 12893007 269205 6554 3309 ELA2 HNE HNE 5 0.8 Immunohistochemical studies show presence of HNE in neurofibrilary tangles and in senile plaques in AD in 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201137 12893007 269205 20996 11179 SOD1 ALS ALS 25 2.9 in the cytoplasm of the residual motor neurons in sporadic ALS in Lewy bodies in neocortical and brain stem neurons in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00118312467196082<>ScoreDetail__5468|IGFALS|0.000361573749745768__11179|SOD1|0.00118312467196082__ 0 0 0 0 0 201138 12893007 269206 6554 3309 ELA2 HNE HNE 4 0.8 Thus increased levels of HNE in neurodegenerative disorders and immunohistochemical distribution of HNE in brain 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201139 12893007 269206 6554 3309 ELA2 HNE HNE 12 0.8 levels of HNE in neurodegenerative disorders and immunohistochemical distribution of HNE in brain tissue indicate pathophysiological role of oxidative stress in 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201140 12893007 269206 6554 3309 ELA2 HNE HNE 27 0.8 pathophysiological role of oxidative stress in these diseases and especially HNE in formation of abnormal filament deposites 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201141 12893007 269213 18723 10261 ROS1 ROS ROS 0 0.3 ROS induce peroxidation of the lipids (cellular cellular membrane lipids or 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201142 12893007 269214 18723 10261 ROS1 ROS ROS 13 0.3 with macromolecules the aldehydes are much more stable than the ROS so they can spread from site of origin and act 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201143 12893007 269215 6554 3309 ELA2 HNE HNE 19 0.8 fatty acids PUFAs peroxidation is highly reactive aldehyde 4-hydroxynonenal (HNE) HNE ( Uchida and Stadtman 1992 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201144 12893007 269216 18723 10261 ROS1 ROS ROS 23 0.3 conditions based on the production of reactive oxygen species (ROS) ROS ([ Esterbauer et al Wataya et al 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201145 12893007 269218 6554 3309 ELA2 HNE HNE 24 0.8 chronic and acute oxidative stress with evidence for contribution of HNE to pathogenesis of specific pathomorphologies in neuronal degeneration 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201146 12893007 269220 6554 3309 ELA2 HNE HNE 3 0.8 Lipid peroxidation and HNE in Alzheimer_amp_#x2019 s disease 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201147 12893007 269226 926 620 APP amyloid amyloid 8 1.0 These patients carry mutant genes for membrane spanning amyloid precursor protein (APP) APP 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 201148 12893007 269226 926 620 APP APP APP 11 0.6 carry mutant genes for membrane spanning amyloid precursor protein (APP) APP 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201149 12893007 269227 926 620 APP APP APP 0 0.6 APP have tree isoforms ( containing 695 751 and 770 amino 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201150 12893007 269229 926 620 APP amyloid amyloid 10 1.0 The core of these plaques contains a distinct form of amyloid _amp_#x3b2 -protein (BAP), BAP which is 40 amino acids in 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 201151 12893007 269229 19965 24624 SIL1 BAP BAP 12 0.1 plaques contains a distinct form of amyloid _amp_#x3b2 -protein (BAP), BAP which is 40 amino acids in length 6 JUMiner_v2.2 1 0 0 2 24624 TotalCon:2<>24624|SIL1|64374|Complete__30306|PHB2|11331|Complete__<>AvaiableGeneRif=2<>BEST:24624|SIL1|0.000219298245614035<>ScoreDetail__24624|SIL1|0.000219298245614035__30306|PHB2|0__ 0 0 0 0 0 201152 12893007 269230 926 620 APP APP APP 9 0.6 BAP is derived by proteolysis from a much larger APP 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201153 12893007 269230 19965 24624 SIL1 BAP BAP 0 0.0 BAP is derived by proteolysis from a much larger APP 1 JUMiner_v2.2 1 0 0 2 24624 TotalCon:2<>24624|SIL1|64374|Complete__30306|PHB2|11331|Complete__<>AvaiableGeneRif=2<>BEST:24624|SIL1|0.000219298245614035<>ScoreDetail__24624|SIL1|0.000219298245614035__30306|PHB2|0__ 0 0 0 0 0 201154 12893007 269231 926 620 APP APP APP 3 0.6 Normally degradation of APP involves a proteolytic cleavage in the middle of the BAP 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201155 12893007 269231 19965 24624 SIL1 BAP BAP 13 0.0 APP involves a proteolytic cleavage in the middle of the BAP domain with the release of fragment in the extracellular fluid 1 JUMiner_v2.2 1 0 0 2 24624 TotalCon:2<>24624|SIL1|64374|Complete__30306|PHB2|11331|Complete__<>AvaiableGeneRif=2<>BEST:24624|SIL1|0.000219298245614035<>ScoreDetail__24624|SIL1|0.000219298245614035__30306|PHB2|0__ 0 0 0 0 0 201156 12893007 269232 926 620 APP APP APP 3 0.6 In AD the APP molecule is cut at both ends of the BAP domain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201157 12893007 269232 926 620 APP amyloid amyloid 28 1.0 molecule which is toxic and accumulates in neuritic plaques as amyloid fibrils ([ Price et al . 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 201158 12893007 269232 19965 24624 SIL1 BAP BAP 12 0.0 the APP molecule is cut at both ends of the BAP domain releasing an intact BAP molecule which is toxic and 1 JUMiner_v2.2 1 0 0 2 24624 TotalCon:2<>24624|SIL1|64374|Complete__30306|PHB2|11331|Complete__<>AvaiableGeneRif=2<>BEST:24624|SIL1|0.000219298245614035<>ScoreDetail__24624|SIL1|0.000219298245614035__30306|PHB2|0__ 0 0 0 0 0 201159 12893007 269232 19965 24624 SIL1 BAP BAP 17 0.0 at both ends of the BAP domain releasing an intact BAP molecule which is toxic and accumulates in neuritic plaques as 1 JUMiner_v2.2 1 0 0 2 24624 TotalCon:2<>24624|SIL1|64374|Complete__30306|PHB2|11331|Complete__<>AvaiableGeneRif=2<>BEST:24624|SIL1|0.000219298245614035<>ScoreDetail__24624|SIL1|0.000219298245614035__30306|PHB2|0__ 0 0 0 0 0 201160 12893007 269233 926 620 APP amyloid amyloid 4 1.0 However argument against the amyloid cascade toxicity in AD are cognitively normal individuals who have 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 201161 12893007 269235 12337 6871 MAPK1 MAP MAP 19 0.3 of an abnormal form of normally occurring microtubule-associated protein (MAP), MAP termed tau 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201162 12893007 269235 12369 6893 MAPT tau tau 21 2.2 abnormal form of normally occurring microtubule-associated protein (MAP), MAP termed tau 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201163 12893007 269236 12369 6893 MAPT tau tau 1 2.2 Normal tau proteins are microtubule binding proteins predominantly axonal that stabilize the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201164 12893007 269237 12369 6893 MAPT tau tau 3 2.2 In normal brain tau is phosphorylated but the phosphate groups are in postmortal tissue 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201165 12893007 269238 12369 6893 MAPT tau tau 2 2.2 In contrast tau protein in PHF is relatively resistant to postmortem dephosphorylation ([ 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201166 12893007 269239 12369 6893 MAPT tau tau 4 2.2 In AD phosphorylation of tau on aberrant site could result in a protein that does 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201167 12893007 269245 18723 10261 ROS1 ROS ROS 18 0.3 docosahexenoic acid which build the brains phospholipids are vulnerable to ROS because of their double bonds that allow easy hydrogen abstraction 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201168 12893007 269249 11629 6493 LAMC2 CSF CSF 6 0.0 Concentration of F2-IsoP and f4-NP in CSF of AD patients are significantly elevated if compared with controls 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201169 12893007 269253 6554 3309 ELA2 HNE HNE 1 0.8 Determing HNE presence appears to be good solution to show specific onset 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201170 12893007 269254 6554 3309 ELA2 HNE HNE 0 0.8 HNE is neurotoxic 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201171 12893007 269256 6554 3309 ELA2 HNE HNE 4 0.8 After administration at forebrain HNE damages cholinergic neurons and impairs visuospatial memory in rats ( 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201172 12893007 269257 6554 3309 ELA2 HNE HNE 0 0.8 HNE is capable of inducing apoptosis in PC12 cells and cultured 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201173 12893007 269258 6554 3309 ELA2 HNE HNE 8 0.8 There are numerous findings supporting important role of HNE in development of AD 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201174 12893007 269259 6554 3309 ELA2 HNE HNE 5 0.8 Thus significant increase of free HNE in cerebrospinal fluid ([ Lovell et al amygdala hippocampus and 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201175 12893007 269260 6554 3309 ELA2 HNE HNE 5 0.8 Moreover immunocytochemical studies demonstrated that HNE immunoreactivity is present in NFT but only in some SP 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201176 12893007 269261 6554 3309 ELA2 HNE HNE 0 0.8 HNE modification of BAP results in a progressively selective and efficient 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201177 12893007 269261 19965 24624 SIL1 BAP BAP 3 0.0 HNE modification of BAP results in a progressively selective and efficient inhibition of degradation 1 JUMiner_v2.2 1 0 0 2 24624 TotalCon:2<>24624|SIL1|64374|Complete__30306|PHB2|11331|Complete__<>AvaiableGeneRif=2<>BEST:24624|SIL1|0.000219298245614035<>ScoreDetail__24624|SIL1|0.000219298245614035__30306|PHB2|0__ 0 0 0 0 0 201178 12893007 269262 6554 3309 ELA2 HNE HNE 18 0.8 in AD suggests dysfunction of proteasome system while co-existence of HNE immunoreactivity in the same cells suggests the essential role of 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201179 12893007 269263 6554 3309 ELA2 HNE HNE 0 0.8 HNE immunopositivity seems to be associated with the inheritance of apolipoprotein 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201180 12893007 269263 912 613 APOE APOE APOE 13 1.3 be associated with the inheritance of apolipoprotein E 4 (APOE) APOE alleles 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201181 12893007 269264 912 613 APOE APOE APOE 0 1.3 APOE genotype and advancing aging are interacting risk factors for late 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201182 12893007 269265 6554 3309 ELA2 HNE HNE 0 0.8 HNE is more potent crosslinker than malondialdehyde (MDA) MDA for purified 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201183 12893007 269265 6554 3309 ELA2 HNE HNE 21 0.8 and APOE4 and APOE3 is more susceptible to crosslinking by HNE then APOE4 in vitro in P19 neuroglial cell culture ( 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201184 12893007 269265 4062 1787 CDKN2A P19 P19 27 0.3 susceptible to crosslinking by HNE then APOE4 in vitro in P19 neuroglial cell culture ( Montine et al 1 JUMiner_v2.2 1 2 p19 cell 0 2 9951 TotalCon:4<>1787|CDKN2A|1029|Complete__1790|CDKN2D|1032|Complete__15488|IL23A|51561|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=4<>BEST:9951|REG1A|0.000525519415942411<>ScoreDetail__1787|CDKN2A|0.000347301415512588__9951|REG1A|0.000525519415942411__1790|CDKN2D|0.000392098174199341__15488|IL23A|0.00043057392578076__ 0 0 0 0 0 201185 12893007 269266 6554 3309 ELA2 HNE HNE 0 0.8 HNE is toxic for P19 cells causing cross-linking of tau into 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201186 12893007 269266 4062 1787 CDKN2A P19 P19 4 0.3 HNE is toxic for P19 cells causing cross-linking of tau into high molecular weight substances 1 JUMiner_v2.2 1 2 32 0 2 9951 TotalCon:4<>1787|CDKN2A|1029|Complete__1790|CDKN2D|1032|Complete__15488|IL23A|51561|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=4<>BEST:9951|REG1A|0.000525519415942411<>ScoreDetail__1787|CDKN2A|0.000347301415512588__9951|REG1A|0.000525519415942411__1790|CDKN2D|0.000392098174199341__15488|IL23A|0.00043057392578076__ 0 0 0 0 0 201187 12893007 269266 12369 6893 MAPT tau tau 9 2.2 HNE is toxic for P19 cells causing cross-linking of tau into high molecular weight substances that are conjugated with ubiquitin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201188 12893007 269267 6554 3309 ELA2 HNE HNE 13 0.8 enzymes which inactivate the toxic products of oxygen metabolism including HNE ([ Danielson et al 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201189 12893007 269269 6554 3309 ELA2 HNE HNE 8 0.8 This could lead to more pronounced effects of HNE in these brain regions 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201190 12893007 269270 6554 3309 ELA2 HNE HNE 1 0.8 However HNE cannot be considered as the only causative agent in protein 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201191 12893007 269275 6554 3309 ELA2 HNE HNE 14 0.8 a time and concentration dependent manner and more toxic than HNE at 5 _amp_#x3bc M concentration for hippocampal tissue cultures ( 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201192 12893007 269277 12369 6893 MAPT tau tau 11 2.2 preferentially reacts with lysine residues that are prominent components of tau ( Uchida et al and are present in NFT and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201193 12893007 269278 6554 3309 ELA2 HNE HNE 3 0.8 Thus not only HNE but also acrolein is likely to be causative factor in 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201194 12893007 269280 6554 3309 ELA2 HNE HNE 3 0.8 Lipid peroxidation and HNE in amyotrophic lateral sclerosis 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201195 12893007 269281 20996 11179 SOD1 ALS ALS 3 2.9 Amyotrophic lateral sclerosis (ALS) ALS is a progressive neurodegenerative disorder characterized by weakness and spasticity 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00118312467196082<>ScoreDetail__5468|IGFALS|0.000361573749745768__11179|SOD1|0.00118312467196082__ 0 0 0 0 0 201196 12893007 269283 20996 11179 SOD1 ALS ALS 0 2.9 ALS is further classified into sporadic (sALS) sALS and familial (fALS) 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00118312467196082<>ScoreDetail__5468|IGFALS|0.000361573749745768__11179|SOD1|0.00118312467196082__ 0 0 0 0 0 201197 12893007 269284 20996 11179 SOD1 ALS ALS 1 2.9 Sporadic ALS is one of the commonest adult-onset neurodegenerative disorders with a 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00118312467196082<>ScoreDetail__5468|IGFALS|0.000361573749745768__11179|SOD1|0.00118312467196082__ 0 0 0 0 0 201198 12893007 269285 20017 10940 SLC1A2 EAAT2 EAAT2 10 1.8 There is specific loss of the glial glutamate transporter protein EAAT2 in spinal cord of sALS cases ([ Fray et al 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201199 12893007 269286 20996 11179 SOD1 ALS ALS 9 2.9 The primary pathogenic processes underlying motor neuron injury in ALS are multifactorial and the precise molecular pathways of the motor 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00118312467196082<>ScoreDetail__5468|IGFALS|0.000361573749745768__11179|SOD1|0.00118312467196082__ 0 0 0 0 0 201200 12893007 269287 20996 11179 SOD1 ALS ALS 4 2.9 Approximately 10% of all ALS cases are fALS inherited by autosomal dominant or recessive transmission 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00118312467196082<>ScoreDetail__5468|IGFALS|0.000361573749745768__11179|SOD1|0.00118312467196082__ 0 0 0 0 0 201201 12893007 269288 20996 11179 SOD1 SOD SOD 21 2.9 with mutation in the gene encoding the superoxide dismutase (SOD SOD 1 protein ([ Rosen et al 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201202 12893007 269289 20996 11179 SOD1 SOD SOD 5 2.9 Most of the mutation in SOD 1 protein occur outside the active site and produce only 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201203 12893007 269290 20996 11179 SOD1 SOD SOD 0 2.9 SOD 1 is a Cu/Zn-binding Cu Zn-binding ubiquitous antioxidative enzyme that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201204 12893007 269292 20996 11179 SOD1 SOD SOD 5 2.9 Loss of function in mutant SOD 1 proposes that motor neurons injury occurs by direct toxic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201205 12893007 269293 20996 11179 SOD1 SOD SOD 7 2.9 Weakened affinity for copper in the mutant SOD with consequent leakage of copper which may produce competition between 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201206 12893007 269293 20996 11179 SOD1 SOD SOD 19 2.9 consequent leakage of copper which may produce competition between mutant SOD and other copper and zinc binding protein resulting in diminished 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201207 12893007 269294 20996 11179 SOD1 SOD SOD 13 2.9 mutations could cause an alteration in copper active site of SOD 1 ([ Deng et al 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201208 12893007 269295 20996 11179 SOD1 SOD SOD 9 2.9 Such changes could allow potential toxic gain of mutant SOD 1 to react with various subsidiary activities including peroxidase activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201209 12893007 269296 20996 11179 SOD1 SOD SOD 8 2.9 The wide active site channel of the mutant SOD 1 protein may enhance the access of peroxynitrite to the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201210 12893007 269298 20996 11179 SOD1 SOD SOD 1 2.9 Mutant SOD 1 A4V protein aggregation and accumulation in the anterior horns_amp_#x2019 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201211 12893007 269300 18723 10261 ROS1 ROS ROS 1 0.3 Overproduced ROS react with proteins nucleic acids and lipids 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201212 12893007 269301 6554 3309 ELA2 HNE HNE 7 0.8 The end products of lipid peroxidation like HNE are able to react with protein amino groups and cross-link 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201213 12893007 269302 6554 3309 ELA2 HNE HNE 6 0.8 An in vitro study showed that HNE impaires the glutamate and glucose transport and the choline acetyltransferase 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201214 12893007 269303 6554 3309 ELA2 HNE HNE 10 0.8 A study of autopsy materials indicated that increased level of HNE was cause of modification of astrocytic glutamate transporter EAAT2 and 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201215 12893007 269303 20017 10940 SLC1A2 EAAT2 EAAT2 19 1.8 of HNE was cause of modification of astrocytic glutamate transporter EAAT2 and impaired glutamate transport in ALS ( Pedersen et al 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201216 12893007 269303 20996 11179 SOD1 ALS ALS 25 2.9 of astrocytic glutamate transporter EAAT2 and impaired glutamate transport in ALS ( Pedersen et al 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00118312467196082<>ScoreDetail__5468|IGFALS|0.000361573749745768__11179|SOD1|0.00118312467196082__ 0 0 0 0 0 201217 12893007 269304 6554 3309 ELA2 HNE HNE 6 0.8 In the sALS intense immunoreactivity for HNE protein adducts and nepsiloncarboxymethyl-lisine (CML), CML as a lipid peroxidation 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201218 12893007 269304 1607 1014 BCR CML CML 11 0.3 sALS intense immunoreactivity for HNE protein adducts and nepsiloncarboxymethyl-lisine (CML), CML as a lipid peroxidation or protein glycoxidation products present in 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 201219 12893007 269305 20996 11179 SOD1 ALS ALS 15 2.9 not detectable in the spinal cord of sporadic or familial ALS patients ( Shibata et al 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00118312467196082<>ScoreDetail__5468|IGFALS|0.000361573749745768__11179|SOD1|0.00118312467196082__ 0 0 0 0 0 201220 12893007 269309 20996 11179 SOD1 SOD SOD 6 2.9 The relationship between the oxidative stress SOD 1 aggregation and accumulation of specific advanced glycation end products 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201221 12893007 269309 20996 11179 SOD1 ALS ALS 30 2.9 motor neurons needs to be base for understanding pathomechanisms of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00118312467196082<>ScoreDetail__5468|IGFALS|0.000361573749745768__11179|SOD1|0.00118312467196082__ 0 0 0 0 0 201222 12893007 269311 6554 3309 ELA2 HNE HNE 3 0.8 Lipid peroxidation and HNE in Parkinson_amp_#x2019 s disease 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201223 12893007 269327 18723 10261 ROS1 ROS ROS 7 0.3 Oxidative cascade leads to further generation of ROS which induce oxidative damage of DNA particularly in substantia nigra 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201224 12893007 269328 6554 3309 ELA2 HNE HNE 8 0.8 The end products of lipid peroxidation such as HNE are responsible for cytotoxicity in conjunction with oxidative stress acting 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201225 12893007 269329 6554 3309 ELA2 HNE HNE 0 0.8 HNE is present in Lewy bodies in PD and diffuse Lewy 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201226 12893007 269332 6554 3309 ELA2 HNE HNE 16 0.8 synaptosomes with ascorbic acid induced the production of TBARS and HNE ([ Morel et al 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201227 12893007 269333 6554 3309 ELA2 HNE HNE 6 0.8 Further incubation with ranging concentrations of HNE induced a dose-dependent decrease of dopamine uptake and Na /K 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201228 12893007 269334 6554 3309 ELA2 HNE HNE 4 0.8 These data suggest that HNE is an important mediator of oxidative stress that alters dopamine 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201229 12893007 269335 6554 3309 ELA2 HNE HNE 4 0.8 Such toxic effects of HNE may contribute to the onset and progression of Parkinson_amp_#x2019 s 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201230 12893007 269336 6554 3309 ELA2 HNE HNE 3 0.8 However pathophysiology of HNE in PD as well as in other neurodegenerative diseases should 3 JUMiner_v2.2 1 2 4-hydroxy-2-nonenal 0 0 0 0 0 0 0 0 201634 12901835 269760 20996 11179 SOD1 SOD1 SOD1 11 2.4 expression of mutant G93A copper/zinc copper zinc superoxide dismutase (SOD1), SOD1 associated with familial amyotrophic lateral sclerosis specifically causes a decrease 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201635 12901835 269760 18723 10261 ROS1 ROS ROS 40 0.3 increase in both cytosolic and mitochondrial reactive oxygen species (ROS) ROS production in human neuroblastoma SH-SY5Y cells compared to cells overexpressing 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201636 12901835 269760 20996 11179 SOD1 SOD1 SOD1 52 2.4 in human neuroblastoma SH-SY5Y cells compared to cells overexpressing wild-type SOD1 and untransfected cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201637 12901835 269761 18723 10261 ROS1 ROS ROS 4 0.3 Exposure to N-acetylcysteine lowers ROS production and returns mitochondrial functional assays to control levels 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201638 12901835 269762 20996 11179 SOD1 SOD1 SOD1 5 2.4 No large aggregates of human SOD1 are detectable under basal growth conditions in any of the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201639 12901835 269763 20996 11179 SOD1 SOD1 SOD1 4 2.4 After proteasome activity inhibition SOD1 aggregates can be detected exclusively in G93A-SOD1 cells even though 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 201640 12901835 269764 20996 11179 SOD1 SOD1 SOD1-generated 10 1.9 Our findings indicate that mitochondrial homeostasis is affected by mutant SOD1-generated ROS independently from the formation of aggregates and that this 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201641 12901835 269764 18723 10261 ROS1 ROS ROS 11 0.3 findings indicate that mitochondrial homeostasis is affected by mutant SOD1-generated ROS independently from the formation of aggregates and that this alteration 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201642 12901835 269766 20996 11179 SOD1 ALS ALS 3 1.9 Amyotrophic lateral sclerosis (ALS) ALS is a progressive and devastating neurological syndrome due to upper 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00149003823824291<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.00149003823824291__ 0 0 0 0 0 201643 12901835 269768 20996 11179 SOD1 ALS ALS 13 1.9 1990s it has been demonstrated that about 20% of familial ALS (FALS) FALS patients possess point mutations in the gene coding 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00149003823824291<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.00149003823824291__ 0 0 0 0 0 201644 12901835 269768 20996 11179 SOD1 SOD1 SOD1 30 2.4 coding for the antioxidant enzyme Cu Zn superoxide dismutase (SOD1) SOD1 Siddique et al 1991 Deng et al 1993 and Rosen 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201645 12901835 269769 20996 11179 SOD1 SOD1 SOD1 0 2.4 SOD1 typically has an antioxidant function because it removes the superoxide 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201646 12901835 269770 20996 11179 SOD1 SOD1 sod1 3 2.4 However mutations in sod1 gene do not cause FALS through simple loss of dismutating 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201647 12901835 269770 20996 11179 SOD1 SOD1 SOD1s 31 1.9 et al 1993 several lines of evidence indicate that mutant SOD1s are responsible for the death of motor neurons through the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201648 12901835 269772 18723 10261 ROS1 ROS ROS 8 0.3 One is that imbalance of reactive oxygen species (ROS) ROS metabolism might be elicited by FALS-SOD1 mutants because of modification 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201649 12901835 269773 20996 11179 SOD1 SOD1 SOD1 15 2.4 be responsible for the enhancement of the peroxidative activity of SOD1 as independently reported by two groups Wiedau-Pazos et al 1996 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201650 12901835 269775 20996 11179 SOD1 SOD1 SOD1s 10 1.9 The second hypothesis relies on the observation that misfolded mutant SOD1s might release their metal ions (copper copper and zinc and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201651 12901835 269777 20996 11179 SOD1 SOD1 SOD1 8 2.4 In particular decrease of the copper-buffering properties of SOD1 Steinkuhler et al 1991 could result in an increase of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201652 12901835 269780 20996 11179 SOD1 SOD1 SOD1s 8 1.9 It is not clear at present whether misfolded SOD1s would also bind copper ions and mediate increase in oxidative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201653 12901835 269781 20996 11179 SOD1 SOD1 SOD1 42 2.4 neuron disease with mice devoid of the Copper Chaperone for SOD1 (CCS CCS _amp_#x2212;/_amp_#x2212;) _amp_#x2212 _amp_#x2212 does not rescue the phenotype 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201654 12901835 269781 3838 1613 CCS CCS CCS 43 1.2 with mice devoid of the Copper Chaperone for SOD1 (CCS CCS _amp_#x2212;/_amp_#x2212;) _amp_#x2212 _amp_#x2212 does not rescue the phenotype Subramaniam et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201655 12901835 269782 3838 1613 CCS CCS CCS 7 1.2 However although it is most probable that CCS is not directly involved in ALS mishandling of copper is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201656 12901835 269782 20996 11179 SOD1 ALS ALS 13 1.9 is most probable that CCS is not directly involved in ALS mishandling of copper is still held as the major culprit 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00149003823824291<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.00149003823824291__ 0 0 0 0 0 201657 12901835 269782 20996 11179 SOD1 SOD1 SOD1 30 2.4 as the major culprit in oxidative stress induced by mutant SOD1 Bush 2002 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201658 12901835 269783 20996 11179 SOD1 ALS ALS 37 1.9 were shown in postmortem brain tissue of FALS and sporadic ALS (SALS) SALS patients Bowling et al 1993 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00149003823824291<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.00149003823824291__ 0 0 0 0 0 201659 12901835 269784 20996 11179 SOD1 SOD1 SOD1 8 2.4 The recent demonstration that a substantial amount of SOD1 (previously previously thought of as being exclusively a cytosolic enzyme 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201660 12901835 269784 20996 11179 SOD1 ALS ALS 60 1.9 damage occurring both in patients and in animal models of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00149003823824291<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.00149003823824291__ 0 0 0 0 0 201661 12901835 269785 18723 10261 ROS1 ROS ROS 19 0.3 the electron transport mitochondria are the major intracellular source of ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201662 12901835 269786 18723 10261 ROS1 ROS ROS 17 0.3 chain enzymes and impairment of energy metabolism contributing to further ROS generation as a result of electron leak at respiratory complexes 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201663 12901835 269788 20996 11179 SOD1 SOD1 SOD1-linked 12 1.9 reductase defects have been shown both in postmortem brains from SOD1-linked FALS patients Browne et al 1998 and in skeletal muscle 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201664 12901835 269789 20996 11179 SOD1 ALS ALS 11 1.9 increased number of mtDNA point mutations in spinal cord of ALS patients has been recently reported Wiedemann et al 2002 and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00149003823824291<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.00149003823824291__ 0 0 0 0 0 201665 12901835 269789 20996 11179 SOD1 SOD1 SOD1 43 2.4 spinal motor neurons of transgenic mice carrying G93A mutant human SOD1 Warita et al 2001 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201666 12901835 269790 18723 10261 ROS1 ROS ROS 10 0.3 In the present study we investigated the subcellular production of ROS and mitochondrial function in human neuroblastoma SH-SY5Y cell lines expressing 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201667 12901835 269790 14042 7625 NA NAC NAC 34 0.0 the effect of treatment with the glutathione-precursor N -acetylcysteine (NAC) NAC 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 201668 12901835 269793 20996 11179 SOD1 SOD1 SOD1 21 2.4 by site-directed mutagenesis of the cDNA coding for that mutant SOD1 cloning in expression vectors and transfection of parental human neuroblastoma 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201669 12901835 269819 18723 10261 ROS1 ROS ROS 6 0.3 Whole-cell and mitochondrial reactive oxygen species (ROS) ROS levels 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201670 12901835 269820 18723 10261 ROS1 ROS ROS 29 0.3 2001 were used to quantify levels of whole-cell and mitochondrial ROS respectively 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201671 12901835 269821 20247 20116 SLC25A29 CACL CaCl 27 1.0 NaCl 5.6 mM KCl 3.6 mM NaHCO 3 2.3 mM CaCl 2 5.6 mM glucose 5 mM Hepes 1.2 mM MgCl 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 201672 12901835 269826 20996 11179 SOD1 SOD1 SOD1 20 2.4 using the Immun-blot kit from Bio-Rad with a polyclonal antihuman SOD1 antibody Steinkuhler et al 1991 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201673 12901835 269827 3778 10620 CCL21 ECL ECL 5 0.0 Labeled proteins were detected using ECL Western blotting analysis system (Amersham Amersham Pharmacia Biotech 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201674 12901835 269830 20996 11179 SOD1 SOD1 SOD1 18 2.4 for 2 h at 37_amp_#xb0 C with a monoclonal antimouse SOD1 antibody (Sigma) Sigma 1 300 and for 2 h at 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201675 12901835 269844 18723 10261 ROS1 ROS ROS 3 0.3 Whole-cell and mitochondrial ROS production Intracellular levels of free radicals were tested using the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201676 12901835 269845 18723 10261 ROS1 ROS ROS 13 0.3 the ionized free acid (DCFH), DCFH which then reacts with ROS in particular cytosolic peroxides to form the fluorescent 2_amp_#x2032 7_amp_#x2032 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201677 12901835 269846 18723 10261 ROS1 ROS ROS 36 0.3 signal of diffuse extranuclear fluorescence suggesting both cytosolic and mitochondrial ROS accumulation ( Fig 2B and C 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201678 12901835 269847 18723 10261 ROS1 ROS ROS 7 0.3 WT cells showed a reduced production of ROS compared to SH cells ( P _amp_#x3c 0.05 in line 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201679 12901835 269847 20996 11179 SOD1 SOD1 SOD1 25 2.4 0.05 in line with the well-known protective role of wild-type SOD1 overexpression against free radicals 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201680 12901835 269848 18723 10261 ROS1 ROS ROS 12 0.3 (1 1 mM 24 h determined a marked decrease in ROS levels exclusively in G93A cells ( P _amp_#x3c 0.001 compared 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201681 12901835 269848 14042 7625 NA NAC NAC 2 0.0 Exposure to NAC (1 1 mM 24 h determined a marked decrease in 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 201682 12901835 269849 18723 10261 ROS1 ROS ROS 3 0.3 Mitochondrial production of ROS in particular superoxide anions and peroxynitrite was determined using DHR 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201683 12901835 269852 18723 10261 ROS1 ROS ROS 5 0.3 After exposure to NAC mitochondrial ROS significantly decreased only in G93A cells ( P _amp_#x3c 0.05 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201684 12901835 269852 14042 7625 NA NAC NAC 3 0.1 After exposure to NAC mitochondrial ROS significantly decreased only in G93A cells ( P 6 JUMiner_v2.2 1 2 n-acetylcysteine 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 201685 12901835 269853 14042 7625 NA NAC NAC 30 0.0 evaluate mitochondrial function under basal conditions and after incubation with NAC (1 1 mM 24 h 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 201686 12901835 269858 14042 7625 NA NAC NAC 7 0.0 The same parameter was completely restored by NAC in G93A cells ( P _amp_#x3c 0.001 compared to untreated 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 201687 12901835 269863 14042 7625 NA NAC NAC 2 0.0 Exposure to NAC under basal condition resulted in a rise of ATP levels 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 201688 12901835 269864 20996 11179 SOD1 SOD1 SOD1 3 2.4 Aggregation of mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201689 12901835 269865 20996 11179 SOD1 SOD1 SOD1 9 2.4 It has been suggested that aggregation of misfolded mutant SOD1 contributes to neurodegeneration in FALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201690 12901835 269866 20996 11179 SOD1 SOD1 SOD1 6 2.4 However it is still debated whether SOD1 aggregates represent a cause a correlate or a consequence of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201691 12901835 269867 20996 11179 SOD1 SOD1 SOD1 10 2.4 In all of our lines no large aggregates of human SOD1 are detectable after immunostaining in basal growth conditions ( Fig 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201692 12901835 269868 20996 11179 SOD1 SOD1 SOD1 13 2.4 localized in the cytoplasm and roughly paralleled the level of SOD1 expression being more intense in transfected cells than in control 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201693 12901835 269869 20996 11179 SOD1 SOD1 SOD1-positive 12 1.9 specifically inhibit the proteasome activity with lactacystin for 16 h SOD1-positive aggregates localize in the cytoplasm of 30_amp_#x2013 40% cells expressing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201694 12901835 269869 20996 11179 SOD1 SOD1 SOD1s 23 1.9 localize in the cytoplasm of 30_amp_#x2013 40% cells expressing mutant SOD1s but not in control cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201695 12901835 269870 20996 11179 SOD1 SOD1 SOD1 11 2.4 is paralleled by the appearance of an insoluble fraction containing SOD1 in extracts from cells expressing mutant SOD1 as seen in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201696 12901835 269870 20996 11179 SOD1 SOD1 SOD1 18 2.4 insoluble fraction containing SOD1 in extracts from cells expressing mutant SOD1 as seen in Western blot experiments where detergent-soluble and -insoluble 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201697 12901835 269873 20996 11179 SOD1 ALS ALS 34 1.9 biochemical parameters that appear to be altered also in sporadic ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00149003823824291<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.00149003823824291__ 0 0 0 0 0 201698 12901835 269874 20996 11179 SOD1 SOD1 SOD1 16 2.4 to demonstrate that human neuroblastoma SH-SY5Y cell lines carrying G93A SOD1 mutation possess remarkable biochemical abnormalities compared to control cells such 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201699 12901835 269875 18723 10261 ROS1 ROS ROS 28 0.3 or apoptosis under basal growth conditions a significant increase in ROS production was found to occur both in cytosol and mitochondria 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201700 12901835 269876 20996 11179 SOD1 SOD1 SOD1 5 2.4 This provides evidence that G93A SOD1 mutation acts as a remarkable source of intracellular oxidative stress 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201701 12901835 269878 20996 11179 SOD1 ALS ALS 10 1.9 Previous studies reported a certain degree of mitochondrial dysfunction in ALS experimental models as well as in the central nervous system 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00149003823824291<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.00149003823824291__ 0 0 0 0 0 201702 12901835 269878 20996 11179 SOD1 ALS ALS 25 1.9 as in the central nervous system and peripheral tissues from ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00149003823824291<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.00149003823824291__ 0 0 0 0 0 201703 12901835 269879 20996 11179 SOD1 SOD1 SOD1 26 2.4 and mitochondrial ultrastructural abnormalities were found in animal models carrying SOD1 mutations Wong et al 1995 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201704 12901835 269881 24185 29175 WDTC1 ADP ADP 19 0.0 complex II and IV and no changes in the ATP ADP ratio in a motor neuron cell line transfected with G93A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201705 12901835 269885 20996 11179 SOD1 SOD1 SOD1 14 2.4 be a direct consequence of the pro-oxidant activity of mutant SOD1 indeed the use of NAC promptly reverts both increase in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201706 12901835 269885 18723 10261 ROS1 ROS ROS 25 0.3 indeed the use of NAC promptly reverts both increase in ROS levels and mitochondrial alterations 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201707 12901835 269885 14042 7625 NA NAC NAC 19 0.0 the pro-oxidant activity of mutant SOD1 indeed the use of NAC promptly reverts both increase in ROS levels and mitochondrial alterations 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 201708 12901835 269886 14042 7625 NA NAC NAC 0 0.0 NAC is a membrane-permeable antioxidant molecule that is rapidly hydrolyzed to 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 201709 12901835 269887 14042 7625 NA NAC NAC 15 0.0 the cell is the limiting factor in glutathione synthesis so NAC acts enhancing the naturally occurring glutathione (GSH) GSH Sen 1998 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 201710 12901835 269890 20996 11179 SOD1 SOD1 SOD1 21 2.4 survival and motor performance in transgenic mice with a G93A SOD1 mutation Andreassen et al 2000 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201711 12901835 269890 14042 7625 NA NAC NAC 9 0.0 In agreement with this observation one study showed that NAC improves survival and motor performance in transgenic mice with a 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>7625|NA|4663|No_GeneRif__14374|NLRP1|22861|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 201712 12901835 269892 20996 11179 SOD1 SOD1 SOD1 8 2.4 When we specifically inhibit the proteasome activity insoluble SOD1 aggregates localize in the cytoplasm of cells expressing mutant SOD1s 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201713 12901835 269892 20996 11179 SOD1 SOD1 SOD1s 18 1.9 SOD1 aggregates localize in the cytoplasm of cells expressing mutant SOD1s but not in control cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201714 12901835 269894 14373 7808 NGF NGF NGF 27 1.2 is not causative of death in nerve growth factor (NGF)-differentiated NGF -differentiated PC12 cells transfected with mutant SOD1s (SODMT, SODMT V148G 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201715 12901835 269894 20996 11179 SOD1 SOD1 SOD1s 33 1.9 growth factor (NGF)-differentiated NGF -differentiated PC12 cells transfected with mutant SOD1s (SODMT, SODMT V148G or A4V 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201716 12901835 269895 20996 11179 SOD1 SOD1 SOD1 38 2.4 survey on the properties of a large number of mutant SOD1 in vitro Hayward et al 2002 and Rodriguez et al 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 201717 12901835 269896 18723 10261 ROS1 ROS ROS 11 0.3 conclusion our data indicate that altered mitochondrial function and increased ROS production might be the primary effect of FALS-linked G93A mutation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 201718 12901835 269897 20996 11179 SOD1 ALS ALS 12 1.9 suggest that the use of antioxidants in the therapy of ALS should be further examined with the specific aim to protect 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00149003823824291<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.00149003823824291__ 0 0 0 0 0 202210 12909279 270734 20996 11179 SOD1 ALS ALS 23 2.8 observed both in post-mortem samples and in experimental models for ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202211 12909279 270739 20996 11179 SOD1 ALS ALS 15 2.8 neurones is the typical feature of amyotrophic lateral sclerosis (ALS), ALS a progressive lethal disease occurring both sporadically (sALS) sALS and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202212 12909279 270740 20996 11179 SOD1 ALS ALS 0 2.8 ALS is one of the most common neurodegenerative disorders with an 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202213 12909279 270741 20996 11179 SOD1 ALS ALS 5 2.8 Recent epidemiological evidences indicate that ALS occurrence is growing in many countries a fact that may 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202214 12909279 270743 20996 11179 SOD1 ALS ALS 1 2.8 Although ALS patients show some degree of heterogeneity as far as symptoms 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202215 12909279 270745 20996 11179 SOD1 ALS ALS 8 2.8 Present evidence indicates that loss of neurones in ALS results from a complex interplay among oxidative injury excitotoxic stimulation 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202216 12909279 270746 20996 11179 SOD1 ALS ALS 10 2.8 The roles of excitotoxicity cytoskeletal abnormalities and protein aggregates in ALS have been recently and exhaustively reviewed by others 17 40 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202217 12909279 270747 20996 11179 SOD1 ALS ALS 19 2.8 oxidative stress is a major culprit in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202218 12909279 270751 20996 11179 SOD1 ALS ALS 9 2.8 A role for oxidative stress in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202219 12909279 270752 18723 10261 ROS1 ROS ROS 18 0.9 (physiological) physiological production of potentially toxic reactive oxygen species (ROS) ROS such as superoxide hydrogen peroxide and hydroxyl radical and the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202220 12909279 270754 18723 10261 ROS1 ROS ROS 25 0.9 of ROS-generating electron leakage (2) 2 interception of potentially dangerous ROS i.e scavenging by antioxidant molecules and (3) 3 repair of 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202221 12909279 270754 18723 10261 ROS1 ROS ROS 42 0.9 3 repair of damage i.e removal of molecules damaged by ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202222 12909279 270754 18723 10261 ROS1 ROS ROS-generating 17 0.0 three levels (1) 1 prevention of damage i.e prevention of ROS-generating electron leakage (2) 2 interception of potentially dangerous ROS i.e 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202223 12909279 270755 18723 10261 ROS1 ROS ROS 33 0.9 redox cycling_amp_#x201d i.e alternative oxidisation and reduction during which toxic ROS are generated 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202224 12909279 270757 18723 10261 ROS1 ROS ROS 46 0.9 e.g membrane polyunsaturated lipids and an inherently high flux of ROS generated during neurochemical reactions such as dopamine oxidation 39 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202225 12909279 270759 20996 11179 SOD1 ALS ALS 7 2.8 A role for ROS-mediated oxidative stress in ALS was proposed by many investigators who reported that typical oxidation 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202226 12909279 270759 20996 11179 SOD1 ALS ALS 36 2.8 and membrane phospholipids are elevated both in sporadic and familial ALS patients and in several model systems as well 4 6 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202227 12909279 270759 18723 10261 ROS1 ROS ROS-mediated 3 0.0 A role for ROS-mediated oxidative stress in ALS was proposed by many investigators who 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202228 12909279 270760 18723 10261 ROS1 ROS ROS 14 0.9 become prominent in mitochondria in which the majority of cellular ROS is produced and targets mitochondrial proteins lipids as well as 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202229 12909279 270762 20996 11179 SOD1 ALS ALS 17 2.8 death of motor neurones which is likely to occur in ALS 35 and 59 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202230 12909279 270763 18723 10261 ROS1 ROS ROS 2 0.9 In fact ROS are very well known inducers of cell death they regulate 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202231 12909279 270763 18723 10261 ROS1 ROS ROS 22 0.9 regulate early and late steps of apoptosis and inhibition of ROS production also protects against apoptosis ( 29 and references therein 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202232 12909279 270764 20996 11179 SOD1 ALS ALS 13 2.8 the concept that oxidative stress plays a major role in ALS as in other neurodegenerative diseases is provided by the observation 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202233 12909279 270764 20996 11179 SOD1 SOD1 SOD1 37 2.7 coding for the antioxidant enzyme Cu Zn superoxide dismutase (SOD1) SOD1 have been reported in fALS patients 21 and 80 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202234 12909279 270765 20996 11179 SOD1 SOD1 SOD1 0 2.7 SOD1 is a very well-characterised homodimeric enzyme present in virtually every 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202235 12909279 270766 20996 11179 SOD1 SOD1 SOD1 0 2.7 SOD1 binds zinc and copper ions with the Cu atom playing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202236 12909279 270766 18723 10261 ROS1 ROS ROS 28 0.9 the removal of superoxide and prevention of further generation of ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202237 12909279 270767 20996 11179 SOD1 SOD1 SOD1 7 2.7 Linkage studies have revealed that mutations in SOD1 are responsible for 10_amp_#x2013 15% of fALS cases 40 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202238 12909279 270768 20996 11179 SOD1 SOD1 SOD1 7 2.7 To date there are about 100 different SOD1 point mutations ( www.als.org reported in fALS families with various 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202239 12909279 270769 20996 11179 SOD1 SOD1 SOD1 20 2.7 and result in alteration of amino acids scattered throughout the SOD1 structure while some mutations affect the active site others are 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202240 12909279 270773 20996 11179 SOD1 SOD1 SOD1s 10 1.9 For this reason the mechanisms through which expression of mutant SOD1s result in motoneuron injury and death are still controversial 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202241 12909279 270774 20996 11179 SOD1 SOD1 SOD1 13 2.7 believed that the gain of a novel toxic function of SOD1 is responsible for the acquisition of the pathological phenotype 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202242 12909279 270776 20996 11179 SOD1 SOD1 SOD1 0 2.7 SOD1 is an abundant component of many cell types accounting for 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202243 12909279 270777 20996 11179 SOD1 SOD1 SOD1 21 2.7 _amp_#x201c conformational_amp_#x201d diseases formation of insoluble aggregates of misfolded mutant SOD1 contributes to cell death in fALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202244 12909279 270778 20996 11179 SOD1 SOD1 SOD1 6 2.7 However it is still debated whether SOD1 aggregates represent a cause a correlate or a consequence of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202245 12909279 270779 20996 11179 SOD1 SOD1 SOD1 19 2.7 of sALS patients contain cytoplasmic aggregates that show immunoreactivity for SOD1 and ubiquitin similar inclusion bodies were also observed in SOD1-linked 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202246 12909279 270779 20996 11179 SOD1 SOD1 SOD1-linked 29 2.2 SOD1 and ubiquitin similar inclusion bodies were also observed in SOD1-linked fALS patients 12 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202247 12909279 270781 20996 11179 SOD1 SOD1 SOD1 7 2.7 More recent evidence questioned the relevance of SOD1 aggregates in the pathogenesis of fALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202248 12909279 270782 20996 11179 SOD1 SOD1 SOD1 9 2.7 For instance it has been reported that formation of SOD1 aggregates is independent of induction of cell death 52 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202249 12909279 270783 20996 11179 SOD1 SOD1 SOD1 0 2.7 SOD1 aggregates may be toxic through sequestration of other proteins required 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202250 12909279 270784 20996 11179 SOD1 SOD1 SOD1 1 2.7 Also SOD1 aggregates may reduce proteasome activity needed for normal protein turnover 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202251 12909279 270786 18723 10261 ROS1 ROS ROS 12 0.9 of evidence indicate that fALS-SOD1s_amp_#x2019 novel properties involve imbalance of ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202252 12909279 270787 20996 11179 SOD1 SOD1 SOD1s 2 1.9 How mutant SOD1s cause oxidative stress and which molecules represent direct targets/propagators targets 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202253 12909279 270788 18723 10261 ROS1 ROS ROS 2 0.9 Imbalance of ROS metabolism may be elicited by fALS-SOD1 mutants because of their 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202254 12909279 270789 20996 11179 SOD1 SOD1 SOD1 17 2.7 the active site could exacerbate the reported peroxidative activity of SOD1 as suggested by studies in vitro 100 and in vivo 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202255 12909279 270793 20996 11179 SOD1 SOD1 SOD1 36 2.7 it has been suggested that aggregated but still active mutant SOD1 may mediate the formation of ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202256 12909279 270793 18723 10261 ROS1 ROS ROS 42 0.9 but still active mutant SOD1 may mediate the formation of ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202257 12909279 270794 18723 10261 ROS1 ROS ROS 18 0.9 proposed that misfolded fALS-SOD1 may contribute to generation of intracellular ROS simply by loosing their copper-buffering ability (see see below 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202258 12909279 270796 20996 11179 SOD1 ALS ALS 10 2.8 Coping with copper are copper buffering and transport altered in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202259 12909279 270800 20996 11179 SOD1 SOD1 SOD1 36 2.7 uptake intracellular delivery from chaperones (e.g e.g copper chaperone for SOD1 (CCS), CCS COX17 and Atx1 to specific targets (such such 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202260 12909279 270800 3838 1613 CCS CCS CCS 37 1.2 delivery from chaperones (e.g e.g copper chaperone for SOD1 (CCS), CCS COX17 and Atx1 to specific targets (such such as SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202261 12909279 270800 4836 2264 COX17 COX17 COX17 38 0.6 from chaperones (e.g e.g copper chaperone for SOD1 (CCS), CCS COX17 and Atx1 to specific targets (such such as SOD1 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202262 12909279 270800 1277 798 ATOX1 ATX1 Atx1 40 1.3 (e.g e.g copper chaperone for SOD1 (CCS), CCS COX17 and Atx1 to specific targets (such such as SOD1 and cytochrome c 2 JUMiner_v2.2 1 0 0 2 798 TotalCon:2<>10548|ATXN1|6310|Complete__798|ATOX1|475|Complete__<>AvaiableGeneRif=2<>BEST:798|ATOX1|0.00121583085752467<>ScoreDetail__10548|ATXN1|0.000480397441004851__798|ATOX1|0.00121583085752467__ 0 0 0 0 0 202263 12909279 270800 20996 11179 SOD1 SOD1 SOD1 46 2.7 CCS COX17 and Atx1 to specific targets (such such as SOD1 and cytochrome c oxidase and/or and or storage in copper 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202264 12909279 270803 20996 11179 SOD1 SOD1 SOD1-linked 6 2.2 This is not the case in SOD1-linked fALS in which no alteration of total copper content is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202265 12909279 270803 3838 1613 CCS CCS CCS 25 1.2 content is observed not even in experimental conditions in which CCS is missing 90 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202266 12909279 270806 20996 11179 SOD1 SOD1 SOD1-linked 5 2.2 This may be occurring in SOD1-linked fALS since it is known that many mutant SOD1s do 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202267 12909279 270806 20996 11179 SOD1 SOD1 SOD1s 14 1.9 in SOD1-linked fALS since it is known that many mutant SOD1s do not bind metals properly in vitro and possibly in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202268 12909279 270807 20996 11179 SOD1 SOD1 SOD1s 13 1.9 ability to bind copper (and and zinc among different mutant SOD1s have been reported 42 this seems to be to a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202269 12909279 270807 20996 11179 SOD1 SOD1 SOD1 36 2.7 general characteristic of fALS-SOD1s reinforcing the previously suggested hypothesis that SOD1 plays a crucial role in copper buffering 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202270 12909279 270809 20996 11179 SOD1 SOD1 sod1 2 2.7 In man sod1 is present in a single copy per haploid genome and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202271 12909279 270809 20996 11179 SOD1 SOD1 SOD1 31 2.7 penetrance close to 1 with patients usually heterozygous for mutant SOD1 except for some families carrying the mutation D90A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202272 12909279 270810 20996 11179 SOD1 SOD1 SOD1 5 2.7 Therefore alteration of half of SOD1 molecules in patients may result in a relevant imbalance of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202273 12909279 270810 20996 11179 SOD1 SOD1 SOD1 25 2.7 of either copper buffering or copper chemistry especially considering that SOD1 is a very abundant protein representing up to 1% of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202274 12909279 270814 20996 11179 SOD1 SOD1 SOD1 42 2.7 models 16 and 32 inhibit the peroxidase activity of mutant SOD1 A4V and G93A in vitro 100 rescue elevation of ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202275 12909279 270814 18723 10261 ROS1 ROS ROS 54 0.9 SOD1 A4V and G93A in vitro 100 rescue elevation of ROS levels in lymphoblasts from fALS patients 82 and revert the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202276 12909279 270824 20996 11179 SOD1 ALS ALS 22 2.8 reported in only one investigation in a limited sample of ALS patients 96 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202277 12909279 270825 3838 1613 CCS CCS CCS 12 1.2 transgenic fALS-mice model alteration of Cu metabolism via removal of CCS does not induce decrease of serum Cp 90 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202278 12909279 270826 20996 11179 SOD1 SOD1 SOD1-linked 27 2.2 Cp has been described 68 that could be altered in SOD1-linked fALS because of copper mishandling and cause iron mishandling 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202279 12909279 270827 20996 11179 SOD1 SOD SOD 24 1.9 yeast Saccharomyces cerevisiae 20 and 87 in which lack of SOD causes a substantial increase in the Fe demand of the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202280 12909279 270830 20996 11179 SOD1 SOD SOD-defective 6 1.9 The increased Fe demand of the SOD-defective yeast cell may reflect its aim to continuously reconstitute the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202281 12909279 270831 24231 12780 WNT2 IRP IRP 21 0.0 mitochondria respiratory chain but also of the so-called _amp_#x201c IRE_amp_#x2013 IRP machinery_amp_#x201d (iron-responsive iron-responsive element_amp_#x2013 iron regulatory protein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202282 12909279 270833 24231 12780 WNT2 IRP IRPs 0 0.0 IRPs are cytosolic factors binding to a mRNA-hairpin structure known as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202283 12909279 270834 24231 12780 WNT2 IRP IRP 11 0.0 of low Fe availability the Fe_amp_#x2013 S cluster in the IRP is open therefore allowing the IRP to bind to the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202284 12909279 270834 24231 12780 WNT2 IRP IRP 17 0.0 S cluster in the IRP is open therefore allowing the IRP to bind to the IRE 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202285 12909279 270835 24231 12780 WNT2 IRP IRP 16 0.0 the 3_amp_#x2032 untranslated region of the mRNA the binding of IRP usually causes an up-regulation of the coded protein as for 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202286 12909279 270836 24231 12780 WNT2 IRP IRP 3 0.0 Conversely binding of IRP to an IRE in the 5_amp_#x2032 untranslated region of the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202287 12909279 270837 166 118 ACO2 aconitase aconitase 28 1.3 involved in mitochondrial metabolism such as Complex I 53 and aconitase 51 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202288 12909279 270838 20996 11179 SOD1 ALS ALS 1 2.8 In ALS patients an imbalance in ROS production_amp_#x2014 either caused directly by 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202289 12909279 270838 18723 10261 ROS1 ROS ROS 6 0.9 In ALS patients an imbalance in ROS production_amp_#x2014 either caused directly by mutant SOD1 or indirectly by 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202290 12909279 270838 20996 11179 SOD1 SOD1 SOD1 12 2.7 an imbalance in ROS production_amp_#x2014 either caused directly by mutant SOD1 or indirectly by other mechanisms_amp_#x2014 could be responsible for damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202291 12909279 270838 24231 12780 WNT2 IRP IRP 34 0.0 in turn this could cause inactivation both of the IRE_amp_#x2013 IRP machinery and of mitochondrial enzymes ( Fig 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202292 12909279 270839 20996 11179 SOD1 SOD1 SOD1-linked 14 2.2 complexes has been reported in patients and in models for SOD1-linked fALS 19 49 60 61 and 101 and there is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202293 12909279 270839 20996 11179 SOD1 ALS ALS 44 2.8 altered iron homeostasis may be implicated in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202294 12909279 270842 24231 12780 WNT2 IRP IRP-regulated 22 0.5 ii Fe_amp_#x2013 S-cluster status nor (iii) iii transcription of IRE_amp_#x2013 IRP-regulated genes have been studied in patients suffering from fALS or 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202295 12909279 270842 20996 11179 SOD1 ALS ALS 35 2.8 been studied in patients suffering from fALS or in any ALS model system 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202296 12909279 270843 20996 11179 SOD1 ALS ALS 6 2.8 That metal homeostasis is altered in ALS is indicated also by observations on the level of expression 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202297 12909279 270845 20996 11179 SOD1 SOD1 SOD1 17 2.7 that the metal-mediated free radical generation derived either from mutant SOD1 or from mishandled metal ions might be related to the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202298 12909279 270846 20996 11179 SOD1 ALS ALS 5 2.8 Finally a possible link between ALS and metal homeostasis is represented by modulation of proteasome functionality 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202299 12909279 270849 18723 10261 ROS1 ROS ROS 47 0.9 depending on the cell type or on the extent of ROS production 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202300 12909279 270852 10668 6115 IREB2 IRP2 IRP-2 24 1.2 but also in the regulation of translation-regulatory factors such as IRP-2 a factor involved in intracellular iron metabolism which is broken 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202301 12909279 270853 10668 6115 IREB2 IRP2 IRP-2 10 1.2 In this view proteasomal inhibition may disrupt normal turnover of IRP-2 thus causing elevated Fe levels within the cell which_amp_#x2014 as 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202302 12909279 270853 18723 10261 ROS1 ROS ROS 24 0.9 within the cell which_amp_#x2014 as mentioned for copper_amp_#x2014 can generate ROS causing oxidative stress and inactivating other crucial enzymes (e.g e.g 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202303 12909279 270856 20996 11179 SOD1 SOD1 SOD1-linked 18 2.2 clinically indistinguishable therefore studies on the less frequent genetically inherited SOD1-linked form of the disease are thought to be potentially useful 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202304 12909279 270856 20996 11179 SOD1 ALS ALS 34 2.8 thought to be potentially useful for a general understanding of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202305 12909279 270857 20996 11179 SOD1 SOD1 SOD1 19 2.7 in order to understand cellular alterations induced by mutation of SOD1 17 and 48 up to date no study has shed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202306 12909279 270857 20996 11179 SOD1 SOD1 SOD1 54 2.7 patients and in the transgenic mice model (while while mutant SOD1 is expressed ubiquitously 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202307 12909279 270858 20996 11179 SOD1 ALS ALS 25 2.8 to restrict the field of possible pathogenic mechanisms operating in ALS to a few plausible pathways possibly converging to two common 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202308 12909279 270858 18723 10261 ROS1 ROS ROS 42 0.9 converging to two common steps represented by the alteration of ROS ( Fig 4 and of calcium homeostasis 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202309 12909279 270860 18723 10261 ROS1 ROS ROS 23 0.9 in part by a defect in intracellular protection against increased ROS production and calcium levels 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 202310 12909279 270861 20996 11179 SOD1 ALS ALS 13 2.8 the understanding of the selective vulnerability of motor neurones in ALS has been made using the fALS-mice model 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202311 12909279 270864 20996 11179 SOD1 SOD1 SOD1 6 2.7 Therefore the neurotoxic effect of mutant SOD1 seems to be not a simple consequence of its expression 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202312 12909279 270865 20996 11179 SOD1 SOD1 SOD1 15 2.7 findings indicating that neuroinflammatory processes mediate the pathogenic effect of SOD1 mutation (and, and more in general ALS pathogenesis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202313 12909279 270865 20996 11179 SOD1 ALS ALS 21 2.8 pathogenic effect of SOD1 mutation (and, and more in general ALS pathogenesis 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202314 12909279 270867 20996 11179 SOD1 ALS ALS 17 2.8 factor involved in inflammatory response is altered in astrocytes from ALS patients 62 and in human cells expressing mutant fALS-SOD1 14 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202315 12909279 270868 14533 7872 NOS1 NOS NOS 12 1.2 expression of several proteins such as nitric oxide synthase (NOS) NOS 93 and COX2 70 that might be involved in mechanisms 1 JUMiner_v2.2 1 0 0 2 7873 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7873|NOS2A|0.000474682520103884<>ScoreDetail__7873|NOS2A|0.000474682520103884__7872|NOS1|0.000433079922414797__ 0 0 0 0 0 202316 12909279 270868 17610 9605 PTGS2 COX2 COX2 17 1.3 proteins such as nitric oxide synthase (NOS) NOS 93 and COX2 70 that might be involved in mechanisms of inflammation-mediated neurodegeneration 1 JUMiner_v2.2 1 1 UserEdit 0 2 9605 TotalCon:2<>7421|MT-CO2|4513|Complete__9605|PTGS2|5743|Complete__<>AvaiableGeneRif=2<>BEST:9605|PTGS2|0.000536714124144385<>ScoreDetail__7421|MT-CO2|0.000364928974008948__9605|PTGS2|0.000536714124144385__ 1 1 13732 7421 MT-CO2 0 202317 12909279 270868 20996 11179 SOD1 ALS ALS 37 2.8 of inflammation-mediated neurodegeneration and be crucial in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202318 12909279 270869 17610 9605 PTGS2 COX2 COX2 1 1.3 Indeed COX2 and NOS activity are dramatically increased in post-mortem spinal cord 1 JUMiner_v2.2 1 1 UserEdit 0 2 9605 TotalCon:2<>7421|MT-CO2|4513|Complete__9605|PTGS2|5743|Complete__<>AvaiableGeneRif=2<>BEST:9605|PTGS2|0.000536714124144385<>ScoreDetail__7421|MT-CO2|0.000364928974008948__9605|PTGS2|0.000536714124144385__ 1 1 13732 7421 MT-CO2 0 202319 12909279 270869 14533 7872 NOS1 NOS NOS 3 1.2 Indeed COX2 and NOS activity are dramatically increased in post-mortem spinal cord samples from 1 JUMiner_v2.2 1 0 0 2 7873 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7873|NOS2A|0.000474682520103884<>ScoreDetail__7873|NOS2A|0.000474682520103884__7872|NOS1|0.000433079922414797__ 0 0 0 0 0 202320 12909279 270869 20996 11179 SOD1 ALS ALS 15 2.8 are dramatically increased in post-mortem spinal cord samples from sporadic ALS patients and in astrocytes from fALS-mice 2 and 15 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202321 12909279 270870 17610 9605 PTGS2 COX2 COX2 3 1.3 Increased levels of COX2 and of the pro-inflammatory prostaglandin PGE2 were found in the 1 JUMiner_v2.2 1 1 UserEdit 0 2 9605 TotalCon:2<>7421|MT-CO2|4513|Complete__9605|PTGS2|5743|Complete__<>AvaiableGeneRif=2<>BEST:9605|PTGS2|0.000536714124144385<>ScoreDetail__7421|MT-CO2|0.000364928974008948__9605|PTGS2|0.000536714124144385__ 1 1 13732 7421 MT-CO2 0 202322 12909279 270870 20996 11179 SOD1 ALS ALS 17 2.8 pro-inflammatory prostaglandin PGE2 were found in the cerebrospinal fluid from ALS patients 3 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202323 12909279 270871 17610 9605 PTGS2 COX2 COX2 4 1.3 Treatment with a selective COX2 inhibitor markedly inhibits production of PGE2 in the spinal cord 1 JUMiner_v2.2 1 1 UserEdit 0 2 9605 TotalCon:2<>7421|MT-CO2|4513|Complete__9605|PTGS2|5743|Complete__<>AvaiableGeneRif=2<>BEST:9605|PTGS2|0.000536714124144385<>ScoreDetail__7421|MT-CO2|0.000364928974008948__9605|PTGS2|0.000536714124144385__ 1 1 13732 7421 MT-CO2 0 202324 12909279 270871 20996 11179 SOD1 ALS ALS 16 2.8 markedly inhibits production of PGE2 in the spinal cord of ALS mice protecting motor neurones and significantly prolonging survival 23 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202325 12909279 270872 20996 11179 SOD1 ALS ALS 20 2.8 response oxidative stress and apoptotic events in the pathogenesis of ALS is still unclear and the contributions of different cellular types 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202326 12909279 270872 20996 11179 SOD1 ALS ALS 35 2.8 the contributions of different cellular types to the pathogenesis of ALS are unknown 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202327 12909279 270876 20996 11179 SOD1 ALS ALS 6 2.8 Which is the main alteration preluding ALS is still actively debated 17 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202328 12909279 270877 20996 11179 SOD1 ALS ALS 27 2.8 one of the main mechanisms operating in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202329 12909279 270878 18723 10261 ROS1 ROS ROS-induced 8 0.0 Neurodegeneration may arise by converging pathways such as ROS-induced damage of critical molecular targets proteasomal inhibition and consequent accumulation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202330 12909279 270879 20996 11179 SOD1 SOD1 SOD1 21 2.7 the only (partially) partially understood is the presence of mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202331 12909279 270880 20996 11179 SOD1 SOD1 SOD1 7 2.7 The general concept is that upon mutation SOD1 is partially misfolded and binds copper improperly 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202332 12909279 270882 20996 11179 SOD1 ALS ALS 7 2.8 Interestingly this concept is not exclusive of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000818801693862644<>ScoreDetail__5468|IGFALS|0.000607639548219996__11179|SOD1|0.000818801693862644__ 0 0 0 0 0 202333 12909279 270884 20996 11179 SOD1 SOD SOD-like 5 1.9 In both cases evidence of SOD-like activity arising from copper bound to peptide A_amp_#x3b2 and to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 202334 12909279 270884 17264 9353 PRDX2 PrP PrP 18 1.1 from copper bound to peptide A_amp_#x3b2 and to the protein PrP respectively has been provided 11 and 47 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.000813320654702895<>ScoreDetail__1325|C4BPA|0.000515189789270757__47|ABCB6|0.000348999534667287__9353|PRDX2|0.000813320654702895__9449|PRNP|0.000539111205998924__ 0 0 0 0 0 202335 12909279 270885 17264 9353 PRDX2 PrP PrP 11 1.1 would not be surprising to learn that copper-bound A_amp_#x3b2 and PrP are also able to induce the formation of the noxious 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:4<>9353|PRDX2|7001|Complete__9449|PRNP|5621|Complete__47|ABCB6|10058|Complete__1325|C4BPA|722|Complete__<>AvaiableGeneRif=4<>BEST:9353|PRDX2|0.000813320654702895<>ScoreDetail__1325|C4BPA|0.000515189789270757__47|ABCB6|0.000348999534667287__9353|PRDX2|0.000813320654702895__9449|PRNP|0.000539111205998924__ 0 0 0 0 0 196436 14572730 262121 20996 11179 SOD1 ALS ALS 11 1.4 scientific evidence of a link between amyotrophic lateral sclerosis (ALS) ALS and soccer is lacking new cases of the disease in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196437 14572730 262123 20996 11179 SOD1 ALS ALS 24 1.4 an inquiry in 1999 to investigate the high incidence of ALS and other diseases_amp_#x2014 such as liver tumours and leukaemia_amp_#x2014 in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196438 14572730 262124 20996 11179 SOD1 ALS ALS 15 1.4 who played between 1960 and 1997 eight have died from ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196439 14572730 262126 20996 11179 SOD1 ALS ALS 7 1.4 The details of any current cases of ALS diagnosed since 1997 are protected under pretrial investigation secrecy but 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196440 14572730 262126 20996 11179 SOD1 ALS ALS 33 1.4 number of players who have died or are affected by ALS is now more than 30 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196441 14572730 262127 20996 11179 SOD1 ALS ALS 4 1.4 The other peculiarity of ALS in Italian soccer players is that age at disease onset 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196442 14572730 262129 20996 11179 SOD1 ALS ALS 4 1.4 The potential link between ALS and soccer might offer new perspectives on the cause of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196443 14572730 262130 20996 11179 SOD1 ALS ALS 9 1.4 The elucidation of the underlying mechanisms and cause of ALS is of overwhelming importance for finding new effective treatments 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196444 14572730 262131 20996 11179 SOD1 ALS ALS 6 1.4 To date the risk factors for ALS that are supported by epidemiological observations are age family history 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196445 14572730 262132 20996 11179 SOD1 ALS ALS 27 1.4 yet been thoroughly investigated are suspected as possible causes of ALS in soccer professionals 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196446 14572730 262133 20996 11179 SOD1 ALS ALS 8 1.4 Why should soccer players be more prone to ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196447 14572730 262134 18723 10261 ROS1 ROS ROS 8 0.0 Previous studies have reported that reactive oxygen species (ROS) ROS are generated during exercise although most evidence for this is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 196448 14572730 262134 18723 10261 ROS1 ROS ROS 28 0.0 is indirect 3 In soccer players an increased production of ROS may result from the combination of strenuous exercise with other 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 196449 14572730 262136 20996 11179 SOD1 ALS ALS 18 1.4 one of many causative factors in several neurodegenerative diseases including ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196450 14572730 262137 18723 10261 ROS1 ROS ROS 23 0.0 of easily oxidized substrates and an inherently high production of ROS during high respiratory activity and during neurochemical reactions such as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 196451 14572730 262138 18723 10261 ROS1 ROS ROS 8 0.0 Furthermore metal ions which facilitate the production of ROS accumulate in the CNS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 196452 14572730 262140 20996 11179 SOD1 ALS ALS 9 1.4 In light of this neuronal loss in patients with ALS might result from a complex interplay of excitotoxic stimulation genetic 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196453 14572730 262141 20996 11179 SOD1 ALS ALS 1 1.4 In ALS the neurotoxic effect of increased ROS production seems not to 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196454 14572730 262141 20996 11179 SOD1 SOD SOD 47 1.4 a mutant form of copper/zinc copper zinc superoxide dismutase (SOD) SOD 1 in patients with familial ALS which supports a crucial 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 196455 14572730 262141 20996 11179 SOD1 ALS ALS 53 1.4 zinc superoxide dismutase (SOD) SOD 1 in patients with familial ALS which supports a crucial role of glia in the pathogenesis 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196456 14572730 262141 20996 11179 SOD1 ALS ALS 65 1.4 supports a crucial role of glia in the pathogenesis of ALS 6 7 and 8 Several findings indicate that neuroinflammatory processes 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196457 14572730 262141 20996 11179 SOD1 ALS ALS 78 1.4 7 and 8 Several findings indicate that neuroinflammatory processes mediate ALS pathogenesis and markers of neuroinflammation such as concentrations of cyclooxygenase-2 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196458 14572730 262141 20996 11179 SOD1 ALS ALS 96 1.4 concentrations of cyclooxygenase-2 and prostaglandin E2 are substantially increased in ALS 9 and 10 If activated glial cells participate directly in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196459 14572730 262141 20996 11179 SOD1 ALS ALS 113 1.4 cells participate directly in the death of motor neurons in ALS chronic use of anti-inflammatory drugs should prevent this damage in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196460 14572730 262141 18723 10261 ROS1 ROS ROS 7 0.0 In ALS the neurotoxic effect of increased ROS production seems not to be simply mediated by damage to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 196461 14572730 262145 20996 11179 SOD1 ALS ALS 11 1.4 evidence of the occurrence of apoptotic death of neurons in ALS is accumulating 11 but the association between inflammatory response oxidative 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 196462 14572730 262145 20996 11179 SOD1 ALS ALS 30 1.4 response oxidative stress and apoptotic events in the pathogenesis of ALS is still unclear 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00061475931389728<>ScoreDetail__5468|IGFALS|0.000264668189669583__11179|SOD1|0.00061475931389728__ 0 0 0 0 0 186249 14625013 249317 20996 11179 SOD1 SOD1 mSOD1 11 1.4 human mutated form (G93A) G93A of Cu Zn-superoxide dismutase (mSOD1) mSOD1 develop motor neuron degeneration resembling amyotrophic lateral sclerosis 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186250 14625013 249320 20996 11179 SOD1 SOD1 mSOD1 22 1.4 0.375 g/kg) g kg on disease onset and survival of mSOD1 transgenic mice 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186251 14625013 249322 20996 11179 SOD1 SOD1 mSOD1 7 1.4 We conclude that zinc sulfate amplifies the mSOD1 transgenic mouse phenotype 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186252 14625013 249324 20996 11179 SOD1 ALS ALS 3 1.4 Amyotrophic lateral sclerosis (ALS) ALS is a devastating neurodegenerative disease characterized by a loss of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00120429707745792<>ScoreDetail__5468|IGFALS|0.000628468385575624__11179|SOD1|0.00120429707745792__ 0 0 0 0 0 186253 14625013 249325 20996 11179 SOD1 SOD1 SOD1 16 1.4 but mutations in the gene encoding Cu Zn-superoxide dismutase (SOD1) SOD1 are found in approximately 2% of ALS patients 12 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186254 14625013 249325 20996 11179 SOD1 ALS ALS 23 1.4 Zn-superoxide dismutase (SOD1) SOD1 are found in approximately 2% of ALS patients 12 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00120429707745792<>ScoreDetail__5468|IGFALS|0.000628468385575624__11179|SOD1|0.00120429707745792__ 0 0 0 0 0 186255 14625013 249326 20996 11179 SOD1 SOD1 SOD1 4 1.4 Transgenic mice overexpressing human SOD1 carrying the G93A mutation (mSOD1) mSOD1 develop a rapidly progressive 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186256 14625013 249326 20996 11179 SOD1 SOD1 mSOD1 9 1.4 Transgenic mice overexpressing human SOD1 carrying the G93A mutation (mSOD1) mSOD1 develop a rapidly progressive muscular weakness due to motor neuron 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186257 14625013 249326 20996 11179 SOD1 ALS ALS 28 1.4 motor neuron degeneration and serve as an animal model for ALS 6 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00120429707745792<>ScoreDetail__5468|IGFALS|0.000628468385575624__11179|SOD1|0.00120429707745792__ 0 0 0 0 0 186258 14625013 249327 20996 11179 SOD1 SOD1 SOD1 0 1.4 SOD1 is a metalloenzyme that catalyzes the conversion of superoxide to 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186259 14625013 249329 20996 11179 SOD1 SOD1 mSOD1 4 1.4 Such gained properties of mSOD1 include increased formation of free radicals with hydrogen peroxide as 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186260 14625013 249330 20996 11179 SOD1 SOD1 SOD1 7 1.4 In vitro studies showed that mutations in SOD1 destabilize the protein and decrease the affinity of SOD1 for 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186261 14625013 249330 20996 11179 SOD1 SOD1 SOD1 16 1.4 in SOD1 destabilize the protein and decrease the affinity of SOD1 for zinc up to 50-fold compared to the wild type 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186262 14625013 249331 20996 11179 SOD1 SOD1 SOD1 1 1.4 Zinc-deficient SOD1 leads to an increase in nitrotyrosine formation and induces apoptosis 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186263 14625013 249332 20996 11179 SOD1 SOD1 SOD1 8 1.4 This toxicity required copper to be bound to SOD1 and was not present when SOD1 was replete with zinc 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186264 14625013 249332 20996 11179 SOD1 SOD1 SOD1 14 1.4 to be bound to SOD1 and was not present when SOD1 was replete with zinc 3 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186265 14625013 249336 20996 11179 SOD1 SOD1 mSOD1 11 1.4 upregulation of MT's is seen in the spinal cord of mSOD1 transgenic mice 11 and reduction of MT-I and -II significantly 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186266 14625013 249336 20996 11179 SOD1 SOD1 mSOD1 27 1.4 and reduction of MT-I and -II significantly reduces survival of mSOD1 transgenic mice 10 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186267 14625013 249337 20996 11179 SOD1 SOD1 SOD1 36 1.4 expression of MT's would be neuroprotective in transgenic high-copy human SOD1 G93A mice (Jackson Jackson Laboratory Bar Harbor MN 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186268 14625013 249339 20996 11179 SOD1 SOD1 SOD1 2 1.4 G93A male SOD1 mice were crossbred with non-transgenic Balb/C Balb C females 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186269 14625013 249343 20996 11179 SOD1 SOD1 SOD1 4 1.4 Prior to the G93A SOD1 experiment the effect of high dose zinc sulphate on hematological 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186270 14625013 249345 20996 11179 SOD1 SOD1 SOD1 3 1.4 In the G93A SOD1 mice the hind-paw extension reflex test was performed 5 days 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186271 14625013 249367 20996 11179 SOD1 SOD1 mSOD1 2 1.4 In untreated mSOD1 transgenic mice a similar though clearly more intense staining pattern 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186272 14625013 249367 20996 11179 SOD1 SOD1 mSOD1 28 1.4 in immunoreactivity for MT's were observed between zinc-treated and untreated mSOD1 transgenic mice ( Figs 2B C 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186273 14625013 249368 20996 11179 SOD1 SOD1 mSOD1 33 1.4 would attenuate motor neuron death and thus extend survival of mSOD1 transgenic mice 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186274 14625013 249369 20996 11179 SOD1 SOD1 mSOD1 19 1.4 zinc sulphate (0.375 0.375 g/kg) g kg decreased survival of mSOD1 transgenic mice 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186275 14625013 249371 20996 11179 SOD1 SOD1 mSOD1 26 1.4 level in the spinal cord of both treated and untreated mSOD1 transgenic mice but a further upregulation of MT in the 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186276 14625013 249373 20996 11179 SOD1 SOD1 mSOD1 4 1.4 The selective toxicity in mSOD1 transgenic mice may be due to enhanced motor neuron death 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186277 14625013 249375 20996 11179 SOD1 SOD1 mSOD1 16 1.4 raises two related questions why is zinc not neuroprotective in mSOD1 transgenic mice and why does it even appear to accelerate 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186278 14625013 249376 20996 11179 SOD1 SOD1 mSOD1 27 1.4 maximum in the spinal cord (and and intestinal wall of mSOD1 transgenic mice 11 so that a further upregulation cannot be 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186279 14625013 249377 20996 11179 SOD1 SOD1 mSOD1 42 1.4 direct toxic effect of zinc on motor neurons 18 of mSOD1 transgenic mice 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 186280 14625013 249379 20996 11179 SOD1 ALS ALS 41 1.4 a good therapeutic approach to confer neuroprotection in patients with ALS but may also shed a new light on the role 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00120429707745792<>ScoreDetail__5468|IGFALS|0.000628468385575624__11179|SOD1|0.00120429707745792__ 0 0 0 0 0 187160 14648077 250303 18723 10261 ROS1 ROS ROSs 7 0.0 Abstract Living cells produce reactive oxygen species (ROSs) ROSs 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187161 14648077 250304 20996 11179 SOD1 SOD1 SOD1 18 7.9 developed both an antioxidant system containing superoxide dismutase 1 (SOD1) SOD1 and a redox system including peroxiredoxin2 (Prx2, Prx2 thioredoxin peroxidase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187162 14648077 250304 17264 9353 PRDX2 PRX2 Prx2 25 3.9 1 (SOD1) SOD1 and a redox system including peroxiredoxin2 (Prx2, Prx2 thioredoxin peroxidase and glutathione peroxidase1 (GPx1): GPx1 SOD1 converts superoxide 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187163 14648077 250304 8759 4553 GPX1 GPX1 GPx1 31 2.2 including peroxiredoxin2 (Prx2, Prx2 thioredoxin peroxidase and glutathione peroxidase1 (GPx1): GPx1 SOD1 converts superoxide radicals into hydrogen peroxide (H H 2 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187164 14648077 250304 20996 11179 SOD1 SOD1 SOD1 32 7.9 peroxiredoxin2 (Prx2, Prx2 thioredoxin peroxidase and glutathione peroxidase1 (GPx1): GPx1 SOD1 converts superoxide radicals into hydrogen peroxide (H H 2 O 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187165 14648077 250304 17264 9353 PRDX2 PRX2 Prx2 64 3.9 (H H 2 O and oxygen (O O 2 by Prx2 and GPx1 that directly regulate the redox system 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187166 14648077 250304 8759 4553 GPX1 GPX1 GPx1 66 2.2 2 O and oxygen (O O 2 by Prx2 and GPx1 that directly regulate the redox system 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187167 14648077 250304 18723 10261 ROS1 ROS ROSs 5 0.0 To protect themselves from these ROSs the cells have developed both an antioxidant system containing superoxide 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187168 14648077 250305 17264 9353 PRDX2 PRX2 Prx2 12 3.9 biological significance of the interaction of the redox system (Prx2/GPx1) Prx2 GPx1 with SOD1 in SOD1-mutated motor neurons in vivo we 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187169 14648077 250305 8759 4553 GPX1 GPX1 GPx1 12 2.2 significance of the interaction of the redox system (Prx2/GPx1) Prx2 GPx1 with SOD1 in SOD1-mutated motor neurons in vivo we produced 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187170 14648077 250305 20996 11179 SOD1 SOD1 SOD1 14 7.9 the interaction of the redox system (Prx2/GPx1) Prx2 GPx1 with SOD1 in SOD1-mutated motor neurons in vivo we produced an affinity-purified 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187171 14648077 250305 20996 11179 SOD1 SOD1 SOD1-mutated 16 1.7 of the redox system (Prx2/GPx1) Prx2 GPx1 with SOD1 in SOD1-mutated motor neurons in vivo we produced an affinity-purified rabbit antibody 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187172 14648077 250305 17264 9353 PRDX2 PRX2 Prx2 28 3.9 neurons in vivo we produced an affinity-purified rabbit antibody against Prx2 and investigated the immunohistochemical localization of Prx2 and GPx1 in 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187173 14648077 250305 17264 9353 PRDX2 PRX2 Prx2 35 3.9 rabbit antibody against Prx2 and investigated the immunohistochemical localization of Prx2 and GPx1 in neuronal Lewy body-like hyaline inclusions (LBHIs) LBHIs 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187174 14648077 250305 8759 4553 GPX1 GPX1 GPx1 37 2.2 against Prx2 and investigated the immunohistochemical localization of Prx2 and GPx1 in neuronal Lewy body-like hyaline inclusions (LBHIs) LBHIs in the 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187175 14648077 250305 20996 11179 SOD1 SOD1 SOD1 74 7.9 and an Ala Val substitution at codon 4 in the SOD1 gene as well as in transgenic rats expressing human SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187176 14648077 250305 20996 11179 SOD1 SOD1 SOD1 84 7.9 SOD1 gene as well as in transgenic rats expressing human SOD1 with H46R and G93A mutations 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187177 14648077 250306 20996 11179 SOD1 SOD1 SOD1-mutated 7 1.7 The LBHIs in motor neurons from the SOD1-mutated FALS patients and transgenic rats showed identical immunoreactivities for Prx2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187178 14648077 250306 17264 9353 PRDX2 PRX2 Prx2 17 3.9 SOD1-mutated FALS patients and transgenic rats showed identical immunoreactivities for Prx2 and GPx1 the reaction product deposits with the antibodies against 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187179 14648077 250306 8759 4553 GPX1 GPX1 GPx1 19 2.2 patients and transgenic rats showed identical immunoreactivities for Prx2 and GPx1 the reaction product deposits with the antibodies against Prx2 and 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187180 14648077 250306 17264 9353 PRDX2 PRX2 Prx2 28 3.9 and GPx1 the reaction product deposits with the antibodies against Prx2 and GPx1 were localized in the LBHIs 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187181 14648077 250306 8759 4553 GPX1 GPX1 GPx1 30 2.2 the reaction product deposits with the antibodies against Prx2 and GPx1 were localized in the LBHIs 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187182 14648077 250307 20996 11179 SOD1 SOD1 SOD1 8 7.9 In addition the localizations of the immunoreactivities for SOD1 and Prx2/GPx1 Prx2 GPx1 were similar in the inclusions the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187183 14648077 250307 17264 9353 PRDX2 PRX2 Prx2 10 3.9 addition the localizations of the immunoreactivities for SOD1 and Prx2/GPx1 Prx2 GPx1 were similar in the inclusions the co-aggregation of Prx2/GPx1 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187184 14648077 250307 8759 4553 GPX1 GPX1 GPx1 10 2.2 the localizations of the immunoreactivities for SOD1 and Prx2/GPx1 Prx2 GPx1 were similar in the inclusions the co-aggregation of Prx2/GPx1 Prx2 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187185 14648077 250307 17264 9353 PRDX2 PRX2 Prx2 19 3.9 GPx1 were similar in the inclusions the co-aggregation of Prx2/GPx1 Prx2 GPx1 with SOD1 in neuronal LBHIs in mutant SOD1-related FALS 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187186 14648077 250307 8759 4553 GPX1 GPX1 GPx1 19 2.2 were similar in the inclusions the co-aggregation of Prx2/GPx1 Prx2 GPx1 with SOD1 in neuronal LBHIs in mutant SOD1-related FALS patients 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187187 14648077 250307 20996 11179 SOD1 SOD1 SOD1 21 7.9 in the inclusions the co-aggregation of Prx2/GPx1 Prx2 GPx1 with SOD1 in neuronal LBHIs in mutant SOD1-related FALS patients and transgenic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187188 14648077 250307 20996 11179 SOD1 SOD1 SOD1-related 27 1.7 Prx2/GPx1 Prx2 GPx1 with SOD1 in neuronal LBHIs in mutant SOD1-related FALS patients and transgenic rats was evident 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187189 14648077 250308 17264 9353 PRDX2 PRX2 Prx2 5 3.9 Based on the fact that Prx2/GPx1 Prx2 GPx1 directly regulates the redox system such co-aggregation of Prx2/GPx1 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187190 14648077 250308 8759 4553 GPX1 GPX1 GPx1 5 2.2 Based on the fact that Prx2/GPx1 Prx2 GPx1 directly regulates the redox system such co-aggregation of Prx2/GPx1 Prx2 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187191 14648077 250308 17264 9353 PRDX2 PRX2 Prx2 14 3.9 GPx1 directly regulates the redox system such co-aggregation of Prx2/GPx1 Prx2 GPx1 with SOD1 in neuronal LBHIs may lead to the 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187192 14648077 250308 8759 4553 GPX1 GPX1 GPx1 14 2.2 directly regulates the redox system such co-aggregation of Prx2/GPx1 Prx2 GPx1 with SOD1 in neuronal LBHIs may lead to the breakdown 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187193 14648077 250308 20996 11179 SOD1 SOD1 SOD1 16 7.9 the redox system such co-aggregation of Prx2/GPx1 Prx2 GPx1 with SOD1 in neuronal LBHIs may lead to the breakdown of the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187194 14648077 250308 20996 11179 SOD1 SOD1 SOD1-mediated 34 1.7 breakdown of the redox system itself thereby amplifying the mutant SOD1-mediated toxicity in mutant SOD1-linked FALS patients and transgenic rats expressing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187195 14648077 250308 20996 11179 SOD1 SOD1 SOD1-linked 38 1.7 system itself thereby amplifying the mutant SOD1-mediated toxicity in mutant SOD1-linked FALS patients and transgenic rats expressing human mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187196 14648077 250308 20996 11179 SOD1 SOD1 SOD1 47 7.9 mutant SOD1-linked FALS patients and transgenic rats expressing human mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187197 14648077 250310 18723 10261 ROS1 ROS ROSs 7 0.0 Introduction Living cells produce reactive oxygen species (ROSs) ROSs during physiological processes and in response to external stimuli such 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187198 14648077 250311 18723 10261 ROS1 ROS ROSs 6 0.0 To protect itself from potentially destructive ROSs each cell of living organisms has developed a sophisticated antioxidant 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187199 14648077 250313 20996 11179 SOD1 SOD SOD 11 1.7 first antioxidant enzyme group three isoforms of superoxide dismutase (SOD) SOD EC 1.15.1.1 have been identified SOD1 SOD2 and SOD3 9 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187200 14648077 250313 20996 11179 SOD1 SOD1 SOD1 17 7.9 of superoxide dismutase (SOD) SOD EC 1.15.1.1 have been identified SOD1 SOD2 and SOD3 9 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187201 14648077 250313 20997 11180 SOD2 SOD2 SOD2 18 0.9 superoxide dismutase (SOD) SOD EC 1.15.1.1 have been identified SOD1 SOD2 and SOD3 9 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187202 14648077 250313 20998 11181 SOD3 SOD3 SOD3 18 0.9 superoxide dismutase (SOD) SOD EC 1.15.1.1 have been identified SOD1 SOD2 and SOD3 9 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187203 14648077 250313 20998 11181 SOD3 SOD3 SOD3 20 0.9 (SOD) SOD EC 1.15.1.1 have been identified SOD1 SOD2 and SOD3 9 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187204 14648077 250314 17269 16753 PRDX6 PRX Prx 7 0.3 In the second enzyme group the peroxiredoxin (Prx) Prx and glutathione peroxidase (GPx) GPx families as well as catalase 2 JUMiner_v2.2 1 0 0 2 16753 TotalCon:2<>13797|PRX|57716|Complete__16753|PRDX6|9588|Complete__<>AvaiableGeneRif=2<>BEST:16753|PRDX6|0.000780469888783041<>ScoreDetail__16753|PRDX6|0.000780469888783041__13797|PRX|0.00061525129982669__ 0 0 0 0 0 187205 14648077 250315 20996 11179 SOD1 SOD SOD 1 1.7 Unlike SOD and catalase enzymes of the Prx and GPx families require 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187206 14648077 250315 17269 16753 PRDX6 PRX Prx 7 0.3 Unlike SOD and catalase enzymes of the Prx and GPx families require secondary enzymes and cofactors to function 2 JUMiner_v2.2 1 0 0 2 16753 TotalCon:2<>13797|PRX|57716|Complete__16753|PRDX6|9588|Complete__<>AvaiableGeneRif=2<>BEST:16753|PRDX6|0.000780469888783041<>ScoreDetail__16753|PRDX6|0.000780469888783041__13797|PRX|0.00061525129982669__ 0 0 0 0 0 187207 14648077 250319 17264 9353 PRDX2 PRX2 Prx2 1 3.9 Peroxiredoxin2 (Prx2) Prx2 is a novel organ-specific antioxidative enzyme that is mainly expressed 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187208 14648077 250320 17269 16753 PRDX6 PRX Prx 6 0.3 This protein is a member of Prx family whose members possess reactive cysteine residues 23 2 JUMiner_v2.2 1 0 0 2 16753 TotalCon:2<>13797|PRX|57716|Complete__16753|PRDX6|9588|Complete__<>AvaiableGeneRif=2<>BEST:16753|PRDX6|0.000780469888783041<>ScoreDetail__16753|PRDX6|0.000780469888783041__13797|PRX|0.00061525129982669__ 0 0 0 0 0 187209 14648077 250321 17264 9353 PRDX2 PRX2 Prx2 0 3.9 Prx2 requires thioredoxin reductase (TR) TR as a secondary enzyme as 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187210 14648077 250321 17264 9353 PRDX2 PRX2 Prx2 25 3.9 as cofactors to function at high efficiency the activity of Prx2 in the thioredoxin/TR/NADPH thioredoxin TR NADPH system is over five 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187211 14648077 250321 17264 9353 PRDX2 PRX2 Prx2 38 3.9 NADPH system is over five times higher than that of Prx2 by itself 5 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187212 14648077 250322 17264 9353 PRDX2 PRX2 Prx2 3 3.9 In this milieu Prx2 is also called thioredoxin peroxidase 1 (thioredoxin-dependent thioredoxin-dependent peroxide reductase 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187213 14648077 250323 17264 9353 PRDX2 PRX2 Prx2 13 3.9 to controlling the intracellular content of H 2 O 2 Prx2 directly regulates the redox signals of the thioredoxin/TR/NADPH thioredoxin TR 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187214 14648077 250324 8759 4553 GPX1 GPX1 GPx1 11 2.2 EC 1.11.1.9 a classical selenium-dependent isoform (also also assigned as GPx1 was first described as an enzyme that protects hemoglobin from 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187215 14648077 250324 9038 4827 HBB hemoglobin hemoglobin 20 1.0 as GPx1 was first described as an enzyme that protects hemoglobin from oxidative degradation in red blood cells 25 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187216 14648077 250326 8759 4553 GPX1 GPX1 GPx1 2 2.2 Among them GPx1 is considered as the major enzyme responsible for removing intracytoplasmic 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187217 14648077 250327 17264 9353 PRDX2 PRX2 Prx2 1 3.9 Like Prx2 GPx1 needs glutathione reductase (GR) GR as a secondary enzyme 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187218 14648077 250327 8759 4553 GPX1 GPX1 GPx1 2 2.2 Like Prx2 GPx1 needs glutathione reductase (GR) GR as a secondary enzyme as 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187219 14648077 250328 17264 9353 PRDX2 PRX2 Prx2 1 3.9 Therefore Prx2 and GPx1 directly control the redox system 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187220 14648077 250328 8759 4553 GPX1 GPX1 GPx1 3 2.2 Therefore Prx2 and GPx1 directly control the redox system 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187221 14648077 250329 20996 11179 SOD1 SOD1 SOD1 16 7.9 amyotrophic lateral sclerosis (FALS) FALS are caused by a mutant SOD1 15 17 18 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187222 14648077 250330 20996 11179 SOD1 SOD1 SOD1 0 7.9 SOD1 is thought to be an essential component of neuronal Lewy 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187223 14648077 250330 20996 11179 SOD1 SOD1 SOD1-mutated 26 1.7 LBHIs in affected anterior horn cells are morphological hallmarks of SOD1-mutated motor neurons of FALS patients 3 11 12 13 14 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187224 14648077 250331 20996 11179 SOD1 SOD1 SOD1-mutated 6 1.7 To cope with destructive ROSs even SOD1-mutated motor neurons induce mutant and wild-type SOD1 as well as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187225 14648077 250331 20996 11179 SOD1 SOD1 SOD1 13 7.9 destructive ROSs even SOD1-mutated motor neurons induce mutant and wild-type SOD1 as well as Prx2 and GPx1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187226 14648077 250331 17264 9353 PRDX2 PRX2 Prx2 17 3.9 motor neurons induce mutant and wild-type SOD1 as well as Prx2 and GPx1 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187227 14648077 250331 8759 4553 GPX1 GPX1 GPx1 19 2.2 induce mutant and wild-type SOD1 as well as Prx2 and GPx1 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187228 14648077 250331 18723 10261 ROS1 ROS ROSs 4 0.1 To cope with destructive ROSs even SOD1-mutated motor neurons induce mutant and wild-type SOD1 as 6 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 187229 14648077 250332 17264 9353 PRDX2 PRX2 Prx2 2 3.9 Considering that Prx2 and GPx1 interact not only with wild-type SOD1 but also 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187230 14648077 250332 8759 4553 GPX1 GPX1 GPx1 4 2.2 Considering that Prx2 and GPx1 interact not only with wild-type SOD1 but also with mutant 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187231 14648077 250332 20996 11179 SOD1 SOD1 SOD1 10 7.9 Considering that Prx2 and GPx1 interact not only with wild-type SOD1 but also with mutant SOD1 the interaction of Prx2/GPx1 Prx2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187232 14648077 250332 20996 11179 SOD1 SOD1 SOD1 15 7.9 interact not only with wild-type SOD1 but also with mutant SOD1 the interaction of Prx2/GPx1 Prx2 GPx1 with SOD1 has been 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187233 14648077 250332 17264 9353 PRDX2 PRX2 Prx2 19 3.9 SOD1 but also with mutant SOD1 the interaction of Prx2/GPx1 Prx2 GPx1 with SOD1 has been suggested to contribute to mutant 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187234 14648077 250332 8759 4553 GPX1 GPX1 GPx1 19 2.2 but also with mutant SOD1 the interaction of Prx2/GPx1 Prx2 GPx1 with SOD1 has been suggested to contribute to mutant SOD1 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187235 14648077 250332 20996 11179 SOD1 SOD1 SOD1 21 7.9 with mutant SOD1 the interaction of Prx2/GPx1 Prx2 GPx1 with SOD1 has been suggested to contribute to mutant SOD1 aggregation toxicity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187236 14648077 250332 20996 11179 SOD1 SOD1 SOD1 29 7.9 GPx1 with SOD1 has been suggested to contribute to mutant SOD1 aggregation toxicity Prx2/GPx1 Prx2 GPx1 possibly aggregate as LBHIs in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187237 14648077 250332 17264 9353 PRDX2 PRX2 Prx2 32 3.9 been suggested to contribute to mutant SOD1 aggregation toxicity Prx2/GPx1 Prx2 GPx1 possibly aggregate as LBHIs in SOD1-mutated motor neurons 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187238 14648077 250332 8759 4553 GPX1 GPX1 GPx1 32 2.2 suggested to contribute to mutant SOD1 aggregation toxicity Prx2/GPx1 Prx2 GPx1 possibly aggregate as LBHIs in SOD1-mutated motor neurons 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187239 14648077 250332 20996 11179 SOD1 SOD1 SOD1-mutated 38 1.7 aggregation toxicity Prx2/GPx1 Prx2 GPx1 possibly aggregate as LBHIs in SOD1-mutated motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187240 14648077 250333 17264 9353 PRDX2 PRX2 Prx2 4 3.9 Furthermore the aggregation of Prx2/GPx1 Prx2 GPx1 might affect the intracytoplasmic redox regulation and amplify mutant 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187241 14648077 250333 8759 4553 GPX1 GPX1 GPx1 4 2.2 Furthermore the aggregation of Prx2/GPx1 Prx2 GPx1 might affect the intracytoplasmic redox regulation and amplify mutant SOD1-mediated 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187242 14648077 250333 20996 11179 SOD1 SOD1 SOD1-mediated 14 1.7 GPx1 might affect the intracytoplasmic redox regulation and amplify mutant SOD1-mediated toxicity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187243 14648077 250334 17264 9353 PRDX2 PRX2 Prx2 9 3.9 To clarify the biological significance of the interaction of Prx2/GPx1 Prx2 GPx1 (redox redox system with SOD1 in SOD1-mutated motor neurons 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187244 14648077 250334 8759 4553 GPX1 GPX1 GPx1 9 2.2 clarify the biological significance of the interaction of Prx2/GPx1 Prx2 GPx1 (redox redox system with SOD1 in SOD1-mutated motor neurons in 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187245 14648077 250334 20996 11179 SOD1 SOD1 SOD1 13 7.9 the interaction of Prx2/GPx1 Prx2 GPx1 (redox redox system with SOD1 in SOD1-mutated motor neurons in vivo we first produced an 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187246 14648077 250334 20996 11179 SOD1 SOD1 SOD1-mutated 15 1.7 of Prx2/GPx1 Prx2 GPx1 (redox redox system with SOD1 in SOD1-mutated motor neurons in vivo we first produced an antibody against 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187247 14648077 250334 17264 9353 PRDX2 PRX2 Prx2 26 3.9 motor neurons in vivo we first produced an antibody against Prx2 and analyzed the characteristic expressions of both Prx2 and GPx1 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187248 14648077 250334 17264 9353 PRDX2 PRX2 Prx2 34 3.9 antibody against Prx2 and analyzed the characteristic expressions of both Prx2 and GPx1 in neuronal LBHIs in SOD1-mutated motor neurons of 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187249 14648077 250334 8759 4553 GPX1 GPX1 GPx1 36 2.2 Prx2 and analyzed the characteristic expressions of both Prx2 and GPx1 in neuronal LBHIs in SOD1-mutated motor neurons of humans and 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187250 14648077 250334 20996 11179 SOD1 SOD1 SOD1-mutated 41 1.7 expressions of both Prx2 and GPx1 in neuronal LBHIs in SOD1-mutated motor neurons of humans and animal models 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187251 14648077 250336 17264 9353 PRDX2 PRX2 Prx2 5 3.9 Preparation of polyclonal antibody against Prx2 A synthetic peptide corresponding to the C-terminal region of Prx2 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187252 14648077 250336 17264 9353 PRDX2 PRX2 Prx2 15 3.9 Prx2 A synthetic peptide corresponding to the C-terminal region of Prx2 (amino amino acids 184_amp_#x2013 198 NH 2 -KPNVDDSKEYFSKHN-COOH with or 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187253 14648077 250337 17264 9353 PRDX2 PRX2 Prx2 18 3.9 of the C-terminal region of the human rat or mouse Prx2 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187254 14648077 250339 17264 9353 PRDX2 PRX2 Prx2 6 3.9 To prepare immunogen 6 mg synthesized Prx2 peptide was conjugated with 6 mg keyhole limpet hemocyanin (KLH) 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187255 14648077 250344 17264 9353 PRDX2 PRX2 Prx2 17 3.9 an affinity column of immobilized KLH conjugated with the synthetic Prx2 peptide as described previously 16 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187256 14648077 250352 17264 9353 PRDX2 PRX2 Prx2 6 3.9 Fig 1 Specificity of antibody against Prx2 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187257 14648077 250353 17264 9353 PRDX2 PRX2 Prx2 7 3.9 The immunoreactivity of the antibody to HSA-conjugated Prx2 peptide ( solid circles and native HSA ( open circles 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187258 14648077 250354 17264 9353 PRDX2 PRX2 Prx2 6 3.9 The anti-Prx2 antibody recognizes the HSA-conjugated Prx2 peptide but does not react with HAS ( Prx2 peroxiredoxin2 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187259 14648077 250354 17264 9353 PRDX2 PRX2 Prx2 15 3.9 HSA-conjugated Prx2 peptide but does not react with HAS ( Prx2 peroxiredoxin2 ELISA enzyme-linked immunosorbent assay HAS human serum albumin 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187260 14648077 250354 9028 4818 HAS1 HAS HAS 13 0.1 recognizes the HSA-conjugated Prx2 peptide but does not react with HAS ( Prx2 peroxiredoxin2 ELISA enzyme-linked immunosorbent assay HAS human serum 6 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 187261 14648077 250354 9028 4818 HAS1 HAS HAS 21 0.0 react with HAS ( Prx2 peroxiredoxin2 ELISA enzyme-linked immunosorbent assay HAS human serum albumin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187262 14648077 250358 20996 11179 SOD1 SOD1 SOD1 0 7.9 SOD1 analysis revealed that the members of the Japanese Oki family 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187263 14648077 250360 20996 11179 SOD1 SOD SOD 13 1.7 of five FALS cases ( FALS familial amyotrophic lateral sclerosis SOD superoxide dismutase LBHI Lewy body-like hyaline inclusion 2-bp two-base pair 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187264 14648077 250360 19701 8723 SERPINA5 PCI PCI 24 0.0 superoxide dismutase LBHI Lewy body-like hyaline inclusion 2-bp two-base pair PCI posterior column involvement type detected ND not determined As asphyxia 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187265 14648077 250361 20996 11179 SOD1 SOD1 SOD1 18 7.9 transgenic line (H46R-4) H46R-4 in which the level of human SOD1 with the H46R mutation was 6 times the level of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187266 14648077 250361 20996 11179 SOD1 SOD1 SOD1 33 7.9 was 6 times the level of that of endogenous rat SOD1 27 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187267 14648077 250362 20996 11179 SOD1 SOD1 SOD1 14 7.9 transgenic line (G93A-39) G93A-39 in which the level of human SOD1 with the G93A mutation was 2.5 times the level of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187268 14648077 250362 20996 11179 SOD1 SOD1 SOD1 27 7.9 G93A mutation was 2.5 times the level of endogenous rat SOD1 27 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187269 14648077 250372 17264 9353 PRDX2 PRX2 Prx2 11 3.9 following primary antibodies were utilized an affinity-purified rabbit antibody against Prx2 (concentration: concentration 1 _amp_micro;g/ml), _amp_micro g ml a polyclonal antibody 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187270 14648077 250372 8759 4553 GPX1 GPX1 GPx1 19 2.2 concentration 1 _amp_micro;g/ml), _amp_micro g ml a polyclonal antibody to GPx1 diluted 1 2 000 in 1% bovine serum albumin-containing phosphate-buffered 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187271 14648077 250372 20996 11179 SOD1 SOD1 SOD1 41 7.9 BSA-PBS pH 7.4 2 and a polyclonal antibody to human SOD1 (diluted diluted 1 10 000 in 1% BSA-PBS pH 7.4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187272 14648077 250378 17264 9353 PRDX2 PRX2 Prx2 23 3.9 had been preabsorbed with an excess amount of the synthetic Prx2 peptide 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187273 14648077 250380 17264 9353 PRDX2 PRX2 Prx2 9 3.9 Results We successfully produced an affinity-purified rabbit antibody against Prx2 peptide (amino amino acids 184_amp_#x2013 198 although this amino acid 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187274 14648077 250380 17264 9353 PRDX2 PRX2 Prx2 37 3.9 of the human rat mouse Chinese hamster or Bos Taurus Prx2 this peptide does not share homology with other members of 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187275 14648077 250380 17269 16753 PRDX6 PRX Prx 49 0.3 peptide does not share homology with other members of the Prx family or any other peptide sequence in GenomeNet and applied 2 JUMiner_v2.2 1 0 0 2 16753 TotalCon:2<>13797|PRX|57716|Complete__16753|PRDX6|9588|Complete__<>AvaiableGeneRif=2<>BEST:16753|PRDX6|0.000780469888783041<>ScoreDetail__16753|PRDX6|0.000780469888783041__13797|PRX|0.00061525129982669__ 0 0 0 0 0 187276 14648077 250381 17264 9353 PRDX2 PRX2 Prx2 6 3.9 This anti-Prx2 antibody recognized the HSA-conjugated Prx2 peptide but did not react with HSA (Fig Fig 1 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187277 14648077 250382 19701 8723 SERPINA5 PCI PCI 19 0.0 revealed a subtype of FALS with posterior column involvement (PCI) PCI 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187278 14648077 250384 19701 8723 SERPINA5 PCI PCI 28 0.0 multisystem degeneration in addition to the features of FALS with PCI 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187279 14648077 250387 20996 11179 SOD1 SOD1 SOD1-linked 2 1.7 In mutant SOD1-linked FALS patients the neuronal LBHIs were generally composed of eosinophilic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187280 14648077 250392 17264 9353 PRDX2 PRX2 Prx2 0 3.9 Prx2 immunoreactivity in normal spinal cords was identified in almost all 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187281 14648077 250393 17264 9353 PRDX2 PRX2 Prx2-immunostaining 2 3.3 In addition Prx2-immunostaining was found throughout the neuropil with considerably lower intensity (Fig 1 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187282 14648077 250394 17264 9353 PRDX2 PRX2 Prx2 7 3.9 With respect to the intracellular localization of Prx2 immunostaining of the neuronal cytoplasm and proximal dendrites was specifically 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187283 14648077 250396 17264 9353 PRDX2 PRX2 Prx2 16 3.9 that had been pretreated with an excess of the synthetic Prx2 produced no staining (Fig Fig 3 D 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187284 14648077 250399 8759 4553 GPX1 GPX1 GPx1 5 2.2 B C Immunostaining for GPx1 ( B and Prx2 ( C 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187285 14648077 250399 17264 9353 PRDX2 PRX2 Prx2 10 3.9 B C Immunostaining for GPx1 ( B and Prx2 ( C 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187286 14648077 250400 8759 4553 GPX1 GPX1 GPx1 0 2.2 GPx1 and Prx2 immunoreactivities are found diffusely in the neuropil with 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187287 14648077 250400 17264 9353 PRDX2 PRX2 Prx2 2 3.9 GPx1 and Prx2 immunoreactivities are found diffusely in the neuropil with considerably less 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187288 14648077 250401 8759 4553 GPX1 GPX1 GPx1 7 2.2 No counterstaining ( HE hematoxylin and eosin GPx1 glutathione peroxidase1 Prx2 peroxiredoxin2 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187289 14648077 250401 17264 9353 PRDX2 PRX2 Prx2 10 3.9 No counterstaining ( HE hematoxylin and eosin GPx1 glutathione peroxidase1 Prx2 peroxiredoxin2 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187290 14648077 250403 17264 9353 PRDX2 PRX2 Prx2 4 3.9 Fig 3 Detection of Prx2 and GPx1 in the normal motor neurons of the human 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187291 14648077 250403 8759 4553 GPX1 GPX1 GPx1 6 2.2 Fig 3 Detection of Prx2 and GPx1 in the normal motor neurons of the human spinal cord 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187292 14648077 250406 8759 4553 GPX1 GPX1 GPx1 6 2.2 B Immunostaining with the antibody against GPx1 showing GPx1-positive neurons 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187293 14648077 250406 8759 4553 GPX1 GPX1 GPx1-positive 8 1.9 B Immunostaining with the antibody against GPx1 showing GPx1-positive neurons 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187294 14648077 250407 17264 9353 PRDX2 PRX2 Prx2 6 3.9 C Immunostaining with the antibody to Prx2 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187295 14648077 250409 8759 4553 GPX1 GPX1 GPx1 13 2.2 the normal motor neurons in the spinal cord co-express both GPx1 ( B and Prx2 ( C although their staining intensities 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187296 14648077 250409 17264 9353 PRDX2 PRX2 Prx2 18 3.9 in the spinal cord co-express both GPx1 ( B and Prx2 ( C although their staining intensities in neurons vary 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187297 14648077 250410 17264 9353 PRDX2 PRX2 Prx2 12 3.9 with anti-Prx2 antibody pretreated with an excess of the synthetic Prx2 peptide 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187298 14648077 250412 8759 4553 GPX1 GPX1 GPx1 1 2.2 E GPx1 immunostaining of the neuronal cytoplasm and proximal dendrites is observed 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187299 14648077 250413 17264 9353 PRDX2 PRX2 Prx2 1 3.9 F Prx2 immunostaining of the neuronal cytoplasm and proximal dendrites is observed 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187300 14648077 250414 8759 4553 GPX1 GPX1 GPx1 10 2.2 B _amp_#x2013 F No counterstaining ( HE hematoxylin and eosin GPx1 glutathione peroxidase1 Prx2 peroxiredoxin2 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187301 14648077 250414 17264 9353 PRDX2 PRX2 Prx2 13 3.9 No counterstaining ( HE hematoxylin and eosin GPx1 glutathione peroxidase1 Prx2 peroxiredoxin2 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187302 14648077 250415 17264 9353 PRDX2 PRX2 Prx2 21 3.9 _amp_micro m A neuropil staining pattern similar to that for Prx2 was observed with GPx1 weak GPx1 immunoreactivity was diffusely seen 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187303 14648077 250415 8759 4553 GPX1 GPX1 GPx1 25 2.2 staining pattern similar to that for Prx2 was observed with GPx1 weak GPx1 immunoreactivity was diffusely seen in the neuropil in 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187304 14648077 250415 8759 4553 GPX1 GPX1 GPx1 27 2.2 similar to that for Prx2 was observed with GPx1 weak GPx1 immunoreactivity was diffusely seen in the neuropil in transverse sections 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187305 14648077 250416 8759 4553 GPX1 GPX1 GPx1 0 2.2 GPx1 immunostaining was observed in the cytoplasm with cell bodies and 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187306 14648077 250417 17264 9353 PRDX2 PRX2 Prx2 5 3.9 The stainability and intensity of Prx2 and GPx1 in the normal anterior horn cells of the 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187307 14648077 250417 8759 4553 GPX1 GPX1 GPx1 7 2.2 The stainability and intensity of Prx2 and GPx1 in the normal anterior horn cells of the spinal cords 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187308 14648077 250418 17264 9353 PRDX2 PRX2 Prx2 14 3.9 the normal motor neurons in the spinal cords co-expressed both Prx2 and GPx1 (Fig Fig 3 A_amp_#x2013 C although the staining 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187309 14648077 250418 8759 4553 GPX1 GPX1 GPx1 16 2.2 motor neurons in the spinal cords co-expressed both Prx2 and GPx1 (Fig Fig 3 A_amp_#x2013 C although the staining intensities of 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187310 14648077 250419 20996 11179 SOD1 SOD1 SOD1 48 7.9 C family and the transgenic rats expressing two different human SOD1 mutations (H46R H46R and G93A were intensely immunostained by the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187311 14648077 250419 20996 11179 SOD1 SOD1 SOD1 61 7.9 and G93A were intensely immunostained by the antibody against human SOD1 (Figs Figs 4 A D 5 A D 6 A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187312 14648077 250420 17264 9353 PRDX2 PRX2 Prx2 7 3.9 Most neuronal LBHIs were also immunoreactive for Prx2 although the intensity of Prx2 immunoreactivity in the LBHIs varied 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187313 14648077 250420 17264 9353 PRDX2 PRX2 Prx2 12 3.9 LBHIs were also immunoreactive for Prx2 although the intensity of Prx2 immunoreactivity in the LBHIs varied (Figs Figs 4 C F 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187314 14648077 250421 17264 9353 PRDX2 PRX2 Prx2 20 3.9 rats (H46R H46R and G93A showed a similar immunoreactivity for Prx2 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187315 14648077 250422 17264 9353 PRDX2 PRX2 Prx2 1 3.9 The Prx2 immunolocalization in many intracytoplasmic and intraneuritic LBHIs was similar to 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187316 14648077 250422 20996 11179 SOD1 SOD1 SOD1 14 7.9 many intracytoplasmic and intraneuritic LBHIs was similar to that of SOD1 in both diseases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187317 14648077 250423 17264 9353 PRDX2 PRX2 Prx2 13 3.9 halo-type LBHIs the reaction product deposits of the antibody against Prx2 were generally restricted to the periphery (Fig Fig 4 C 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187318 14648077 250424 17264 9353 PRDX2 PRX2 Prx2 3 3.9 In ill-defined LBHIs Prx2 immunostaining was distributed throughout each inclusion 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187319 14648077 250425 17264 9353 PRDX2 PRX2 Prx2 6 3.9 In some inclusions however expression of Prx2 was observed in only part of the inclusion (Fig Fig 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187320 14648077 250426 8759 4553 GPX1 GPX1 GPx1 4 2.2 With respect to the GPx1 immunostaining in the neuronal LBHIs similar stainability and immunolocalization to 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187321 14648077 250426 17264 9353 PRDX2 PRX2 Prx2 15 3.9 immunostaining in the neuronal LBHIs similar stainability and immunolocalization to Prx2 were confirmed in the core and halo types as well 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187322 14648077 250427 8759 4553 GPX1 GPX1 GPx1 3 2.2 The immunoreactivity for GPx1 in the FALS patients was similar to that in the 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187323 14648077 250428 17264 9353 PRDX2 PRX2 Prx2 1 3.9 Like Prx2 the immunolocalization of GPx1 was similar to that of SOD1 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187324 14648077 250428 8759 4553 GPX1 GPX1 GPx1 5 2.2 Like Prx2 the immunolocalization of GPx1 was similar to that of SOD1 in both diseases 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187325 14648077 250428 20996 11179 SOD1 SOD1 SOD1 11 7.9 Prx2 the immunolocalization of GPx1 was similar to that of SOD1 in both diseases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187326 14648077 250429 8759 4553 GPX1 GPX1 GPx1-immunoreactive 0 1.9 GPx1-immunoreactive products in many core and halo-type inclusions were mainly localized 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187327 14648077 250431 20996 11179 SOD1 SOD1 SOD1 30 7.9 an FALS patient with a two-base pair deletion in the SOD1 gene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187328 14648077 250432 20996 11179 SOD1 SOD1 SOD1 3 7.9 A Immunostaining for SOD1 immunoreactivity is mostly restricted to the halo 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187329 14648077 250433 8759 4553 GPX1 GPX1 GPx1 3 2.2 B Immunostaining for GPx1 immunoreactivity is located in the SOD1-positive portion of the LBHI 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187330 14648077 250433 20996 11179 SOD1 SOD1 SOD1-positive 9 1.7 B Immunostaining for GPx1 immunoreactivity is located in the SOD1-positive portion of the LBHI 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187331 14648077 250434 17264 9353 PRDX2 PRX2 Prx2 3 3.9 C Immunoreactivity for Prx2 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187332 14648077 250435 20996 11179 SOD1 SOD1 SOD1 5 7.9 Co-localization of the three proteins SOD1 GPx1 and Prx2 in the LBHI is evident 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187333 14648077 250435 8759 4553 GPX1 GPX1 GPx1 6 2.2 Co-localization of the three proteins SOD1 GPx1 and Prx2 in the LBHI is evident 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187334 14648077 250435 17264 9353 PRDX2 PRX2 Prx2 8 3.9 Co-localization of the three proteins SOD1 GPx1 and Prx2 in the LBHI is evident 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187335 14648077 250436 20996 11179 SOD1 SOD1 SOD1 15 7.9 core and halo-type LBHI in a transgenic rat expressing human SOD1 with an H46R mutation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187336 14648077 250437 20996 11179 SOD1 SOD1 SOD1 2 7.9 Immunostaining for SOD1 ( D GPx1 ( E and Prx2 ( F 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187337 14648077 250437 8759 4553 GPX1 GPX1 GPx1 6 2.2 Immunostaining for SOD1 ( D GPx1 ( E and Prx2 ( F 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187338 14648077 250437 17264 9353 PRDX2 PRX2 Prx2 11 3.9 Immunostaining for SOD1 ( D GPx1 ( E and Prx2 ( F 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187339 14648077 250438 20996 11179 SOD1 SOD1 SOD1 5 7.9 Similar stainability and immunolocalization of SOD1 GPx1 and Prx2 in the LBHI are observed ( LBHI 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187340 14648077 250438 8759 4553 GPX1 GPX1 GPx1 6 2.2 Similar stainability and immunolocalization of SOD1 GPx1 and Prx2 in the LBHI are observed ( LBHI Lewy 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187341 14648077 250438 17264 9353 PRDX2 PRX2 Prx2 8 3.9 Similar stainability and immunolocalization of SOD1 GPx1 and Prx2 in the LBHI are observed ( LBHI Lewy body-like hyaline 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187342 14648077 250438 20996 11179 SOD1 SOD1 SOD1 25 7.9 LBHI Lewy body-like hyaline inclusion FALS familial amyotrophic lateral sclerosis SOD1 superoxide dismutase 1 GPx1 glutathione peroxidase1 Prx2 peroxiredoxin2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187343 14648077 250438 8759 4553 GPX1 GPX1 GPx1 29 2.2 inclusion FALS familial amyotrophic lateral sclerosis SOD1 superoxide dismutase 1 GPx1 glutathione peroxidase1 Prx2 peroxiredoxin2 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187344 14648077 250438 17264 9353 PRDX2 PRX2 Prx2 32 3.9 amyotrophic lateral sclerosis SOD1 superoxide dismutase 1 GPx1 glutathione peroxidase1 Prx2 peroxiredoxin2 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187345 14648077 250441 20996 11179 SOD1 SOD1 SOD1 16 7.9 LBHI in an FALS patient with an A4V mutation in SOD1 gene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187346 14648077 250442 20996 11179 SOD1 SOD1 SOD1 2 7.9 Immunostaining for SOD1 ( A GPx1 ( B and Prx2 ( C 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187347 14648077 250442 8759 4553 GPX1 GPX1 GPx1 6 2.2 Immunostaining for SOD1 ( A GPx1 ( B and Prx2 ( C 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187348 14648077 250442 17264 9353 PRDX2 PRX2 Prx2 11 3.9 Immunostaining for SOD1 ( A GPx1 ( B and Prx2 ( C 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187349 14648077 250444 20996 11179 SOD1 SOD1 SOD1 17 7.9 an FALS patient with a two-base pair deletion in the SOD1 gene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187350 14648077 250445 20996 11179 SOD1 SOD1 SOD1 2 7.9 Immunostaining for SOD1 ( D GPx1 ( E and Prx2 ( F 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187351 14648077 250445 8759 4553 GPX1 GPX1 GPx1 6 2.2 Immunostaining for SOD1 ( D GPx1 ( E and Prx2 ( F 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187352 14648077 250445 17264 9353 PRDX2 PRX2 Prx2 11 3.9 Immunostaining for SOD1 ( D GPx1 ( E and Prx2 ( F 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187353 14648077 250446 8759 4553 GPX1 GPX1 GPx1 1 2.2 Immunostaining GPx1 ( E and Prx2 ( F are observed in only 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187354 14648077 250446 17264 9353 PRDX2 PRX2 Prx2 6 3.9 Immunostaining GPx1 ( E and Prx2 ( F are observed in only part of the SOD1-positive 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187355 14648077 250446 20996 11179 SOD1 SOD1 SOD1-positive 17 1.7 Prx2 ( F are observed in only part of the SOD1-positive LBHI 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187356 14648077 250447 20996 11179 SOD1 SOD1 SOD1 26 7.9 LBHI Lewy body-like hyaline inclusion FALS familial amyotrophic lateral sclerosis SOD1 superoxide dismutase 1 GPx1 glutathione peroxidase1 Prx2 peroxiredoxin2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187357 14648077 250447 8759 4553 GPX1 GPX1 GPx1 30 2.2 inclusion FALS familial amyotrophic lateral sclerosis SOD1 superoxide dismutase 1 GPx1 glutathione peroxidase1 Prx2 peroxiredoxin2 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187358 14648077 250447 17264 9353 PRDX2 PRX2 Prx2 33 3.9 amyotrophic lateral sclerosis SOD1 superoxide dismutase 1 GPx1 glutathione peroxidase1 Prx2 peroxiredoxin2 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187359 14648077 250449 20996 11179 SOD1 SOD1 SOD1 15 7.9 the spinal anterior horn in a transgenic rat expressing human SOD1 with an H46R mutation immunostained with antibodies against SOD1 ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187360 14648077 250449 20996 11179 SOD1 SOD1 SOD1 24 7.9 human SOD1 with an H46R mutation immunostained with antibodies against SOD1 ( A and Prx2 ( B 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187361 14648077 250449 17264 9353 PRDX2 PRX2 Prx2 29 3.9 H46R mutation immunostained with antibodies against SOD1 ( A and Prx2 ( B 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187362 14648077 250450 20996 11179 SOD1 SOD1 SOD1 11 7.9 and sausage-like LBHIs in the neuropil are positive for both SOD1 and Prx2 ( arrows ( SOD1 superoxide dismutase1 LBHI Lewy 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187363 14648077 250450 17264 9353 PRDX2 PRX2 Prx2 13 3.9 LBHIs in the neuropil are positive for both SOD1 and Prx2 ( arrows ( SOD1 superoxide dismutase1 LBHI Lewy body-like hyaline 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187364 14648077 250450 20996 11179 SOD1 SOD1 SOD1 18 7.9 are positive for both SOD1 and Prx2 ( arrows ( SOD1 superoxide dismutase1 LBHI Lewy body-like hyaline inclusion Prx2 peroxiredoxin2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187365 14648077 250450 17264 9353 PRDX2 PRX2 Prx2 26 3.9 arrows ( SOD1 superoxide dismutase1 LBHI Lewy body-like hyaline inclusion Prx2 peroxiredoxin2 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187366 14648077 250452 20996 11179 SOD1 SOD1 SOD1 15 7.9 the spinal anterior horn in a transgenic rat expressing human SOD1 with an H46R mutation immunostained with antibodies against SOD1 ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187367 14648077 250452 20996 11179 SOD1 SOD1 SOD1 24 7.9 human SOD1 with an H46R mutation immunostained with antibodies against SOD1 ( A and GPx1 ( B 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187368 14648077 250452 8759 4553 GPX1 GPX1 GPx1 29 2.2 H46R mutation immunostained with antibodies against SOD1 ( A and GPx1 ( B 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187369 14648077 250453 20996 11179 SOD1 SOD1 SOD1 9 7.9 Round LBHIs in the neuropil are positive for both SOD1 and GPx1 ( arrows ( SOD1 superoxide dismutase1 LBHI Lewy 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187370 14648077 250453 8759 4553 GPX1 GPX1 GPx1 11 2.2 LBHIs in the neuropil are positive for both SOD1 and GPx1 ( arrows ( SOD1 superoxide dismutase1 LBHI Lewy body-like hyaline 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187371 14648077 250453 20996 11179 SOD1 SOD1 SOD1 16 7.9 are positive for both SOD1 and GPx1 ( arrows ( SOD1 superoxide dismutase1 LBHI Lewy body-like hyaline inclusion GPx1 glutathione peroxidase1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187372 14648077 250453 8759 4553 GPX1 GPX1 GPx1 24 2.2 arrows ( SOD1 superoxide dismutase1 LBHI Lewy body-like hyaline inclusion GPx1 glutathione peroxidase1 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187373 14648077 250454 20996 11179 SOD1 SOD1 SOD1 15 7.9 50 _amp_micro m Noticeably the co-localization of the three proteins SOD1 Prx2 and GPx1 in neuronal LBHIs in SOD1-mutated FALS patients 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187374 14648077 250454 17264 9353 PRDX2 PRX2 Prx2 16 3.9 _amp_micro m Noticeably the co-localization of the three proteins SOD1 Prx2 and GPx1 in neuronal LBHIs in SOD1-mutated FALS patients and 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187375 14648077 250454 8759 4553 GPX1 GPX1 GPx1 18 2.2 Noticeably the co-localization of the three proteins SOD1 Prx2 and GPx1 in neuronal LBHIs in SOD1-mutated FALS patients and transgenic rats 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187376 14648077 250454 20996 11179 SOD1 SOD1 SOD1-mutated 23 1.7 three proteins SOD1 Prx2 and GPx1 in neuronal LBHIs in SOD1-mutated FALS patients and transgenic rats (H46R H46R and G93A was 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187377 14648077 250456 17264 9353 PRDX2 PRX2 Prx2 12 3.9 LBHIs the precise intra-inclusional immunolocalizations of the three proteins differed Prx2 (Fig Fig 5 D F and GPx1 (Fig Fig 5 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187378 14648077 250456 8759 4553 GPX1 GPX1 GPx1 18 2.2 three proteins differed Prx2 (Fig Fig 5 D F and GPx1 (Fig Fig 5 D E immunostaining was observed in only 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187379 14648077 250456 20996 11179 SOD1 SOD1 SOD1-positive 32 1.7 E immunostaining was observed in only some areas of the SOD1-positive LBHIs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187380 14648077 250457 17264 9353 PRDX2 PRX2 Prx2 5 3.9 Discussion Under normal physiological conditions Prx2 and GPx1 immunoreactivities in the spinal cord anterior horns in 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187381 14648077 250457 8759 4553 GPX1 GPX1 GPx1 7 2.2 Discussion Under normal physiological conditions Prx2 and GPx1 immunoreactivities in the spinal cord anterior horns in humans and 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187382 14648077 250458 17263 9352 PRDX1 PRX1 Prx1 1 1.3 Like Prx1 26 33 intranuclear localization in some neurons is also observed 2 JUMiner_v2.2 1 0 0 2 9142 TotalCon:2<>9352|PRDX1|5052|Complete__9142|PRRX1|5396|Complete__<>AvaiableGeneRif=2<>BEST:9142|PRRX1|0.00120135497085237<>ScoreDetail__9352|PRDX1|0.000566692733651773__9142|PRRX1|0.00120135497085237__ 0 0 0 0 0 187383 14648077 250458 17264 9353 PRDX2 PRX2 Prx2 16 3.9 33 intranuclear localization in some neurons is also observed in Prx2 immunostaining 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187384 14648077 250459 17264 9353 PRDX2 PRX2 Prx2 3 3.9 Considering that endogenous Prx2 and GPx1 within the neuronal cytoplasm are extremely effective regulators 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187385 14648077 250459 8759 4553 GPX1 GPX1 GPx1 5 2.2 Considering that endogenous Prx2 and GPx1 within the neuronal cytoplasm are extremely effective regulators of the 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187386 14648077 250459 17264 9353 PRDX2 PRX2 Prx2 32 3.9 almost all of the normal spinal motor neurons co-expressed both Prx2 and GPx1 confirms that these motor neurons maintain themselves using 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187387 14648077 250459 8759 4553 GPX1 GPX1 GPx1 34 2.2 of the normal spinal motor neurons co-expressed both Prx2 and GPx1 confirms that these motor neurons maintain themselves using the intracellular 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187388 14648077 250459 17264 9353 PRDX2 PRX2 Prx2 45 3.9 that these motor neurons maintain themselves using the intracellular Prx2/GPx1 Prx2 GPx1 system that is the redox system 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187389 14648077 250459 8759 4553 GPX1 GPX1 GPx1 45 2.2 these motor neurons maintain themselves using the intracellular Prx2/GPx1 Prx2 GPx1 system that is the redox system 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187390 14648077 250460 20996 11179 SOD1 SOD1 SOD1 13 7.9 As expected 12 13 16 27 30 SOD1 protein (probably probably the mutant form was found to aggregate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187391 14648077 250460 20996 11179 SOD1 SOD1 SOD1 35 7.9 anterior horn cells as neuronal LBHIs in FALS patients with SOD1 gene mutations and transgenic rats expressing human SOD1 with H46R 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187392 14648077 250460 20996 11179 SOD1 SOD1 SOD1 43 7.9 patients with SOD1 gene mutations and transgenic rats expressing human SOD1 with H46R and G93A mutations 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187393 14648077 250461 20996 11179 SOD1 SOD1 SOD1 3 7.9 Intense co-expression of SOD1 Prx2 and GPx1 in neuronal LBHIs in both diseases was 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187394 14648077 250461 17264 9353 PRDX2 PRX2 Prx2 4 3.9 Intense co-expression of SOD1 Prx2 and GPx1 in neuronal LBHIs in both diseases was evident 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187395 14648077 250461 8759 4553 GPX1 GPX1 GPx1 6 2.2 Intense co-expression of SOD1 Prx2 and GPx1 in neuronal LBHIs in both diseases was evident 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187396 14648077 250462 20996 11179 SOD1 SOD1 SOD1-mutated 3 1.7 To eliminate ROSs SOD1-mutated motor neurons in mutant SOD1-linked FALS and transgenic rats (G46R 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187397 14648077 250462 20996 11179 SOD1 SOD1 SOD1-linked 8 1.7 To eliminate ROSs SOD1-mutated motor neurons in mutant SOD1-linked FALS and transgenic rats (G46R G46R and G93A induce mutant/wild-type 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187398 14648077 250462 20996 11179 SOD1 SOD1 SOD1 18 7.9 transgenic rats (G46R G46R and G93A induce mutant/wild-type mutant wild-type SOD1 as an antioxidant system and Prx2/GPx1 Prx2 GPx1 as a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187399 14648077 250462 17264 9353 PRDX2 PRX2 Prx2 24 3.9 mutant/wild-type mutant wild-type SOD1 as an antioxidant system and Prx2/GPx1 Prx2 GPx1 as a redox system 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187400 14648077 250462 8759 4553 GPX1 GPX1 GPx1 24 2.2 mutant wild-type SOD1 as an antioxidant system and Prx2/GPx1 Prx2 GPx1 as a redox system 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187401 14648077 250462 18723 10261 ROS1 ROS ROSs 2 0.2 To eliminate ROSs SOD1-mutated motor neurons in mutant SOD1-linked FALS and transgenic rats 5 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 187402 14648077 250463 20996 11179 SOD1 SOD1 SOD1 7 7.9 In this in vivo milieu where mutant SOD1 exists Prx2 and GPx1 would aberrantly interact with the mutant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187403 14648077 250463 17264 9353 PRDX2 PRX2 Prx2 9 3.9 In this in vivo milieu where mutant SOD1 exists Prx2 and GPx1 would aberrantly interact with the mutant SOD1 which 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187404 14648077 250463 8759 4553 GPX1 GPX1 GPx1 11 2.2 this in vivo milieu where mutant SOD1 exists Prx2 and GPx1 would aberrantly interact with the mutant SOD1 which is assumed 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187405 14648077 250463 20996 11179 SOD1 SOD1 SOD1 18 7.9 exists Prx2 and GPx1 would aberrantly interact with the mutant SOD1 which is assumed to aggregate easily by itself 8 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187406 14648077 250464 20996 11179 SOD1 SOD1 SOD1 7 7.9 Among the multiple theories of how mutant SOD1 contributes to motor neuron death in mutant SOD1-related FALS and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187407 14648077 250464 20996 11179 SOD1 SOD1 SOD1-related 15 1.7 how mutant SOD1 contributes to motor neuron death in mutant SOD1-related FALS and transgenic animal models expressing human mutant SOD1 the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187408 14648077 250464 20996 11179 SOD1 SOD1 SOD1 24 7.9 mutant SOD1-related FALS and transgenic animal models expressing human mutant SOD1 the aggregation of mutant SOD1 in neurons leads to part 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187409 14648077 250464 20996 11179 SOD1 SOD1 SOD1 29 7.9 animal models expressing human mutant SOD1 the aggregation of mutant SOD1 in neurons leads to part of the mutant SOD1-mediated toxicity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187410 14648077 250464 20996 11179 SOD1 SOD1 SOD1-mediated 38 1.7 mutant SOD1 in neurons leads to part of the mutant SOD1-mediated toxicity through the formation of advanced glycation endproduct-modified SOD1 that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187411 14648077 250464 20996 11179 SOD1 SOD1 SOD1 47 7.9 mutant SOD1-mediated toxicity through the formation of advanced glycation endproduct-modified SOD1 that is insoluble and cytotoxic 16 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187412 14648077 250465 20996 11179 SOD1 SOD1 SOD1 16 7.9 with a two-base pair deletion at codon 126 of the SOD1 gene (Oki Oki family and G85R transgenic mice has revealed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187413 14648077 250465 20996 11179 SOD1 SOD1 SOD1 31 7.9 G85R transgenic mice has revealed that not only does mutant SOD1 provoke inclusion formation but that normal SOD1 also co-aggregates in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187414 14648077 250465 20996 11179 SOD1 SOD1 SOD1 38 7.9 only does mutant SOD1 provoke inclusion formation but that normal SOD1 also co-aggregates in these inclusions 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187415 14648077 250466 20996 11179 SOD1 SOD1 SOD1 11 7.9 with the facts that there are neuronal LBHIs positive for SOD1 Prx2 and GPx1 in the milieu where mutant SOD1 exists 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187416 14648077 250466 17264 9353 PRDX2 PRX2 Prx2 12 3.9 the facts that there are neuronal LBHIs positive for SOD1 Prx2 and GPx1 in the milieu where mutant SOD1 exists but 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187417 14648077 250466 8759 4553 GPX1 GPX1 GPx1 14 2.2 that there are neuronal LBHIs positive for SOD1 Prx2 and GPx1 in the milieu where mutant SOD1 exists but no LBHIs 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187418 14648077 250466 20996 11179 SOD1 SOD1 SOD1 20 7.9 for SOD1 Prx2 and GPx1 in the milieu where mutant SOD1 exists but no LBHIs (no no aggregations exist under physiological 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187419 14648077 250466 17264 9353 PRDX2 PRX2 Prx2 38 3.9 physiological conditions our study demonstrates an aberrant interaction of Prx2/GPx1 Prx2 GPx1 with mutant SOD1 the aggregation of which results in 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187420 14648077 250466 8759 4553 GPX1 GPX1 GPx1 38 2.2 conditions our study demonstrates an aberrant interaction of Prx2/GPx1 Prx2 GPx1 with mutant SOD1 the aggregation of which results in neuronal 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187421 14648077 250466 20996 11179 SOD1 SOD1 SOD1 41 7.9 demonstrates an aberrant interaction of Prx2/GPx1 Prx2 GPx1 with mutant SOD1 the aggregation of which results in neuronal LBHIs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187422 14648077 250467 17264 9353 PRDX2 PRX2 Prx2 5 3.9 In addition intra-inclusional co-aggregation of Prx2/GPx1 Prx2 GPx1 with mutant SOD1 causes the intracytoplasmic reduction of Prx2/GPx1, 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187423 14648077 250467 8759 4553 GPX1 GPX1 GPx1 5 2.2 In addition intra-inclusional co-aggregation of Prx2/GPx1 Prx2 GPx1 with mutant SOD1 causes the intracytoplasmic reduction of Prx2/GPx1, Prx2 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187424 14648077 250467 20996 11179 SOD1 SOD1 SOD1 8 7.9 In addition intra-inclusional co-aggregation of Prx2/GPx1 Prx2 GPx1 with mutant SOD1 causes the intracytoplasmic reduction of Prx2/GPx1, Prx2 GPx1 thereby reducing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187425 14648077 250467 17264 9353 PRDX2 PRX2 Prx2 14 3.9 GPx1 with mutant SOD1 causes the intracytoplasmic reduction of Prx2/GPx1, Prx2 GPx1 thereby reducing the availability of the redox system 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187426 14648077 250467 8759 4553 GPX1 GPX1 GPx1 14 2.2 with mutant SOD1 causes the intracytoplasmic reduction of Prx2/GPx1, Prx2 GPx1 thereby reducing the availability of the redox system 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187427 14648077 250468 20996 11179 SOD1 SOD SOD 9 1.7 A similar aberrant interaction of the copper chaperone for SOD (CCS) CCS and SOD1 (probably probably CCS-mutant SOD1 also occurs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187428 14648077 250468 3838 1613 CCS CCS CCS 10 1.2 similar aberrant interaction of the copper chaperone for SOD (CCS) CCS and SOD1 (probably probably CCS-mutant SOD1 also occurs in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187429 14648077 250468 20996 11179 SOD1 SOD1 SOD1 12 7.9 interaction of the copper chaperone for SOD (CCS) CCS and SOD1 (probably probably CCS-mutant SOD1 also occurs in the formation of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187430 14648077 250468 3838 1613 CCS CCS CCS-mutant 14 1.2 copper chaperone for SOD (CCS) CCS and SOD1 (probably probably CCS-mutant SOD1 also occurs in the formation of the neuronal LBHIs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187431 14648077 250468 20996 11179 SOD1 SOD1 SOD1 15 7.9 chaperone for SOD (CCS) CCS and SOD1 (probably probably CCS-mutant SOD1 also occurs in the formation of the neuronal LBHIs in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187432 14648077 250468 20996 11179 SOD1 SOD1 SOD1-linked 27 1.7 occurs in the formation of the neuronal LBHIs in mutant SOD1-linked FALS 19 and the mutant SOD1 transgenic mouse model 32 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187433 14648077 250468 20996 11179 SOD1 SOD1 SOD1 35 7.9 neuronal LBHIs in mutant SOD1-linked FALS 19 and the mutant SOD1 transgenic mouse model 32 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187434 14648077 250469 12369 6893 MAPT tau tau 16 0.8 been observed for normal cytosolic constitutive proteins including tubulin and tau protein as well as neuron-specific constitutive proteins containing phosphorylated neurofilament 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187435 14648077 250470 20996 11179 SOD1 SOD1 SOD1 18 7.9 normal constitutive proteins with the aberrant interaction of cytotoxic mutant SOD1 with Prx2/GPx1 Prx2 GPx1 directly regulating a redox system our 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187436 14648077 250470 17264 9353 PRDX2 PRX2 Prx2 20 3.9 with the aberrant interaction of cytotoxic mutant SOD1 with Prx2/GPx1 Prx2 GPx1 directly regulating a redox system our finding leads us 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187437 14648077 250470 8759 4553 GPX1 GPX1 GPx1 20 2.2 the aberrant interaction of cytotoxic mutant SOD1 with Prx2/GPx1 Prx2 GPx1 directly regulating a redox system our finding leads us to 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187438 14648077 250470 17264 9353 PRDX2 PRX2 Prx2 37 3.9 leads us to speculate that not only co-aggregation of Prx2/GPx1 Prx2 GPx1 and SOD1 into LBHIs but also intracytoplasmic reduction of 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187439 14648077 250470 8759 4553 GPX1 GPX1 GPx1 37 2.2 us to speculate that not only co-aggregation of Prx2/GPx1 Prx2 GPx1 and SOD1 into LBHIs but also intracytoplasmic reduction of Prx2/GPx1 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187440 14648077 250470 20996 11179 SOD1 SOD1 SOD1 39 7.9 speculate that not only co-aggregation of Prx2/GPx1 Prx2 GPx1 and SOD1 into LBHIs but also intracytoplasmic reduction of Prx2/GPx1 Prx2 GPx1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187441 14648077 250470 17264 9353 PRDX2 PRX2 Prx2 47 3.9 and SOD1 into LBHIs but also intracytoplasmic reduction of Prx2/GPx1 Prx2 GPx1 in both diseases may partly contribute to the breakdown 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187442 14648077 250470 8759 4553 GPX1 GPX1 GPx1 47 2.2 SOD1 into LBHIs but also intracytoplasmic reduction of Prx2/GPx1 Prx2 GPx1 in both diseases may partly contribute to the breakdown of 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187443 14648077 250470 20996 11179 SOD1 SOD1 SOD1-mutated 64 1.7 to the breakdown of the redox system itself in these SOD1-mutated neurons and this may be one of the endogenous mechanisms 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187444 14648077 250472 17264 9353 PRDX2 PRX2 Prx2 10 3.9 remains to be determined whether this aberrant interaction of Prx2/GPx1 Prx2 GPx1 with mutant SOD1 is a direct or an indirect 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187445 14648077 250472 8759 4553 GPX1 GPX1 GPx1 10 2.2 to be determined whether this aberrant interaction of Prx2/GPx1 Prx2 GPx1 with mutant SOD1 is a direct or an indirect effect 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187446 14648077 250472 20996 11179 SOD1 SOD1 SOD1 13 7.9 whether this aberrant interaction of Prx2/GPx1 Prx2 GPx1 with mutant SOD1 is a direct or an indirect effect based on the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187447 14648077 250472 20996 11179 SOD1 SOD1 SOD1-mutated 26 1.7 direct or an indirect effect based on the pathogenesis of SOD1-mutated FALS disease itself or whether Prx2 and GPx1 play a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187448 14648077 250472 17264 9353 PRDX2 PRX2 Prx2 32 3.9 on the pathogenesis of SOD1-mutated FALS disease itself or whether Prx2 and GPx1 play a primary or a secondary role to 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187449 14648077 250472 8759 4553 GPX1 GPX1 GPx1 34 2.2 pathogenesis of SOD1-mutated FALS disease itself or whether Prx2 and GPx1 play a primary or a secondary role to mutant SOD1 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187450 14648077 250472 20996 11179 SOD1 SOD1 SOD1 44 7.9 GPx1 play a primary or a secondary role to mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187451 14648077 250473 17264 9353 PRDX2 PRX2 Prx2 13 3.9 to emphasize that the aberrant interaction and co-aggregation of Prx2/GPx1 Prx2 GPx1 and SOD1 (probably probably Prx2/GPx1 Prx2 GPx1 and mutant 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187452 14648077 250473 8759 4553 GPX1 GPX1 GPx1 13 2.2 emphasize that the aberrant interaction and co-aggregation of Prx2/GPx1 Prx2 GPx1 and SOD1 (probably probably Prx2/GPx1 Prx2 GPx1 and mutant SOD1 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187453 14648077 250473 20996 11179 SOD1 SOD1 SOD1 15 7.9 the aberrant interaction and co-aggregation of Prx2/GPx1 Prx2 GPx1 and SOD1 (probably probably Prx2/GPx1 Prx2 GPx1 and mutant SOD1 in FALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187454 14648077 250473 17264 9353 PRDX2 PRX2 Prx2 17 3.9 co-aggregation of Prx2/GPx1 Prx2 GPx1 and SOD1 (probably probably Prx2/GPx1 Prx2 GPx1 and mutant SOD1 in FALS patients with SOD1 gene 2 JUMiner_v2.2 1 0 0 2 9353 TotalCon:2<>21338|PRRX2|51450|Complete__9353|PRDX2|7001|Complete__<>AvaiableGeneRif=2<>BEST:9353|PRDX2|0.000576953371140517<>ScoreDetail__9353|PRDX2|0.000576953371140517__21338|PRRX2|0.000482117812061711__ 0 0 0 0 0 187455 14648077 250473 8759 4553 GPX1 GPX1 GPx1 17 2.2 of Prx2/GPx1 Prx2 GPx1 and SOD1 (probably probably Prx2/GPx1 Prx2 GPx1 and mutant SOD1 in FALS patients with SOD1 gene mutations 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187456 14648077 250473 20996 11179 SOD1 SOD1 SOD1 20 7.9 GPx1 and SOD1 (probably probably Prx2/GPx1 Prx2 GPx1 and mutant SOD1 in FALS patients with SOD1 gene mutations and transgenic rats 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187457 14648077 250473 20996 11179 SOD1 SOD1 SOD1 25 7.9 Prx2/GPx1 Prx2 GPx1 and mutant SOD1 in FALS patients with SOD1 gene mutations and transgenic rats expressing human SOD1 mutations may 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187458 14648077 250473 20996 11179 SOD1 SOD1 SOD1 33 7.9 patients with SOD1 gene mutations and transgenic rats expressing human SOD1 mutations may amplify a more marked mutant SOD1-mediated toxicity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 187459 14648077 250473 20996 11179 SOD1 SOD1 SOD1-mediated 41 1.7 expressing human SOD1 mutations may amplify a more marked mutant SOD1-mediated toxicity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188327 14660707 251169 20996 11179 SOD1 ALS ALS 29 1.1 during pathophysiological states like hypoxia and amyotrophic lateral sclerosis (ALS), ALS a fatal neurodegenerative disorder 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000974854894232857<>ScoreDetail__5468|IGFALS|0.00017504244779359__11179|SOD1|0.000974854894232857__ 0 0 0 0 0 188328 14660707 251172 18723 10261 ROS1 ROS ROS 38 0.0 _amp_#x003bc m indicating an involvement of reactive oxygen species (ROS) ROS in the activation mechanism 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188329 14660707 251180 20247 20116 SLC25A29 CACL CaCl 36 1.3 2 25 NaHCO 3 1 NaH 2 PO 4 1.5 CaCl 2 30 glucose pH 7.4 325 mosmol l _amp_#x02212 1 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 188330 14660707 251195 19254 10472 RUNX2 CCD CCD 11 0.0 Fluorescence measurements For fluorescence measurements a modified version of the CCD camera system (TILL TILL Photonics Planegg Germany was employed as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188331 14660707 251197 19254 10472 RUNX2 CCD CCD 3 0.0 A 12 bit CCD camera (PCO, PCO Germany was employed to monitor fluorescence changes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188332 14660707 251215 4841 2296 CPA1 CPA CPA 2 0.0 Cyclopiazonic acid (CPA) CPA and oligomycin were dissolved in DMSO (250 250 m m 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188333 14660707 251222 20996 11179 SOD1 ALS ALS 23 1.1 for hypoxia (_amp_#x02018;chemical _amp_#x02018 chemical hypoxia_amp_#x02019 and (ii) ii in ALS a notable decrease in complex IV activity has been observed 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000974854894232857<>ScoreDetail__5468|IGFALS|0.00017504244779359__11179|SOD1|0.000974854894232857__ 0 0 0 0 0 188334 14660707 251261 18723 10261 ROS1 ROS ROS 6 0.0 Superoxide and related reactive oxygen species (ROS) ROS may act as signalling molecules by shifting redox pairs to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188335 14660707 251262 18723 10261 ROS1 ROS ROS 6 0.0 We tested the potential involvement of ROS in mediating I CN by the ability of the antioxidants 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188336 14660707 251262 18723 10261 ROS1 ROS ROS 18 0.0 mediating I CN by the ability of the antioxidants and ROS scavengers ascorbic acid and Trolox to interfere with the induction 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188337 14660707 251267 18723 10261 ROS1 ROS ROS 12 0.0 the experiments suggested that an increase in the formation of ROS following complex IV inhibition was involved in the activation of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188338 14660707 251293 4841 2296 CPA1 CPA CPA 19 0.0 inhibited the ER Ca 2 -ATPase with 50 _amp_#x003bc m CPA for at least 5 min which released Ca 2 from 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188339 14660707 251294 4841 2296 CPA1 CPA CPA 31 0.0 2003 did not invoke a rise in Ca 2 when CPA incubation preceded its action indicating that CPA largely depleted the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188340 14660707 251294 4841 2296 CPA1 CPA CPA 38 0.0 Ca 2 when CPA incubation preceded its action indicating that CPA largely depleted the ER Ca 2 content (not not shown 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188341 14660707 251295 4841 2296 CPA1 CPA CPA 6 0.0 When CN was then added after CPA preincubation it still produced an increase in Ca 2 i 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188342 14660707 251303 12369 6893 MAPT tau tau 13 0.3 2 transients was assessed by determining the recovery time constant tau (_amp_#x003c4;) _amp_#x003c4 after fitting with a single-exponential function 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188343 14660707 251313 20996 11179 SOD1 ALS ALS 81 1.1 is typically tolerant to hypoxia and resistant to damage in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000974854894232857<>ScoreDetail__5468|IGFALS|0.00017504244779359__11179|SOD1|0.000974854894232857__ 0 0 0 0 0 188344 14660707 251323 20996 11179 SOD1 ALS ALS 37 1.1 and in motoneurone disease such as amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000974854894232857<>ScoreDetail__5468|IGFALS|0.00017504244779359__11179|SOD1|0.000974854894232857__ 0 0 0 0 0 188345 14660707 251331 18723 10261 ROS1 ROS ROS 16 0.0 possibly induced by increased levels of reactive oxygen species (ROS), ROS which originate at the respiratory chain when complex IV activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188346 14660707 251332 18723 10261 ROS1 ROS ROS 4 0.0 However the involvement of ROS is challenged by the fact that the activation of I 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188347 14660707 251333 18723 10261 ROS1 ROS ROS 6 0.0 Although a very localized production of ROS that was not represented by the global NADH signal could 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188348 14660707 251337 18723 10261 ROS1 ROS ROS 7 0.0 Taken together despite the plausible involvement of ROS in activation of I CN more experiments are necessary to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188349 14660707 251350 20996 11179 SOD1 ALS ALS 19 1.1 are tolerant to hypoxia and also resistant to degeneration in ALS hyperpolarize under the same conditions 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000974854894232857<>ScoreDetail__5468|IGFALS|0.00017504244779359__11179|SOD1|0.000974854894232857__ 0 0 0 0 0 188350 14660707 251354 20996 11179 SOD1 ALS ALS 45 1.1 hypoxia and their selective degeneration in amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000974854894232857<>ScoreDetail__5468|IGFALS|0.00017504244779359__11179|SOD1|0.000974854894232857__ 0 0 0 0 0 188351 14660707 251355 20996 11179 SOD1 ALS ALS-related 24 1.1 response to CN over a time range of minutes whereas ALS-related motoneurone degeneration occurs over months the experimental protocol of mitochondrial 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000974854894232857<>ScoreDetail__5468|IGFALS|0.00017504244779359__11179|SOD1|0.000974854894232857__ 0 0 0 0 0 188352 14660707 251355 20996 11179 SOD1 ALS ALS-related 42 1.1 protocol of mitochondrial inhibition may still have interesting implications for ALS-related motoneurone pathologies 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000974854894232857<>ScoreDetail__5468|IGFALS|0.00017504244779359__11179|SOD1|0.000974854894232857__ 0 0 0 0 0 188353 14660707 251356 20996 11179 SOD1 SOD1 SOD1 20 1.1 inhibition are paralleled by observations in cell lines expressing mutant SOD1 which show increased basal Ca 2 loads ( Carri et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188354 14660707 251357 20996 11179 SOD1 SOD1 SOD1 23 1.1 resemble increased Na currents and enhanced neuronal excitability in mutant SOD1 mouse spinal MNs ( Kuo et al 2002 2003 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188355 14660707 251358 20996 11179 SOD1 ALS ALS-related 15 1.1 motoneurone responses to mitochondrial inhibition and their selective vulnerability during ALS-related motoneurone disease will be an interesting area for future investigation 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000974854894232857<>ScoreDetail__5468|IGFALS|0.00017504244779359__11179|SOD1|0.000974854894232857__ 0 0 0 0 0 188356 14660707 251375 20996 11179 SOD1 ALS ALS 18 1.1 in MNs to the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), ALS where selective MN degeneration leads to death usually within 5 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000974854894232857<>ScoreDetail__5468|IGFALS|0.00017504244779359__11179|SOD1|0.000974854894232857__ 0 0 0 0 0 188357 14660707 251376 20996 11179 SOD1 ALS ALS 18 1.1 azide or malonate is an accepted in vitro model for ALS based on the selective pattern of neuronal degeneration in spinal 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000974854894232857<>ScoreDetail__5468|IGFALS|0.00017504244779359__11179|SOD1|0.000974854894232857__ 0 0 0 0 0 188358 14660707 251377 20996 11179 SOD1 ALS ALS 6 1.1 Also in a familial form of ALS dysfunction of oxidative phosphorylation induced by a mutated Cu/Zn Cu 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000974854894232857<>ScoreDetail__5468|IGFALS|0.00017504244779359__11179|SOD1|0.000974854894232857__ 0 0 0 0 0 188359 14660707 251377 20996 11179 SOD1 SOD1 SOD1 19 1.1 by a mutated Cu/Zn Cu Zn super oxide dismutase (SOD1) SOD1 is thought to be causally involved in MN degeneration ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 188360 14660707 251378 20996 11179 SOD1 ALS ALS 18 1.1 metabolism have been proposed as causative or modifying factors in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000974854894232857<>ScoreDetail__5468|IGFALS|0.00017504244779359__11179|SOD1|0.000974854894232857__ 0 0 0 0 0 188361 14660707 251379 23910 12680 VEGFA VEGF VEGF 12 2.8 on the observation that impaired vascular endothelial growth factor (VEGF) VEGF synthesis due to hypoxia selectively damages MNs ( Oosthuyse et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189412 14690536 252558 20996 11179 SOD1 SOD1 SOD1 2 2.7 Expression of SOD1 G93A or wild-type SOD1 in primary cultures of astrocytes down-regulates 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189413 14690536 252558 20996 11179 SOD1 SOD1 SOD1 6 2.7 Expression of SOD1 G93A or wild-type SOD1 in primary cultures of astrocytes down-regulates the glutamate transporter GLT-1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189414 14690536 252558 20017 10940 SLC1A2 GLT-1 GLT-1 16 2.5 SOD1 in primary cultures of astrocytes down-regulates the glutamate transporter GLT-1 lack of involvement of oxidative stress 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189415 14690536 252559 20996 11179 SOD1 ALS ALS 11 2.7 is implicated in the aetiology of amyotrophic lateral sclerosis (ALS) ALS with impairment of glutamate transport into astrocytes a possible cause 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0015800604610682<>ScoreDetail__5468|IGFALS|0.000454708627497906__11179|SOD1|0.0015800604610682__ 0 0 0 0 0 189416 14690536 252560 20996 11179 SOD1 SOD1 SOD1 9 2.7 possible that mutations of Cu/Zn Cu Zn superoxide dismutase (SOD1), SOD1 responsible for about 20% of familial ALS down-regulates glutamate transporters 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189417 14690536 252560 20996 11179 SOD1 ALS ALS 16 2.7 superoxide dismutase (SOD1), SOD1 responsible for about 20% of familial ALS down-regulates glutamate transporters via oxidative stress 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0015800604610682<>ScoreDetail__5468|IGFALS|0.000454708627497906__11179|SOD1|0.0015800604610682__ 0 0 0 0 0 189418 14690536 252561 20996 11179 SOD1 SOD1 hSOD1 13 2.7 astrocytes to investigate the effect of the FALS-linked mutant hSOD1(G93A) hSOD1 G93A and wild-type SOD1 (hSOD1wt) hSOD1wt on the glutamate uptake 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189419 14690536 252561 20996 11179 SOD1 SOD1 SOD1 16 2.7 effect of the FALS-linked mutant hSOD1(G93A) hSOD1 G93A and wild-type SOD1 (hSOD1wt) hSOD1wt on the glutamate uptake system 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189420 14690536 252562 20996 11179 SOD1 SOD1 hSOD1 13 2.7 and RT-PCR it was shown that expression of either hSOD1(G93A) hSOD1 G93A or hSOD1wt in astrocytes produced down-regulation of the levels 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189421 14690536 252562 20017 10940 SLC1A2 GLT-1 GLT-1 27 2.5 astrocytes produced down-regulation of the levels of a glutamate transporter GLT-1 without alterations in its mRNA level hSOD1(G93A) hSOD1 G93A or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189422 14690536 252562 20996 11179 SOD1 SOD1 hSOD1 34 2.7 glutamate transporter GLT-1 without alterations in its mRNA level hSOD1(G93A) hSOD1 G93A or hSOD1wt expression caused a decrease of the monomeric 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189423 14690536 252562 20017 10940 SLC1A2 GLT-1 GLT-1 46 2.5 hSOD1wt expression caused a decrease of the monomeric form of GLT-1 without increasing oxidative multimers of GLT-1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189424 14690536 252562 20017 10940 SLC1A2 GLT-1 GLT-1 52 2.5 the monomeric form of GLT-1 without increasing oxidative multimers of GLT-1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189425 14690536 252563 20017 10940 SLC1A2 GLT-1 GLT-1 5 2.5 The effects were selective to GLT-1 since another glutamate transporter GLAST protein and mRNA levels were 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189426 14690536 252563 20018 10941 SLC1A3 GLAST GLAST 10 1.5 The effects were selective to GLT-1 since another glutamate transporter GLAST protein and mRNA levels were not altered 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189427 14690536 252564 20017 10940 SLC1A2 GLT-1 GLT-1 4 2.5 Reflecting the decrease in GLT-1 protein 3H d-aspartate uptake was reduced in cultures expressing hSOD1(G93A) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189428 14690536 252564 20996 11179 SOD1 SOD1 hSOD1 13 2.7 protein 3H d-aspartate uptake was reduced in cultures expressing hSOD1(G93A) hSOD1 G93A or hSOD1wt 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189429 14690536 252565 20017 10940 SLC1A2 GLT-1 GLT-1 4 2.5 The hSOD1-induced decline in GLT-1 protein and 3H d-aspartate uptake was not blocked by the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189430 14690536 252566 20996 11179 SOD1 SOD1 hSOD1 9 2.7 7'-dichlorofluorescein (DCF)-induced DCF -induced fluorescence revealed that expression of hSOD1(G93A) hSOD1 G93A or hSOD1wt in astrocytes does not lead to detectable 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189431 14690536 252567 20017 10940 SLC1A2 GLT-1 GLT-1 6 2.5 This study suggests that levels of GLT-1 protein in astrocytes are reduced rapidly by overexpression of hSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189432 14690536 252567 20996 11179 SOD1 SOD1 hSOD1 16 2.7 GLT-1 protein in astrocytes are reduced rapidly by overexpression of hSOD1 and is due to a property shared between the wild-type 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189698 14698606 252855 20996 11179 SOD1 ALS ALS 21 2.2 crucial role in the pathogenesis of amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189699 14698606 252860 20996 11179 SOD1 ALS ALS 7 2.2 These observations provide a new understanding of ALS pathogenesis that integrates diverse clues into a unified model that 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189700 14698606 252861 20996 11179 SOD1 ALS ALS 3 2.2 Amyotrophic lateral sclerosis (ALS) ALS is a degenerative disease characterized by progressive paralysis usually leading 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189701 14698606 252862 20996 11179 SOD1 SOD1 SOD1 24 2.2 linked to mutations in the enzyme superoxide dismutase 1 (SOD1) SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189702 14698606 252868 20996 11179 SOD1 SOD1 SOD1 17 2.2 recent years has addressed crucial issues including actions of mutant SOD1 modulation of glutamate transport roles of inflammation and the formation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189703 14698606 252870 20996 11179 SOD1 ALS ALS 7 2.2 Rather than examining one particular subset of ALS we hope to suggest an integrative framework applicable to all 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189704 14698606 252872 18723 10261 ROS1 ROS ROS 17 0.0 motor neurons produce large quantities of reactive oxygen species (ROS) ROS which in addition to damaging the motor neurons in which 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189705 14698606 252873 18723 10261 ROS1 ROS ROS 10 0.0 Consequently ambient glutamate levels rise further inducing more motor neuron ROS and setting off a progressive feedforward cascade of selective motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189706 14698606 252879 20996 11179 SOD1 ALS ALS 2 2.2 Excitotoxicity in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189707 14698606 252884 20996 11179 SOD1 ALS ALS 33 2.2 it also plays a role in the slow neurodegeneration in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189708 14698606 252885 20996 11179 SOD1 ALS ALS 9 2.2 First abnormalities in glutamate metabolism have been reported in ALS patients 9 with elevated glutamate levels in the cerebrospinal fluid 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189709 14698606 252888 20996 11179 SOD1 ALS ALS 11 2.2 the only drug proven to slow the course of human ALS is the anti-excitotoxic compound Riluzole 16 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189710 14698606 252897 8790 4572 GRIA2 GLUR2 GluR2 12 1.6 appear to comprise AMPA receptor subunits but to lack the GluR2 AMPA subunit which blocks Ca 2 permeability in heteromeric channels 14 JUMiner_v2.2 1 0 0 2 4572 TotalCon:2<>4572|GRIA2|2891|Complete__4594|GRM2|2912|Complete__<>AvaiableGeneRif=2<>BEST:4572|GRIA2|0.00104746630505174<>ScoreDetail__4594|GRM2|0.000699628930984706__4572|GRIA2|0.00104746630505174__ 0 0 0 0 0 189711 14698606 252898 18723 10261 ROS1 ROS ROS 17 0.0 through Ca-A/K Ca-A K channels has been found to induce ROS generation of mitochondrial origin 17 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189712 14698606 252900 20996 11179 SOD1 ALS ALS 16 2.2 strong cytosolic Ca 2 -binding-protein expression might be resistant in ALS 28 and 29 and overexpression of Ca 2 -binding proteins 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189713 14698606 252900 20996 11179 SOD1 ALS ALS 41 2.2 neurons both in vitro and in an animal model of ALS 30 and 31 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189714 14698606 252901 20996 11179 SOD1 ALS ALS 26 2.2 a subpopulation of motor neurons that is relatively resistant to ALS seems to buffer intracellular Ca 2 more effectively 32 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189715 14698606 252902 18723 10261 ROS1 ROS ROS 37 0.0 caused particularly rapid mitochondrial Ca 2 overload and strong mitochondrial ROS generation 33 ( Figure 1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189716 14698606 252904 20996 11179 SOD1 ALS ALS 6 2.2 How is glutamate transport damaged in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189717 14698606 252906 20017 10940 SLC1A2 GLT-1 GLT-1 5 1.0 Specifically the astrocytic glutamate transporter GLT-1 (also also known as the excitatory amino acid transporter EAAT-2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189718 14698606 252906 20017 10940 SLC1A2 EAAT2 EAAT-2 14 1.0 GLT-1 (also also known as the excitatory amino acid transporter EAAT-2 appears to be particularly affected 34 and 35 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189719 14698606 252907 20996 11179 SOD1 ALS ALS 5 2.2 Thus a crucial aspect of ALS that remains to be explained is the cause or causes 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189720 14698606 252912 20996 11179 SOD1 ALS ALS 12 2.2 idea decreased levels of transporter have been reported in end-stage ALS 34 as well as in some SOD1 transgenic mice 37 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189721 14698606 252912 20996 11179 SOD1 SOD1 SOD1 21 2.2 reported in end-stage ALS 34 as well as in some SOD1 transgenic mice 37 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189722 14698606 252913 20996 11179 SOD1 ALS ALS 6 2.2 These mice provide excellent models of ALS reproducing numerous features of the disease including oxidative damage and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189723 14698606 252918 20996 11179 SOD1 ALS ALS 33 2.2 oxidative modifications of transporter peptides have been reported in both ALS and the SOD1 mutant mouse model 46 and 47 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189724 14698606 252918 20996 11179 SOD1 SOD1 SOD1 36 2.2 transporter peptides have been reported in both ALS and the SOD1 mutant mouse model 46 and 47 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189725 14698606 252921 20996 11179 SOD1 ALS ALS 17 2.2 to transport that leads to excitotoxic motor neuron damage in ALS the question then arises as to the source of the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189726 14698606 252922 18723 10261 ROS1 ROS ROS 9 0.0 One idea that has received attention recently is that ROS might derive from inflammatory processes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189727 14698606 252923 17610 9605 PTGS2 COX-2 COX-2 11 1.0 role for inflammation inhibitors of the enzyme cyclooxygenase 2 (COX-2) COX-2 have shown beneficial effects in SOD1 mutant mouse models 49 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189728 14698606 252923 20996 11179 SOD1 SOD1 SOD1 17 2.2 enzyme cyclooxygenase 2 (COX-2) COX-2 have shown beneficial effects in SOD1 mutant mouse models 49 and 50 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189729 14698606 252924 18723 10261 ROS1 ROS ROS 18 0.0 human and transgenic mouse models these cells can directly produce ROS and might release factors that can trigger glutamate release from 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189730 14698606 252925 20996 11179 SOD1 SOD SOD 9 2.2 Another potential cause of aberrant oxidation is the mutant SOD itself 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189731 14698606 252927 18723 10261 ROS1 ROS ROS 9 0.0 However this mechanism would seem unlikely to bear upon ROS generation in the predominant sporadic forms of the disease 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189732 14698606 252928 18723 10261 ROS1 ROS ROS 10 0.0 In light of observations that excitotoxic activation causes relatively selective ROS production in motor neurons ( Figure 1e f we propose 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189733 14698606 252928 18723 10261 ROS1 ROS ROS 35 0.0 that motor neurons might be an important source of the ROS that damages astrocytic glutamate transport 33 and 54 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189734 14698606 252929 20017 10940 SLC1A2 GLT-1 GLT-1 2 1.0 Indeed the GLT-1 transporter which is damaged in ALS is concentrated in astrocytic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189735 14698606 252929 20996 11179 SOD1 ALS ALS 8 2.2 Indeed the GLT-1 transporter which is damaged in ALS is concentrated in astrocytic processes directly abutting motor neurons 55 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189736 14698606 252930 18723 10261 ROS1 ROS ROS 37 0.0 them particularly susceptible to damage or inhibition by motor neuron ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189737 14698606 252931 18723 10261 ROS1 ROS ROS 28 0.0 to excitotoxic activation motor neurons produce particularly large quantities of ROS which can exit the motor neurons and cause oxidation in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189738 14698606 252932 18723 10261 ROS1 ROS ROS 9 0.0 Furthermore experiments using glutamate uptake autoradiography found that the ROS appears able to induce a rapid disruption of glutamate uptake 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189739 14698606 252933 20996 11179 SOD1 ALS ALS 15 2.2 motor neurons are a principal source of ROS in the ALS spinal cord they show intense labeling for nitrotyrosine a marker 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189740 14698606 252933 18723 10261 ROS1 ROS ROS 12 0.0 the idea that motor neurons are a principal source of ROS in the ALS spinal cord they show intense labeling for 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189741 14698606 252934 20996 11179 SOD1 SOD1 SOD1 34 2.2 occurs in an annular pattern immediately surrounding motor neurons in SOD1 mutant mice 54 ( Figure 2c 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189742 14698606 252934 18723 10261 ROS1 ROS ROS 6 0.0 In addition supporting the hypothesis that ROS emanation from motor neurons contributes to loss of astrocytic glutamate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189743 14698606 252936 20996 11179 SOD1 ALS ALS 18 2.2 motor neurons and astrocytes might play a crucial role in ALS pathogenesis 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189744 14698606 252937 20996 11179 SOD1 ALS ALS 17 2.2 of mechanism that might pertain to motor neuron damage in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189745 14698606 252939 18723 10261 ROS1 ROS ROS 38 0.0 2 buffering results in mitochondrial Ca 2 overload and strong ROS generation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189746 14698606 252940 20996 11179 SOD1 ALS ALS 23 2.2 towards explaining the oxidative damage and mitochondrial abnormalities observed in ALS motor neurons 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189747 14698606 252941 20996 11179 SOD1 ALS ALS 13 2.2 compatible with possible apoptotic contributions to motor neuron loss in ALS 58 because mitochondria which contain cytochrome c and other apoptotic 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189748 14698606 252942 20996 11179 SOD1 ALS ALS 7 2.2 Other pathological features of motor neurons in ALS such as the presence of protein aggregates and neurofilamentous abnormalities 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189749 14698606 252942 18723 10261 ROS1 ROS ROS 24 0.0 aggregates and neurofilamentous abnormalities could be a consequence of the ROS generation resulting after oxidative modification of these proteins 53 59 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189750 14698606 252943 18723 10261 ROS1 ROS ROS 9 0.0 The second idea is that it is specifically the ROS generated within motor neurons in response to excitotoxic activation that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189751 14698606 252945 20996 11179 SOD1 ALS ALS 13 2.2 ideas provide the basis for a feedforward cycle contributing to ALS progression as increases in extracellular glutamate concentration will result in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189752 14698606 252945 18723 10261 ROS1 ROS ROS 27 0.0 in extracellular glutamate concentration will result in greater motor neuron ROS generation and more disruption of astrocytic glutamate transport causing further 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189753 14698606 252946 20996 11179 SOD1 SOD1 SOD1 13 2.2 explain how seemingly disparate inciting factors (for for instance mutant SOD1 environmental toxins trauma inflammation or infection could converge into a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189754 14698606 252948 20996 11179 SOD1 SOD1 SOD1 19 2.2 are integrally involved in disease pathogenesis expression of the mutant SOD1 in either motor neurons or astrocytes alone did not cause 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189755 14698606 252949 20996 11179 SOD1 SOD1 SOD1 5 2.2 Furthermore recent studies of mutant SOD1 chimeras indicate the dependence of motor neuron survival on the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189756 14698606 252951 20996 11179 SOD1 ALS ALS 9 2.2 Specifically if such a feedforward cycle is crucial for ALS progression it would lend support the idea that no single 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 189757 14698606 252952 18723 10261 ROS1 ROS ROS 23 0.0 glutamate release activation of Ca-A/K Ca-A K channels mitochondrial disruption ROS generation and transporter damage is likely to provide greater benefit 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 189758 14698606 252953 20996 11179 SOD1 ALS ALS 3 2.2 Satisfactory models of ALS should provide an explanation for the selective vulnerability of motor 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000895981189262454<>ScoreDetail__5468|IGFALS|0.000255740849272737__11179|SOD1|0.000895981189262454__ 0 0 0 0 0 190795 14739060 254283 6981 22140 FAM20C RNS RNS 19 0.3 reactive oxygen species (ROS) ROS and reactive nitrogen species (RNS) RNS 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 190796 14739060 254283 18723 10261 ROS1 ROS ROS 14 0.0 as accountable for redox regulation involving reactive oxygen species (ROS) ROS and reactive nitrogen species (RNS) RNS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190797 14739060 254289 18723 10261 ROS1 ROS ROS 7 0.0 ATP synthesis is responsible for most of ROS and notably the first produced superoxide anion ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190798 14739060 254290 20996 11179 SOD1 ALS ALS 35 1.3 Parkinson_amp_#x2019 s disease (PD) PD and amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00160093311530149<>ScoreDetail__5468|IGFALS|0.000534659909805198__11179|SOD1|0.00160093311530149__ 0 0 0 0 0 190799 14739060 254290 18723 10261 ROS1 ROS ROS 10 0.0 Mitochondrial dysfunction i.e cell energy impairment apoptosis and overproduction of ROS is a final common pathogenic mechanism in aging and in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190800 14739060 254291 6981 22140 FAM20C RNS RNS 5 0.3 Nitric oxide (NO NO an RNS which can be produced by three isoforms of NO-synthase in 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 190801 14739060 254292 20996 11179 SOD1 ALS ALS 9 1.3 The research on the genetics of inherited forms notably ALS AD PD has improved our understanding of the pathobiology of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00160093311530149<>ScoreDetail__5468|IGFALS|0.000534659909805198__11179|SOD1|0.00160093311530149__ 0 0 0 0 0 190802 14739060 254293 6981 22140 FAM20C RNS RNS 2 0.3 ROS and RNS i.e oxidative stress are not the origin of neuronal death 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 190803 14739060 254293 18723 10261 ROS1 ROS ROS 0 0.1 ROS and RNS i.e oxidative stress are not the origin of 6 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 190804 14739060 254311 18723 10261 ROS1 ROS ROS 14 0.0 is responsible for most of the reactive oxygen species (ROS) ROS and notably the first produced superoxide anion ( in human 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190805 14739060 254312 18723 10261 ROS1 ROS ROS 14 0.0 1_amp_#x2013 2% of the O 2 consumed is converted to ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190806 14739060 254313 6981 22140 FAM20C RNS RNS 11 0.3 is nitric oxide (NO NO a reactive nitrogen species (RNS) RNS 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 190807 14739060 254314 14533 7872 NOS1 nNOS nNOS 36 1.9 account for NO production and include neuronal NO synthase (nNOS; nNOS type I inducible NO synthase (iNOS; iNOS typeII which is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190808 14739060 254314 14535 7873 NOS2A iNOS iNOS 42 1.9 NO synthase (nNOS; nNOS type I inducible NO synthase (iNOS; iNOS typeII which is produced in very large amounts by activated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190809 14739060 254314 14538 7876 NOS3 eNOS eNOS 59 1.9 by activated microglia (macrophages), macrophages and endothelial NO synthase (eNOS; eNOS type III In the CNS nNOS whose expression is regulated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190810 14739060 254314 14533 7872 NOS1 nNOS nNOS 65 1.9 endothelial NO synthase (eNOS; eNOS type III In the CNS nNOS whose expression is regulated by both physiological and pathophysiological stimuli 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190811 14739060 254315 6981 22140 FAM20C RNS RNS 15 0.3 peroxynitrite (ONOO ONOO _amp_#x2013 _amp_#x2013 which is the most reactive RNS 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 190812 14739060 254316 6981 22140 FAM20C RNS RNS 2 0.3 ROS and RNS are the cause of oxidative stress in nervous system 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 190813 14739060 254316 18723 10261 ROS1 ROS ROS 0 0.1 ROS and RNS are the cause of oxidative stress in nervous 6 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 190814 14739060 254317 14535 7873 NOS2A iNOS iNOS 15 1.9 in pathologic conditions especially NO coming from activated microglia (iNOS) iNOS or and from endothelial cells (eNOS) eNOS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190815 14739060 254317 14538 7876 NOS3 eNOS eNOS 21 1.9 activated microglia (iNOS) iNOS or and from endothelial cells (eNOS) eNOS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190816 14739060 254318 18723 10261 ROS1 ROS ROS 4 0.0 The main sources of ROS in inflammatory process are both damaged mitochondria and activated microglia 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190817 14739060 254319 6981 22140 FAM20C RNS RNS 15 0.3 as an imbalance between generation and elimination of ROS and RNS 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 190818 14739060 254319 18723 10261 ROS1 ROS ROS 13 0.1 is described as an imbalance between generation and elimination of ROS and RNS 6 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 190819 14739060 254321 12337 6871 MAPK1 MAP MAP 28 0.3 for neurons astrocytes and microglia such as mitogene-activated protein (MAP) MAP kinase cascade activation ion transport calcium mobilization and apoptosis program 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190820 14739060 254321 18723 10261 ROS1 ROS ROS 8 0.0 It is now recognized that redox regulation involving ROS is key to the modulation of critical cellular functions notably 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190821 14739060 254330 6981 22140 FAM20C RNS RNS 2 0.3 ROS and RNS are involved in both apoptosis and excitotoxicity 27 and 28 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 190822 14739060 254330 18723 10261 ROS1 ROS ROS 0 0.1 ROS and RNS are involved in both apoptosis and excitotoxicity 27 6 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 190823 14739060 254345 14533 7872 NOS1 nNOS nNOS 17 1.9 series of enzymes including protein kinase C proteases phosphatases phospholipases nNOS and xanthine oxidase 32 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190824 14739060 254346 6981 22140 FAM20C RNS RNS 10 0.3 The last three (phospholipase phospholipase A 2 produce ROS and RNS by triggering acide arachidonic cascade 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 190825 14739060 254346 18723 10261 ROS1 ROS ROS 8 0.1 The last three (phospholipase phospholipase A 2 produce ROS and RNS by triggering acide arachidonic cascade 6 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 190826 14739060 254361 6981 22140 FAM20C RNS RNS 13 0.3 result in overproduction of proteolytic enzymes lipid peroxidation ROS and RNS formation 33 and in triggering programmed cell death i.e apoptosis 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 190827 14739060 254361 18723 10261 ROS1 ROS ROS 11 0.1 intracellular responses result in overproduction of proteolytic enzymes lipid peroxidation ROS and RNS formation 33 and in triggering programmed cell death 6 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 190828 14739060 254366 6981 22140 FAM20C RNS RNS 32 0.3 as that triggered by excitotoxicity _amp_#x2022 elevated levels of ROS_amp_#x2013 RNS 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 190829 14739060 254366 1576 990 BCL2 Bcl2 Bcl2 14 0.0 the release of apoptogenic mitochondrial mediators _amp_#x2022 Pro-apoptotic members of Bcl2 family _amp_#x2022 elevated levels of intra-cellular calcium such as that 1 JUMiner_v2.2 1 1 bcl2; 0 0 0 0 0 0 0 0 190830 14739060 254368 5854 21528 DIABLO SMAC Smac 31 1.3 the mitochondria into cytoplasm trigger the caspase chain _amp_#x2022 Smac/Diablo Smac Diablo binds to inhibitors of activated caspases and causes further 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190831 14739060 254369 18723 10261 ROS1 ROS ROS 4 0.0 When the level of ROS exceeds the capacity of the mitochondria and cell to detoxify 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190832 14739060 254372 864 576 APAF1 APAF1 Apaf1 6 0.3 Cytochrome c and the cytosolic factor Apaf1 activate the caspases while apoptosis-initiating factor and caspase activated DNase 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190833 14739060 254378 20996 11179 SOD1 ALS ALS 46 1.3 neurons obtained by cyclooxygenase 2_amp_#xa0 in transgenic mouse model of ALS 15 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00160093311530149<>ScoreDetail__5468|IGFALS|0.000534659909805198__11179|SOD1|0.00160093311530149__ 0 0 0 0 0 190834 14739060 254380 20996 11179 SOD1 ALS ALS 36 1.3 heterozygote gene diseases for example familial amyotrophic lateral sclerosis (ALS), ALS familial Parkinson_amp_#x2019 s disease (PD), PD familial Alzheimer_amp_#x2019 s disease 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00160093311530149<>ScoreDetail__5468|IGFALS|0.000534659909805198__11179|SOD1|0.00160093311530149__ 0 0 0 0 0 190835 14739060 254383 20996 11179 SOD1 ALS ALS 0 1.3 ALS a neurodegenerative disease characterized by the degeneration of motor neurons 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00160093311530149<>ScoreDetail__5468|IGFALS|0.000534659909805198__11179|SOD1|0.00160093311530149__ 0 0 0 0 0 190836 14739060 254383 20996 11179 SOD1 SOD SOD 18 1.3 of motor neurons caused by a missense mutation of CuZn SOD (SOD1) SOD1 is an illustration of how these mechanisms can 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190837 14739060 254383 20996 11179 SOD1 SOD1 SOD1 19 2.1 neurons caused by a missense mutation of CuZn SOD (SOD1) SOD1 is an illustration of how these mechanisms can lead to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190838 14739060 254384 20996 11179 SOD1 SOD1 SOD1 7 2.1 In transgenic mice expressing the human mutant SOD1 gene syndrome develops with many features of ALS including specific 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190839 14739060 254384 20996 11179 SOD1 ALS ALS 15 1.3 human mutant SOD1 gene syndrome develops with many features of ALS including specific cell death of motor neurons progressive weakness and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00160093311530149<>ScoreDetail__5468|IGFALS|0.000534659909805198__11179|SOD1|0.00160093311530149__ 0 0 0 0 0 190840 14739060 254385 20996 11179 SOD1 SOD1 SOD1 21 2.1 to compare the evolution for motor neurons degeneration in mutant SOD1 transgenic mouse with non-transgenic mouse and normal human SOD1 transgenic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190841 14739060 254385 20996 11179 SOD1 SOD1 SOD1 30 2.1 mutant SOD1 transgenic mouse with non-transgenic mouse and normal human SOD1 transgenic mouse 46 50 47 48 and 49 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190842 14739060 254387 20996 11179 SOD1 SOD1 SOD1 4 2.1 The toxicity of mutant SOD1 seems to be due to a gain of function of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190843 14739060 254389 20996 11179 SOD1 SOD1 SOD1 5 2.1 It is also conceivable mutant SOD1 denatures more quickly in vivo than the normal form and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190844 14739060 254390 20996 11179 SOD1 SOD1 SOD1 9 2.1 Oxidative stress may be involved in misfolding of mutant SOD1 to form abnormal protein aggregates found as early as 1_amp_#xa0 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190845 14739060 254391 20996 11179 SOD1 SOD1 SOD1 11 2.1 disorganization of intermediate filaments could be due also to mutant SOD1 induced toxicity as their proteins are vulnerable to oxidative damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190846 14739060 254392 20996 11179 SOD1 ALS ALS 13 1.3 peripherin is found in neuronal inclusions in patients with sporadic ALS and in transgenic mice with SOD1 mutations 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00160093311530149<>ScoreDetail__5468|IGFALS|0.000534659909805198__11179|SOD1|0.00160093311530149__ 0 0 0 0 0 190847 14739060 254392 20996 11179 SOD1 SOD1 SOD1 19 2.1 in patients with sporadic ALS and in transgenic mice with SOD1 mutations 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190848 14739060 254395 20996 11179 SOD1 SOD SOD 22 1.3 of ubiquinated cytoplasmic inclusion bodies some of which contain aggregated SOD 46 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190849 14739060 254397 20996 11179 SOD1 SOD1 SOD1 4 2.1 The studies on mutant SOD1 transgenic mice 46 and 63 revealed an up-regulation of gene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190850 14739060 254398 20996 11179 SOD1 ALS ALS 12 1.3 of other neurodegenerative diseases with familial and sporadic forms like ALS display numerous similitudes 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00160093311530149<>ScoreDetail__5468|IGFALS|0.000534659909805198__11179|SOD1|0.00160093311530149__ 0 0 0 0 0 190851 14739060 254401 926 620 APP amyloid amyloid 11 1.0 forms missense mutation have been identified for gene encoding _amp_#x3b2 -amyloid precursor protein as well as presenilin 1 (PSEN1) PSEN1 and 11 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 190852 14739060 254401 17461 9508 PSEN1 PSEN1 PSEN1 19 0.9 _amp_#x3b2 -amyloid precursor protein as well as presenilin 1 (PSEN1) PSEN1 and presenilin 2 (PSEN2) PSEN2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190853 14739060 254401 17462 9509 PSEN2 PSEN2 PSEN2 23 0.9 well as presenilin 1 (PSEN1) PSEN1 and presenilin 2 (PSEN2) PSEN2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190854 14739060 254402 12369 6893 MAPT tau tau 30 1.9 gene for _amp_#x3b1 2 -macrogobulin and perhaps the gene for tau protein and other factors including environmental contributions and occurrence by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190855 14739060 254402 912 613 APOE APOE APOE 18 0.0 a complex interaction among multiple predisposing genes such as variant APOE the gene for _amp_#x3b1 2 -macrogobulin and perhaps the gene 1 JUMiner_v2.2 1 1 apoe; 0 0 0 0 0 0 0 0 190856 14739060 254403 12369 6893 MAPT tau tau 14 1.9 tangles and senile plaques are both aggregation of proteins microtubular tau protein for the former accumulation of several aggregated proteins (_amp_#x3b2;-amyloid, 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190857 14739060 254403 926 620 APP amyloid amyloid 24 1.0 for the former accumulation of several aggregated proteins (_amp_#x3b2;-amyloid, _amp_#x3b2 -amyloid especially its toxic form A_amp_#x3b2 42 APOE 43 hyperphosphorylated tau 11 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 190858 14739060 254403 12369 6893 MAPT tau tau 37 1.9 -amyloid especially its toxic form A_amp_#x3b2 42 APOE 43 hyperphosphorylated tau ubiquitin presenilin 1_amp_#xa0 and 2 with an inflammatory reaction around 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190859 14739060 254403 926 620 APP amyloid amyloid 50 1.0 2 with an inflammatory reaction around the deposit of _amp_#x3b2 -amyloid for the latter 38 11 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 190860 14739060 254403 912 613 APOE APOE APOE 32 0.0 proteins (_amp_#x3b2;-amyloid, _amp_#x3b2 -amyloid especially its toxic form A_amp_#x3b2 42 APOE 43 hyperphosphorylated tau ubiquitin presenilin 1_amp_#xa0 and 2 with an 1 JUMiner_v2.2 1 1 apoe; 0 0 0 0 0 0 0 0 190861 14739060 254417 4772 26515 COQ10A Q10 Q10 11 0.9 a controlled trial in early PD oral treatment with coenzyme Q10 has slowed the progressive deterioration 56 and in aged mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190862 14739060 254434 166 118 ACO2 aconitase aconitase 9 1.3 may prevent the formation of Fe/S Fe S in mitochondrial aconitase and in complex I 20 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190863 14739060 254448 12580 7008 MELAS MELAS MELAS 18 3.4 as mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes syndrome (MELAS) MELAS 1 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 190864 14739060 254455 4772 26515 COQ10A Q10 Q10 12 0.9 affected sisters clinical and biochemical abnormalities improved remarkably with coenzyme Q10 supplementation 59 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190865 14739060 254464 6981 22140 FAM20C RNS RNS 15 0.3 of aging i.e progressive damage to mtDNA by ROS/RNS ROS RNS 42 and induced changes in redox state of the cell 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 190866 14739060 254464 18723 10261 ROS1 ROS ROS 15 0.3 theory of aging i.e progressive damage to mtDNA by ROS/RNS ROS RNS 42 and induced changes in redox state of the 4 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 190867 14739060 254468 18723 10261 ROS1 ROS ROS 44 0.0 reflect either decreased mitochondrial biogenesis or turnover secondary to cumulative ROS inflicted mitochondrial damage 11 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190868 14739060 254479 22551 11892 TNF TNF TNF 27 0.3 amplification resulting in production of neurotoxins such as cytokine (TNF, TNF IL1 eicosanoides ROS and RNS 9 and 13 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190869 14739060 254479 6981 22140 FAM20C RNS RNS 32 0.3 neurotoxins such as cytokine (TNF, TNF IL1 eicosanoides ROS and RNS 9 and 13 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 190870 14739060 254479 10436 5991 IL1A IL1 IL1 28 0.2 resulting in production of neurotoxins such as cytokine (TNF, TNF IL1 eicosanoides ROS and RNS 9 and 13 5 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190871 14739060 254479 18723 10261 ROS1 ROS ROS 30 0.1 production of neurotoxins such as cytokine (TNF, TNF IL1 eicosanoides ROS and RNS 9 and 13 6 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 190872 14739060 254483 20997 11180 SOD2 MnSOD MnSOD 7 1.8 Tat protein decreases GSH and down regulate MnSOD gene expression leading to oxidative stress 16 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 190873 14739060 254490 20996 11179 SOD1 ALS ALS 3 1.3 Animal models for ALS 17 and 19 AD PD 5 and aging brain 35 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00160093311530149<>ScoreDetail__5468|IGFALS|0.000534659909805198__11179|SOD1|0.00160093311530149__ 0 0 0 0 0 182318 15009657 243177 18723 10261 ROS1 ROS ROS 18 0.0 oxidative stress (OS), OS resulting in reactive oxygen species (ROS) ROS generation from H2O2 and inflammatory processes trigger a cascade of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 182319 15009657 243177 20996 11179 SOD1 ALS ALS 51 0.0 (AD) AD and Huntington's diseases and amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000500389948233718<>ScoreDetail__5468|IGFALS|8.93788172203188e-05__11179|SOD1|0.000500389948233718__ 0 0 0 0 0 182320 15009657 243178 18723 10261 ROS1 ROS ROS 14 0.0 aimed at neutralization of OS-induced neurotoxicity support the application of ROS scavengers transition metals (e.g e.g iron and copper chelators and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183135 15031734 244210 20996 11179 SOD1 ALS ALS 14 1.9 AD Parkinson's disease (PD) PD and amyotrophic lateral sclerosis (ALS), ALS are defined by the progressive loss of specific neuronal cell 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183136 15031734 244212 18723 10261 ROS1 ROS ROS 12 3.3 the result of unregulated production of reactive oxygen species (ROS), ROS such as hydrogen peroxide nitric oxide superoxide and the highly 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183137 15031734 244217 6554 3309 ELA2 HNE HNE 12 0.0 to the formation of breakdown products including 4-hydroxy-2 3-nonenal (HNE), HNE acrolein malondialdehyde and F 2 -isoprostanes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183138 15031734 244218 20996 11179 SOD1 ALS ALS 27 1.9 has been observed in the cerebrospinal fluid (CSF) CSF of ALS patients 4 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183139 15031734 244218 6554 3309 ELA2 HNE HNE 1 0.0 Elevated HNE levels have been observed in AD 1 2 and PD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183140 15031734 244218 6554 3309 ELA2 HNE HNE 17 0.0 AD 1 2 and PD 3 brain tissue whereas increased HNE has been observed in the cerebrospinal fluid (CSF) CSF of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183141 15031734 244218 11629 6493 LAMC2 CSF CSF 25 0.1 increased HNE has been observed in the cerebrospinal fluid (CSF) CSF of ALS patients 4 6 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 183142 15031734 244220 20996 11179 SOD1 ALS ALS 18 1.9 whereas increased TBARs have been observed in the plasma of ALS patients 6 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183143 15031734 244221 211 132 ACTB beta-actin beta-actin 24 0.3 significant protein carbonylation (for for example of creatine kinase and beta-actin 2 and nitration is observed in AD brains whereas increased 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183144 15031734 244223 20996 11179 SOD1 SOD SOD 15 2.2 the activity of the antioxidant proteins catalase superoxide dismutase ( SOD glutathione peroxidase and glutathione reductase are increased in the HIPPOCAMPUS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183145 15031734 244224 18723 10261 ROS1 ROS ROS 2 3.3 How do ROS kill cells 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183146 15031734 244225 18723 10261 ROS1 ROS ROS 4 3.3 As their name suggests ROS are very reactive and will react with a multitude of 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183147 15031734 244228 6554 3309 ELA2 HNE HNE 6 0.0 The oxidatively modified lipids acrolein and HNE induce toxicity by crosslinking to cystine lysine and histidine residues 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183148 15031734 244229 20017 10940 SLC1A2 GLT-1 GLT-1 35 1.0 inhibition of the neuronal glucose transporter type-3 the glutamate transporter GLT-1 (Ref Ref 13 as well as the Na K ATPases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183149 15031734 244229 6554 3309 ELA2 HNE HNE 14 0.0 uptake of glutamate and glucose from cell culture 12 whereas HNE modifies proteins resulting in a multitude of effects including inhibition 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183150 15031734 244230 10824 6204 JUN c-Jun c-Jun 2 1.3 HNE activates c-Jun aminoterminal kinases and mitogen-activated protein kinase-1 (also also known as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183151 15031734 244230 12359 6876 MAPK14 p38 p38 12 1.2 aminoterminal kinases and mitogen-activated protein kinase-1 (also also known as p38 thereby stimulating an apoptotic cascade 15 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.000586105713037067<>ScoreDetail__1189|AHSA1|0.000276525398256688__6878|MAPK4|0.000484348834213577__6871|MAPK1|0.000586105713037067__6876|MAPK14|0.000409638528257453__ 0 0 0 0 0 183152 15031734 244230 6554 3309 ELA2 HNE HNE 0 0.1 HNE activates c-Jun aminoterminal kinases and mitogen-activated protein kinase-1 (also also 6 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 183153 15031734 244231 18723 10261 ROS1 ROS ROS 16 3.3 of enzymes (for for example glutamine synthase superoxide dismutase whereas ROS interactions with DNA lead to mutations 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183154 15031734 244232 18723 10261 ROS1 ROS ROS 4 3.3 The excessive generation of ROS leads to dysregulation of intracellular calcium signalling and such dysregulation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183155 15031734 244233 18723 10261 ROS1 ROS ROS-induced 11 0.0 of the downstream events that occurs in response to an ROS-induced calcium influx is an excitotoxic response 19 20 that is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183156 15031734 244234 20996 11179 SOD1 ALS ALS 22 1.9 and stroke as well as the neurodegenerative diseases AD PD ALS and Huntington's disease (reviewed reviewed in Ref 21 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183157 15031734 244235 18723 10261 ROS1 ROS ROS 2 3.3 How are ROS generated 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183158 15031734 244236 18723 10261 ROS1 ROS ROS 3 3.3 The generation of ROS requires the activation of molecular oxygen 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183159 15031734 244239 18723 10261 ROS1 ROS ROS 24 3.3 O 2 and metal ions to activate molecular oxygen as ROS the subsequent free radicals are an intrinsic part of normal 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183160 15031734 244240 18723 10261 ROS1 ROS ROS 1 3.3 As ROS are also toxic cells have developed highly elaborate means of 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183161 15031734 244240 18723 10261 ROS1 ROS ROS 21 3.3 of regulating both metal ion interactions and the generation of ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183162 15031734 244242 18723 10261 ROS1 ROS ROS 0 3.3 ROS are produced by a number of different pathways including direct 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183163 15031734 244246 18723 10261 ROS1 ROS ROS 11 3.3 example of this is the interplay between calcium signalling and ROS generation although increases in intracellular calcium have been reported to 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183164 15031734 244246 18723 10261 ROS1 ROS ROS 26 3.3 intracellular calcium have been reported to induce the production of ROS 22 at subtoxic levels ROS have been shown to be 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183165 15031734 244246 18723 10261 ROS1 ROS ROS 32 3.3 to induce the production of ROS 22 at subtoxic levels ROS have been shown to be important cell signallers and will 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183166 15031734 244247 18723 10261 ROS1 ROS ROS 21 3.3 disruption of calcium homeostasis is a cause or consequence of ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183167 15031734 244248 18723 10261 ROS1 ROS ROS 11 3.3 a general principle the chemical origin of the majority of ROS is the reaction of molecular oxygen with the redox-active metals 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183168 15031734 244250 18723 10261 ROS1 ROS ROS 11 3.3 unregulated redox-active metals will inappropriately react with oxygen to generate ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183169 15031734 244251 20996 11179 SOD1 SOD1 SOD1 19 1.9 neurodegenerative disorders (A A beta in AD alpha-synuclein in PD SOD1 in ALS frataxin in Friedreich's ataxia ( Box 1 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183170 15031734 244251 20996 11179 SOD1 ALS ALS 21 1.9 (A A beta in AD alpha-synuclein in PD SOD1 in ALS frataxin in Friedreich's ataxia ( Box 1 and alpha-B-crystallin in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183171 15031734 244254 18723 10261 ROS1 ROS ROS 21 3.3 biometals to foster the release of inappropriate redox activity and ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183172 15031734 244260 926 620 APP amyloid amyloid 25 1.0 peptide (A A beta that is cleaved from the membrane-bound amyloid precursor protein (APP) APP 33 34 35 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 183173 15031734 244260 926 620 APP APP APP 28 0.3 that is cleaved from the membrane-bound amyloid precursor protein (APP) APP 33 34 35 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183174 15031734 244261 926 620 APP APP APP 4 0.3 Although the function of APP is unknown recent evidence suggests it functions in maintaining copper 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183175 15031734 244263 926 620 APP amyloid amyloid 10 1.0 Recent results have highlighted the importance of Zn 2 in amyloid plaque formation for example age- and female-sex-related plaque formation in 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 183176 15031734 244267 926 620 APP amyloid amyloid 10 1.0 neurotransmission high concentrations of Zn (300 300 beta precipitation into amyloid commences in the synapse 36 41 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 183177 15031734 244272 11629 6493 LAMC2 CSF CSF 17 0.0 includes a 2.2-times increase in the concentration of Cu in CSF 45 and an accompanying increase of plasma Cu in AD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183178 15031734 244274 926 620 APP amyloid amyloid 8 1.0 Notably the Fe that is found within the amyloid deposits of human brain and in amyloid-bearing APP transgenic mice 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 183179 15031734 244274 926 620 APP APP APP 16 0.3 within the amyloid deposits of human brain and in amyloid-bearing APP transgenic mice is redox-active 38 48 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183180 15031734 244286 20996 11179 SOD1 SOD1 SOD1 46 1.9 with the resulting coordination sphere reminiscent of that observed in SOD1 ( Fig 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183181 15031734 244287 18723 10261 ROS1 ROS ROS 46 3.3 them is redox active 51 and might be important in ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183182 15031734 244294 926 620 APP amyloid amyloid 13 1.0 how zinc originating from the synapse becomes so enriched in amyloid in AD 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 183183 15031734 244297 926 620 APP amyloid amyloid 5 1.0 The Zn 2 in the amyloid mass partially quenches H 2 O 2 production which explains 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 183184 15031734 244297 926 620 APP amyloid amyloid 18 1.0 quenches H 2 O 2 production which explains why plaque amyloid burden correlates poorly with clinical dementia 54 whereas soluble A 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 183185 15031734 244315 18723 10261 ROS1 ROS ROS 29 3.3 accumulation of dopamine in the cytoplasm and subsequent generation of ROS through its interaction with iron a process that increases with 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183186 15031734 244323 20996 11179 SOD1 ALS ALS 0 1.9 ALS is distinguished by the loss of the lower motor neurons 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183187 15031734 244324 20996 11179 SOD1 ALS ALS 5 1.9 Like the other neurodegenerative diseases ALS is characterized by the deposition of a misfolded protein in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183188 15031734 244324 20996 11179 SOD1 SOD SOD 22 2.2 protein in neural tissue in this instance copper/zinc copper zinc SOD 89 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183189 15031734 244325 20996 11179 SOD1 SOD SOD 7 2.2 There are more than 100 mutations of SOD associated with the familial forms of the disease 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183190 15031734 244326 20996 11179 SOD1 SOD SOD 19 2.2 these mutations lead to a toxic gain of function by SOD 90 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183191 15031734 244327 20996 11179 SOD1 SOD SOD 28 2.2 that the toxicity is due to misfolded aggregated forms of SOD whereas the other proposes that SOD becomes a pro-oxidant protein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183192 15031734 244327 20996 11179 SOD1 SOD SOD 34 2.2 misfolded aggregated forms of SOD whereas the other proposes that SOD becomes a pro-oxidant protein generating ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183193 15031734 244327 18723 10261 ROS1 ROS ROS 40 3.3 the other proposes that SOD becomes a pro-oxidant protein generating ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183194 15031734 244329 20996 11179 SOD1 SOD SOD 2 2.2 Mutations of SOD a cupro-enzyme that detoxifies the ROS superoxide can convert the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183195 15031734 244329 18723 10261 ROS1 ROS ROS 8 3.3 Mutations of SOD a cupro-enzyme that detoxifies the ROS superoxide can convert the protein from an anti-oxidant to a 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183196 15031734 244330 20996 11179 SOD1 ALS ALS 12 1.9 inappropriate metal-mediated redox chemistry is central to the progression of ALS includes the observation that copper chelators inhibit the course of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183197 15031734 244331 20996 11179 SOD1 SOD SOD 10 2.2 These initial observations suggested that the toxicity associated with mutant SOD is the result of a corruption of the active site 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183198 15031734 244332 20996 11179 SOD1 SOD SOD 9 2.2 However if the copper at the active site of SOD is the culprit behind the toxicity then knocking out the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183199 15031734 244332 20996 11179 SOD1 SOD SOD 20 2.2 is the culprit behind the toxicity then knocking out the SOD copper chaperone (CCS), CCS which loads copper into the active 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183200 15031734 244332 3838 1613 CCS CCS CCS 23 0.9 the toxicity then knocking out the SOD copper chaperone (CCS), CCS which loads copper into the active site should abolish the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183201 15031734 244333 3838 1613 CCS CCS CCS 7 0.9 To test this hypothesis Subramaniam 97 crossed CCS knockout mice with an SOD mutant ALS mouse model the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183202 15031734 244333 20996 11179 SOD1 SOD SOD 12 2.2 this hypothesis Subramaniam 97 crossed CCS knockout mice with an SOD mutant ALS mouse model the phenotype of this cross showed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183203 15031734 244333 20996 11179 SOD1 ALS ALS 14 1.9 Subramaniam 97 crossed CCS knockout mice with an SOD mutant ALS mouse model the phenotype of this cross showed reduced SOD 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183204 15031734 244333 20996 11179 SOD1 SOD SOD 24 2.2 ALS mouse model the phenotype of this cross showed reduced SOD activity which is consistent with a low copper load in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183205 15031734 244333 20996 11179 SOD1 ALS ALS 44 1.9 in the active site but the mice still developed the ALS phenotype 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183206 15031734 244334 20996 11179 SOD1 ALS ALS 4 1.9 These results indicate that ALS is not due to a corruption of the active site 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183207 15031734 244335 20996 11179 SOD1 SOD SOD 16 2.2 the possibility that other redox-active lower-affinity metal-binding sites exist on SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183208 15031734 244336 20996 11179 SOD1 SOD SOD 26 2.2 98 and in vitro studies 99 with an H46R mutant SOD linked to familial ALS and which has no SOD activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183209 15031734 244336 20996 11179 SOD1 ALS ALS 30 1.9 studies 99 with an H46R mutant SOD linked to familial ALS and which has no SOD activity have shown that a 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183210 15031734 244336 20996 11179 SOD1 SOD SOD 35 2.2 mutant SOD linked to familial ALS and which has no SOD activity have shown that a surface-exposed cysteine residue in SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183211 15031734 244336 20996 11179 SOD1 SOD SOD 45 2.2 SOD activity have shown that a surface-exposed cysteine residue in SOD is also capable of coordinating copper and is redox active 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183212 15031734 244337 18723 10261 ROS1 ROS ROS 42 3.3 aberrant redox chemistry ( Fig 4 and the generation of ROS and subsequent toxicity remains untested 100 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183213 15031734 244340 18723 10261 ROS1 ROS ROS 7 3.3 Antioxidants are molecules that react preferentially with ROS to inactivate them and have excited great interest because of 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183214 15031734 244346 18723 10261 ROS1 ROS ROS 3 3.3 One consequence of ROS generation is the initiation of excitotoxicity this is modulated through 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183215 15031734 244351 20996 11179 SOD1 ALS ALS 9 1.9 Riluzole is the only drug presently used to treat ALS with any proven efficacy _amp_#8212 the effects of Riluzole are 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183216 15031734 244357 18723 10261 ROS1 ROS ROS 12 3.3 effects attained with antioxidants and therapies targeting downstream effects of ROS generation such as those targeting excitotoxicity are not too surprising 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183217 15031734 244358 18723 10261 ROS1 ROS ROS 18 3.3 to be more effective if it targets the origin of ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183218 15031734 244385 20996 11179 SOD1 ALS ALS 19 1.9 with key proteins in the neurodegenerative diseases AD PD and ALS and the subsequent induction of oxidative stress leading to neurodegeneration 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000956632653061224<>ScoreDetail__5468|IGFALS|0.000456204379562044__11179|SOD1|0.000956632653061224__ 0 0 0 0 0 183219 15031734 244387 18723 10261 ROS1 ROS ROS 2 3.3 Antioxidants targeting ROS and MPACs targeting the upstream metal-protein interactions that generate ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183220 15031734 244387 18723 10261 ROS1 ROS ROS 12 3.3 ROS and MPACs targeting the upstream metal-protein interactions that generate ROS have shown promise in preliminary clinical studies 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183221 15031734 244392 211 132 ACTB beta-actin beta-actin 0 0.3 beta-actin catalase creatine kinase frataxin glucose transporter type-3 glutathione peroxidase glutathione 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183222 15031734 244392 20996 11179 SOD1 SOD SOD 15 2.2 glucose transporter type-3 glutathione peroxidase glutathione reductase mitogen-activated protein kinase-1 SOD alpha-synuclein xanthine dehydrogenase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183223 15031734 244397 18723 10261 ROS1 ROS ROS 3 3.3 Figure 1 ROS generation by abnormal reaction of O 2 with protein-bound Fe 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183224 15031734 244400 18723 10261 ROS1 ROS ROS 15 3.3 at a loading site _amp_#8212 will increase the likelihood that ROS are generated inappropriately as illustrated leading to the oxidative stress 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183225 15031734 244401 18723 10261 ROS1 ROS ROS 4 3.3 A beta amyloid-beta ROS reactive oxygen species SOD superoxide dismutase 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183226 15031734 244401 20996 11179 SOD1 SOD SOD 8 2.2 A beta amyloid-beta ROS reactive oxygen species SOD superoxide dismutase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183227 15031734 244406 18723 10261 ROS1 ROS ROS 13 3.3 pivotal in signal transduction it can induce further production of ROS and elicit an excitotoxicity response 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183228 15031734 244409 18723 10261 ROS1 ROS ROS 4 3.3 Antioxidants deactivate the generated ROS and MPACs seek to inhibit metal interactions with A beta 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183229 15031734 244409 18723 10261 ROS1 ROS ROS 21 3.3 interactions with A beta and prevent the subsequent formation of ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183230 15031734 244410 18723 10261 ROS1 ROS ROS 4 3.3 MPACs metal-protein attenuating compound ROS reactive oxygen species 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183231 15031734 244413 18723 10261 ROS1 ROS ROS 44 3.3 formation of neuromelanin (NM) NM and reactive oxygen species (ROS) ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183232 15031734 244414 18723 10261 ROS1 ROS ROS 7 3.3 Neuromelanin will also coordinate Fe and produce ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 183233 15031734 244417 13412 7214 MPHOSPH6 MPP MPP 0 0.0 MPP 1-methyl-4-phenyl pyridine 1 JUMiner_v2.2 1 0 0 2 7225 TotalCon:2<>7214|MPHOSPH6|10200|Complete__7225|MPZ|4359|Complete__<>AvaiableGeneRif=2<>BEST:7225|MPZ|0.000439956797035246<>ScoreDetail__7214|MPHOSPH6|0.000306582506762849__7225|MPZ|0.000439956797035246__ 0 0 0 0 0 183234 15031734 244420 20996 11179 SOD1 SOD SOD 6 2.2 The normal function of superoxide dismutase (SOD) SOD is to convert toxic superoxide radicals into H 2 O 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183235 15031734 244422 20996 11179 SOD1 SOD SOD 10 2.2 With age-dependent increases in copper levels low-affinity copper sites on SOD such as Cys111 are occupied these sites are redox active 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 183236 15031734 244422 18723 10261 ROS1 ROS ROS 33 3.3 to aberrant redox chemistry and subsequent reactive oxygen species (ROS) ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 177199 15105254 236594 926 620 APP amyloid amyloid 5 1.3 In Alzheimer's disease (AD), AD the amyloid beta-peptide generates reactive oxygen species and induces MAOS resulting in 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 177200 15105254 236597 20996 11179 SOD1 ALS ALS 7 0.9 Increased MAOS occurs in amyotrophic lateral sclerosis (ALS) ALS as the result of genetic abnormalities (e.g., e.g. Cu/Zn-superoxide Cu 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000774752820126889<>ScoreDetail__5468|IGFALS|0.000151541939231682__11179|SOD1|0.000774752820126889__ 0 0 0 0 0 177201 15105254 236599 20996 11179 SOD1 ALS ALS 30 0.9 functional outcome in animal models of AD PD HD and ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000774752820126889<>ScoreDetail__5468|IGFALS|0.000151541939231682__11179|SOD1|0.000774752820126889__ 0 0 0 0 0 169741 15208263 227119 20996 11179 SOD1 SOD1 SOD1 13 1.2 for the ubiquitous anti-oxidant enzyme Cu Zn superoxide dismutase (SOD1) SOD1 are associated with familial amyotrophic lateral sclerosis (fALS), fALS a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 169742 15208263 227120 20996 11179 SOD1 SOD1 SOD1 4 1.2 Expression of a mutant SOD1 typical of fALS patients restricted to either motor neurons or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 169743 15208263 227127 20996 11179 SOD1 SOD1 SOD1-linked 9 1.2 This cross-talk may be crucial for the pathogenesis of SOD1-linked fALS but also for the more common sporadic form of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 172853 15266948 231013 18723 10261 ROS1 ROS ROS 21 0.0 greater risk of damage mediated by reactive oxygen species (ROS) ROS resulting in molecular and cellular dysfunction 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 172996 15289674 231348 20996 11179 SOD1 ALS ALS-associated 16 2.7 neuronal death in an in vitro co-culture model of familial ALS-associated Cu/Zn Cu Zn superoxide dismutase 11 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00289837185937401<>ScoreDetail__5468|IGFALS|0.000274408649360628__11179|SOD1|0.00289837185937401__ 0 0 0 0 0 172997 15289674 231349 20996 11179 SOD1 SOD1 SOD1 4 2.7 Mutations in Cu/Zn-superoxide Cu Zn-superoxide dismutase (SOD1) SOD1 gene have been identified in familial amyotrophic lateral sclerosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 172998 15289674 231351 20996 11179 SOD1 SOD1 SOD1 18 2.7 hybrid cells (VSC4.1) VSC4.1 constitutively expressing a mutant (G93A) G93A SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 172999 15289674 231354 20996 11179 SOD1 SOD1 SOD1 12 2.7 vitro disease model confirmed the extracellular toxicity of the mutant SOD1 cells on the adjacent neurons by generating oxidative stress 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 175551 15333927 234326 20996 11179 SOD1 SOD SOD 4 1.4 Cu Zn superoxide dismutase (Cu,Zn Cu Zn SOD is an essential enzyme for protecting cells from the toxic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 175552 15333927 234327 20996 11179 SOD1 SOD SOD 5 1.4 In humans two distinct Cu Zn SOD genes are located on chromosomes 4 and 21 and mutations 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 175553 15333927 234328 20996 11179 SOD1 SOD SODs 16 0.9 chronically debilitating disease schistosomiasis also produce two distinct Cu Zn SODs in this case one cytosolic and one bearing a signal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 166644 15480846 223891 18723 10261 ROS1 ROS ROS 15 0.0 initiate oxidative stress via generation of reactive oxygen species (ROS), ROS such as hydroxyl radical 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 166645 15480846 223893 12288 6834 MAOB MAOB MAO-B 16 0.9 MAO A and B have not been determined previously since MAO-B inhibitors have been shown to be neuroprotective in cellular and 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 166646 15480846 223894 12287 6833 MAOA MAOA MAO-A 18 0.9 U74600F showed a preference for inhibition of rat brain mitochondrial MAO-A over MAO-B 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 166647 15480846 223894 12288 6834 MAOB MAOB MAO-B 20 0.9 a preference for inhibition of rat brain mitochondrial MAO-A over MAO-B 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 166648 15480846 223895 12287 6833 MAOA MAOA MAO-A 25 0.9 U74500A and U74006F showing a greater selectivity and potency for MAO-A 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 166649 15480846 223897 12287 6833 MAOA MAOA MAO-A 3 0.9 The inhibitions of MAO-A and B by 21-amino steroids (Lazaroids) Lazaroids were time dependent 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 166650 15480846 223899 12287 6833 MAOA MAOA MAO-A 8 0.9 Both Fe 2 and Fe 3 reverse the MAO-A and B inhibition induced by the latter chelators but not 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 166651 15480846 223904 12287 6833 MAOA MAOA MAO-A 5 0.9 Keywords Iron chelators Lazaroids iron MAO-A and MAO-B inhibition reactive oxygen species dopamine neuron degeneration Parkinson 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 166652 15480846 223904 12288 6834 MAOB MAOB MAO-B 7 0.9 Keywords Iron chelators Lazaroids iron MAO-A and MAO-B inhibition reactive oxygen species dopamine neuron degeneration Parkinson s disease 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 166653 15480846 223905 16315 30012 PDF PDF PDF 2 0.3 Contribution in PDF 1 JUMiner_v2.2 1 2 UserEdit 0 2 30012 TotalCon:3<>30012|PDF|64146|Complete__30142|GDF15|9518|Complete__8866|PFDN1|5201|Complete__<>AvaiableGeneRif=3<>BEST:30012|PDF|0.000922849760059062<>ScoreDetail__8866|PFDN1|0.000344530577088717__30142|GDF15|0.000259680304691558__30012|PDF|0.000922849760059062__ 1 1 0 0 0 160367 15535033 214700 20996 11179 SOD1 ALS ALS 12 0.0 proteins in the spinal cord in amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124230571941523<>ScoreDetail__5468|IGFALS|0.000638686131386861__11179|SOD1|0.00124230571941523__ 0 0 0 0 0 160368 15535033 214701 20996 11179 SOD1 ALS ALS 3 0.0 Amyotrophic lateral sclerosis (ALS) ALS is a neurodegenerative disease which has been linked to the 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124230571941523<>ScoreDetail__5468|IGFALS|0.000638686131386861__11179|SOD1|0.00124230571941523__ 0 0 0 0 0 160369 15535033 214702 20996 11179 SOD1 ALS ALS 17 0.0 suggested to be a contributory factor to neuronal death in ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124230571941523<>ScoreDetail__5468|IGFALS|0.000638686131386861__11179|SOD1|0.00124230571941523__ 0 0 0 0 0 160370 15535033 214704 20996 11179 SOD1 ALS ALS 9 0.0 The material consisted of spinal cords of 8 sporadic ALS cases and 5 controls 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124230571941523<>ScoreDetail__5468|IGFALS|0.000638686131386861__11179|SOD1|0.00124230571941523__ 0 0 0 0 0 160371 15535033 214706 19573 10691 SDS SDS SDS-polyacrylamide 5 0.0 Afterwards proteins were separated by SDS-polyacrylamide gel electrophoresis and the protein bound DNPH moieties were detected 11 JUMiner_v2.2 1 0 0 2 10691 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:10691|SDS|0.00116959064327485<>ScoreDetail__10691|SDS|0.00116959064327485__19440|SBDS|0.000411827691293963__ 0 0 0 0 0 160372 15535033 214708 20996 11179 SOD1 ALS ALS 6 0.0 The protein carbonyl content of the ALS spinal cords significantly increased in all examined cases 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124230571941523<>ScoreDetail__5468|IGFALS|0.000638686131386861__11179|SOD1|0.00124230571941523__ 0 0 0 0 0 160373 15535033 214709 20996 11179 SOD1 ALS ALS 2 0.0 In most ALS patients proteins with 125 kDa 70 kDa and 36kDa were 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124230571941523<>ScoreDetail__5468|IGFALS|0.000638686131386861__11179|SOD1|0.00124230571941523__ 0 0 0 0 0 160374 15535033 214711 20996 11179 SOD1 ALS ALS 4 0.0 The morphological examination of ALS spinal cords indicated a pronounced anti-DNPH immune reaction in neurones 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124230571941523<>ScoreDetail__5468|IGFALS|0.000638686131386861__11179|SOD1|0.00124230571941523__ 0 0 0 0 0 160375 15535033 214714 20996 11179 SOD1 ALS ALS 14 0.0 successfully examined the neurochemical features accompanying motor neuron injury in ALS and the results may help to develop a rationale anti-oxidative 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124230571941523<>ScoreDetail__5468|IGFALS|0.000638686131386861__11179|SOD1|0.00124230571941523__ 0 0 0 0 0 151455 15812313 199883 20996 11179 SOD1 SOD1 SOD1 6 3.2 Mutations in the copper_amp_#47 zinc superoxide dismutase (SOD1) SOD1 gene are known to be responsible for familial amyotrophic lateral 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151456 15812313 199884 20996 11179 SOD1 SOD1 SOD1 7 3.2 Alteration of metal binding properties of mutant SOD1 has been proposed to play a role in the pathogenesis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151457 15812313 199885 20996 11179 SOD1 SOD1 SOD1 16 3.2 excess extracellular copper on motor neuronal cells expressing human mutant SOD1 (G93A), G93A and evaluated the neuroprotective effects of energy metabolism 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151458 15812313 199886 20996 11179 SOD1 SOD1 SOD1 7 3.2 Motoneuron-neuroblastoma hybrid (VSC VSC 4.1 cells expressing mutant SOD1 when treated with copper chloride showed reduced viability and increased 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151459 15812313 199888 20996 11179 SOD1 SOD1 SOD1 21 3.2 and production of reactive oxygen species in cells expressing mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151460 15812313 199890 20996 11179 SOD1 ALS ALS 3 2.2 Amyotrophic lateral sclerosis (ALS) ALS is an adult-onset neurodegenerative disease that is characterized by a 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00175123126780039<>ScoreDetail__5468|IGFALS|0.000428007912362488__11179|SOD1|0.00175123126780039__ 0 0 0 0 0 151461 15812313 199891 20996 11179 SOD1 SOD1 SOD1 7 3.2 The mutation in the copper_amp_#47 zinc superoxide dismutase (SOD1) SOD1 gene is known to be associated with the familial ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151462 15812313 199891 20996 11179 SOD1 ALS ALS 17 2.2 SOD1 gene is known to be associated with the familial ALS (FALS) FALS because of some undefined property of mutant SOD1 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00175123126780039<>ScoreDetail__5468|IGFALS|0.000428007912362488__11179|SOD1|0.00175123126780039__ 0 0 0 0 0 151463 15812313 199891 20996 11179 SOD1 SOD1 SOD1 26 3.2 ALS (FALS) FALS because of some undefined property of mutant SOD1 protein _amp_#91 1 _amp_#93 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151464 15812313 199892 20996 11179 SOD1 SOD1 SOD1 0 3.2 SOD1 mutations cause the disease through a gain of function or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151465 15812313 199892 20996 11179 SOD1 SOD SOD 18 2.2 of function or by enhancing an unknown nondismutase activity of SOD _amp_#91 2 _amp_#93 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151466 15812313 199893 20996 11179 SOD1 SOD1 SOD1 5 3.2 Several pathophysiological mechanisms linking the SOD1 mutation with FALS have been proposed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151467 15812313 199894 20996 11179 SOD1 SOD1 SOD1 9 3.2 They include a failure to fold or degrade mutant SOD1 the formation of free radicals the susceptibility of mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151468 15812313 199894 20996 11179 SOD1 SOD1 SOD1 19 3.2 SOD1 the formation of free radicals the susceptibility of mutant SOD1 to disulfide reduction and the release of free copper _amp_#91 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151469 15812313 199895 20996 11179 SOD1 SOD1 SOD1 11 3.2 hypotheses have been proposed concerning the metal binding properties of SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151470 15812313 199897 20996 11179 SOD1 SOD1 SOD1 32 3.2 (NO), NO reacts with the Cu 2_amp_#43 ion of mutant SOD1 to produce nitronium ions which then nitrate proteins and induce 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151471 15812313 199899 20996 11179 SOD1 SOD1 SOD1 16 3.2 and Yim et al _amp_#91 7 _amp_#93 reported that mutant SOD1 has higher peroxidase activity than the wild type (WT), WT 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151472 15812313 199900 20996 11179 SOD1 SOD1 SOD1 11 3.2 et al _amp_#91 8 _amp_#93 proposed that the FALS-associated mutant SOD1 failed to bind or shield Cu 2_amp_#43 as effectively as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151473 15812313 199901 20996 11179 SOD1 SOD1 SOD1 28 3.2 by a mechanism involving the altered copper-dependent activity of mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151474 15812313 199902 20996 11179 SOD1 SOD1 SOD1 7 3.2 If an altered copper binding capacity by SOD1 protein causes a toxic gain of function neurons with SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151475 15812313 199902 20996 11179 SOD1 SOD1 SOD1 17 3.2 SOD1 protein causes a toxic gain of function neurons with SOD1 mutations are likely to be more vulnerable to excess copper 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151476 15812313 199903 20996 11179 SOD1 SOD1 SOD1 2 3.2 Furthermore mutant SOD1 mice have significant elevations in brain or spinal cord copper 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151477 15812313 199904 20996 11179 SOD1 SOD1 SOD1 11 3.2 elevation of copper is probably copper bound to the over-expressed SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151478 15812313 199905 20996 11179 SOD1 SOD1 SOD1 1 3.2 Therefore SOD1 mutant neurons would be more vulnerable to an exogenous load 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151479 15812313 199907 16323 8806 PDHA1 PDH PDH 17 0.3 formation of 4-hydroxy nonenal and it inhibits pyruvate dehydrogenase (PDH) PDH by covalently modifying the lipoic acid moiety of the enzyme 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 17106 9279 PPM2C 0 151480 15812313 199908 16323 8806 PDHA1 PDH PDH 16 0.3 intermediate of energy metabolism thiamine and lipoic acid cofactors of PDH were tested to have neuroprotective effects against copper overload 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 17106 9279 PPM2C 0 151481 15812313 199909 6895 3530 F12 F12 F-12 30 0.0 USA were maintained in Dulbecco_amp_#39 s modified Eagles_amp_#39 s medium_amp_#47 F-12 growth medium (Gibco, Gibco Grand Island New York USA containing 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151482 15812313 199911 20996 11179 SOD1 SOD1 SOD1 5 3.2 WT or mutant (G93A) G93A human SOD1 cDNA (a a gift from Dr Lawrence J Hayward University 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151483 15812313 199912 20996 11179 SOD1 SOD1 SOD1 28 3.2 USA with pcDNA3.1 vector containing cDNA encoding WT or G93A SOD1 and then selected using geneticin (G418 G418 sulfate Gibco 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151484 15812313 199914 20996 11179 SOD1 SOD1 SOD1 31 3.2 or pooled colonies were used for experiments after determining human SOD1 expression by Western blot and immunohistochemical staining 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151485 15812313 199915 20996 11179 SOD1 SOD1 SOD1 4 3.2 The cells expressing human SOD1 were cultured in a medium containing geneticin at 200 microg_amp_#47 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151486 15812313 199917 20996 11179 SOD1 SOD1 SOD1 17 3.2 (Cu Cu 2_amp_#43 on the death of cells expressing mutant SOD1 the cells were treated with various agents prior to exposing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151487 15812313 199932 20996 11179 SOD1 SOD1 SOD1 8 3.2 VSC 4.1 cells expressing human WT or mutant SOD1 (G93A) G93A were exposed to increasing concentrations of Cu 2_amp_#43 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151488 15812313 199934 20996 11179 SOD1 SOD1 SOD1 34 3.2 treatment (250 250 microM in cells expressing WT or mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151489 15812313 199935 20996 11179 SOD1 SOD1 SOD1 4 3.2 In cells expressing WT SOD1 Cu 2_amp_#43 -induced cell death was not affected by trolox 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151490 15812313 199936 20996 11179 SOD1 SOD1 SOD1 5 3.2 However the death of mutant SOD1 cells was significantly attenuated by trolox Z-VAD-FMK and calpeptin ( 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 151491 15812313 199938 20996 11179 SOD1 SOD1 SOD1 44 3.2 attenuate Cu 2_amp_#43 -induced neuronal death in cells expressing mutant SOD1 ( Fig 2a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151492 15812313 199940 20996 11179 SOD1 SOD1 SOD1 5 3.2 The fluorescence staining of mutant SOD1 cells using Hoechst 33342 dye also showed a reduction in 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 151493 15812313 199942 18723 10261 ROS1 ROS ROS 10 0.0 2_amp_#43 treatment was found to increase reactive oxygen species (ROS) ROS in both WT and mutant cells whereas cotreatment with 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151494 15812313 199942 18723 10261 ROS1 ROS ROS 36 0.0 Cu 2_amp_#43 significantly reduced this Cu 2_amp_#43 -induced increase in ROS only in mutant cells ( Fig 3a and b 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151495 15812313 199945 20996 11179 SOD1 SOD1 SOD1 35 3.2 both convert hydrogen peroxide to oxygen and water protected mutant SOD1 cells from Cu 2_amp_#43 toxicity 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 151496 15812313 199947 20996 11179 SOD1 SOD1 SOD1 20 3.2 concentrations reduce the survival of VSC 4.1 cells expressing human SOD1 mutated at G93A and that pyruvate protects these cells from 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151497 15812313 199947 18723 10261 ROS1 ROS ROS 43 0.0 effects of this Cu 2_amp_#43 by inhibiting a build-up of ROS and thus apoptotic cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151498 15812313 199948 20996 11179 SOD1 SOD1 SOD1 22 3.2 functioning of several enzymes including cytochrome c oxidase ceruloplasmin and SOD1 _amp_#91 13 _amp_#93 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151499 15812313 199951 20996 11179 SOD1 SOD1 SOD1 18 3.2 2_amp_#43 reduces the viability of VSC 4.1 cells expressing mutant SOD1 (G93A) G93A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151500 15812313 199954 20996 11179 SOD1 SOD1 SOD1 22 3.2 and calpain and the formation of hydroxyl radicals in mutant SOD1 cells 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 151501 15812313 199958 20996 11179 SOD1 SOD1 SOD1 15 3.2 we found that only pyruvate attenuates the death of mutant SOD1 cells 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 151502 15812313 199959 20996 11179 SOD1 SOD1 SOD1 17 3.2 may be related to the depletion of pyruvate in mutant SOD1 cells 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 151503 15812313 199960 20996 11179 SOD1 ALS ALS 11 2.2 metabolism impairment has previously been reported in neurodegenerative diseases including ALS Huntington_amp_#39 s or Alzheimer_amp_#39 s diseases _amp_#91 12 _amp_#93 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00175123126780039<>ScoreDetail__5468|IGFALS|0.000428007912362488__11179|SOD1|0.00175123126780039__ 0 0 0 0 0 151504 15812313 199962 20996 11179 SOD1 SOD1 SOD1 17 3.2 through this property in VSC 4.1 cells harboring the G93A SOD1 mutation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151505 15812313 199966 20996 11179 SOD1 SOD1 SOD1 18 3.2 2_amp_#43 -induced ROS formation and apoptotic cell death in mutant SOD1 cells 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 151506 15812313 199966 18723 10261 ROS1 ROS ROS 10 0.0 In addition we found that pyruvate reduces Cu 2_amp_#43 -induced ROS formation and apoptotic cell death in mutant SOD1 cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151507 15812313 199967 20996 11179 SOD1 SOD1 SOD1 18 3.2 free radical scavenging action in VSC 4.1 cells expressing mutant SOD1 (G93A) G93A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151508 15812313 199970 20996 11179 SOD1 ALS ALS 26 2.2 our findings suggest that pyruvate may have therapeutic benefits in ALS pathologies involving Cu 2_amp_#43 -induced toxicity 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00175123126780039<>ScoreDetail__5468|IGFALS|0.000428007912362488__11179|SOD1|0.00175123126780039__ 0 0 0 0 0 151509 15812313 199971 20996 11179 SOD1 SOD1 SOD1 13 3.2 found to be toxic to motor neuronal cells expressing mutant SOD1 and pyruvate attenuated this Cu 2_amp_#43 -induced neuronal death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 151510 15812313 199972 20996 11179 SOD1 SOD1 SOD1 25 3.2 and energy metabolism enhancing actions in motor neurons harboring the SOD1 mutation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153881 15850589 203859 20996 11179 SOD1 SOD1 SOD1 5 5.7 Mutations of Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 are found in patients with familial amyotrophic lateral sclerosis (FALS) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153882 15850589 203860 20996 11179 SOD1 SOD1 SOD1 24 5.7 with human wild type (wt) wt or mutant (G93A) G93A SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153883 15850589 203863 20996 11179 SOD1 SOD1 SOD1 30 5.7 was significantly higher in living G93ASOD1 cells compared to wt SOD1 cells 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 153884 15850589 203867 20996 11179 SOD1 SOD1 SOD1 8 5.7 In conclusion even a small amount of mutant SOD1 put motor neurons in a condition of oxidative stress and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153885 15850589 203870 20996 11179 SOD1 ALS ALS 3 2.4 Amyotrophic lateral sclerosis (ALS) ALS is an adult-onset neurodegenerative disease with a very poor prognosis 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0011578060308504<>ScoreDetail__5468|IGFALS|0.000250260688216893__11179|SOD1|0.0011578060308504__ 0 0 0 0 0 153886 15850589 203873 20996 11179 SOD1 ALS ALS 2 2.4 Treatments for ALS tested in clinical trials to date have proved largely ineffective 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0011578060308504<>ScoreDetail__5468|IGFALS|0.000250260688216893__11179|SOD1|0.0011578060308504__ 0 0 0 0 0 153887 15850589 203874 20996 11179 SOD1 ALS ALS 0 2.4 ALS is usually sporadic (SALS), SALS but approximately 10% of cases 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0011578060308504<>ScoreDetail__5468|IGFALS|0.000250260688216893__11179|SOD1|0.0011578060308504__ 0 0 0 0 0 153888 15850589 203876 20996 11179 SOD1 SOD1 SOD1 15 5.7 the gene encoding for Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 and over 100 missense mutations have been described 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153889 15850589 203877 20996 11179 SOD1 SOD1 SOD1 0 5.7 SOD1 is a free radical-scavenging enzyme since it converts the superoxide 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153890 15850589 203878 20996 11179 SOD1 SOD1 SOD1 11 5.7 is now generally accepted that the toxic effect of mutant SOD1 is not due to the loss of dismutase activity but 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153891 15850589 203879 20996 11179 SOD1 SOD1 SOD1 16 5.7 oxidative chemistry and/or and or misfolding and aggregation of mutant SOD1 (for for a review see Ref 1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153892 15850589 203880 20996 11179 SOD1 SOD1 SOD1 3 5.7 Apparently mutation converts SOD1 from an anti-apoptotic gene to a pro-apoptotic one 2 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153893 15850589 203881 20996 11179 SOD1 SOD1 SOD1 3 5.7 The presence of SOD1 not only in the cytosol but also in the mitochondrial 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153894 15850589 203882 20996 11179 SOD1 SOD1 SOD1 12 5.7 and in vitro models were generated by genetic manipulation of SOD1 expression 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153895 15850589 203885 20996 11179 SOD1 SOD1 SOD1 13 5.7 previous in vitro studies of the toxic effects of mutant SOD1 were conducted in cells which did not have a motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153896 15850589 203886 20996 11179 SOD1 SOD1 SOD1 3 5.7 However while mutant SOD1 is ubiquitously expressed the selectivity of damage towards motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153897 15850589 203886 20996 11179 SOD1 SOD1 SOD1 26 5.7 that this cell type has a peculiar susceptibility to mutant SOD1 toxicity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153898 15850589 203887 20996 11179 SOD1 SOD1 SOD1 3 5.7 Accordingly microinjected mutant SOD1 protein caused death in primary motor neurons but not in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153899 15850589 203888 20996 11179 SOD1 SOD1 SOD1 26 5.7 review see Ref 10 and by a selective enrichment of SOD1 in motor neurons of the spinal cord and brainstem 11 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153900 15850589 203889 20996 11179 SOD1 SOD1 SOD1 6 5.7 Recently the effects of human mutant SOD1 were investigated in the NSC-34 motor neuron-like cell line 12 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153901 15850589 203890 20996 11179 SOD1 SOD1 SOD1 27 5.7 wt or mutant G93ASOD1 and investigated the toxicity of mutant SOD1 expressed at levels close to those seen in the human 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153902 15850589 203891 18723 10261 ROS1 ROS ROS 26 0.0 the human disease can cause motor neuron death with increased ROS formation and a decrease in mitochondrial membrane potential (MMP) MMP 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153903 15850589 203896 20996 11179 SOD1 SOD1 SOD1 12 5.7 and generation of NSC-34 cell lines stably transfected with human SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153904 15850589 203898 7361 20442 FBRS FBS FBS 12 0.0 maintained in DMEM (Biochrom, Biochrom Berlin Germany with 5% heat-inactivated FBS (defined defined FBS Hyclone Logan Utah 1 mM glutamine and 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 153905 15850589 203898 7361 20442 FBRS FBS FBS 14 0.0 (Biochrom, Biochrom Berlin Germany with 5% heat-inactivated FBS (defined defined FBS Hyclone Logan Utah 1 mM glutamine and antibiotics (100 100 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 153906 15850589 203899 20996 11179 SOD1 SOD1 SOD1 21 5.7 with the vector cloned with wt or G93A mutant human SOD1 cDNAs 16 using the LipofectAMINE PLUS reagent (Invitrogen Invitrogen Life 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153907 15850589 203901 20996 11179 SOD1 SOD1 SOD1 12 5.7 clones were isolated grown and tested for expression of human SOD1 protein by Western blotting 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153908 15850589 203902 20996 11179 SOD1 SOD1 SOD1 9 5.7 The NSC-34 cell lines transfected with vv or wt SOD1 or G93ASOD1 were maintained in selective medium (0.5 0.5 mg/mL 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153909 15850589 203902 7361 20442 FBRS FBS FBS 23 0.0 medium (0.5 0.5 mg/mL mg mL of G-418 containing 5% FBS 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 153910 15850589 203905 20996 11179 SOD1 SOD1 SOD1 6 5.7 SDS PAGE and Western blotting of SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153911 15850589 203905 19573 10691 SDS SDS SDS 0 0.0 SDS PAGE and Western blotting of SOD1 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000431905855939419<>ScoreDetail__10691|SDS|0.000168861870989531__19440|SBDS|0.000431905855939419__ 0 0 0 0 0 153912 15850589 203907 6603 3331 EMD EMD EMD 15 0.0 superoxide dismutase (Cu/Zn) Cu Zn antibody (1:1000; 1 1000 Calbiochem EMD Biosciences Inc La Jolla CA USA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153913 15850589 203909 20996 11179 SOD1 SOD1 SOD1 4 5.7 Protein bands identified by SOD1 antibody were detected using the ECL-Plus detection system (Amersham Amersham 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153914 15850589 203910 951 644 AR AIS AIS 9 0.0 Films were scanned and band intensities obtained by an AIS Image Analyzer (Imaging Imaging Research Inc. Ontario Canada 1 JUMiner_v2.2 1 0 0 2 15979 TotalCon:2<>644|AR|367|Complete__15979|TP63|8626|Complete__<>AvaiableGeneRif=2<>BEST:15979|TP63|0.000706588244582166<>ScoreDetail__15979|TP63|0.000706588244582166__644|AR|0.00055126884276987__ 0 0 0 0 0 153915 15850589 203911 20996 11179 SOD1 SOD1 SOD1 8 5.7 The continued expression of wt and G93A human SOD1 was routinely checked in order to ensure the cell lines 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153916 15850589 203911 20996 11179 SOD1 SOD1 SOD1 27 5.7 cell lines expressed similar quantities of human wt and mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153917 15850589 203919 18723 10261 ROS1 ROS ROS 6 0.0 Measurement of viability reactive oxygen species (ROS) ROS and mitochondrial membrane potential (MMP) MMP by flow cytometry 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153918 15850589 203932 18723 10261 ROS1 ROS ROS 1 0.0 Intracellular ROS were measured with 2_amp_#x2032 7_amp_#x2032 -dichlorodihydrofluorescein diacetate (H H 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153919 15850589 203953 20996 11179 SOD1 SOD1 SOD1s 4 2.4 The expression of human SOD1s was measured with an anti-human SOD1 antibody which also cross-reacts 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153920 15850589 203953 20996 11179 SOD1 SOD1 SOD1 10 5.7 The expression of human SOD1s was measured with an anti-human SOD1 antibody which also cross-reacts with murine SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153921 15850589 203953 20996 11179 SOD1 SOD1 SOD1 17 5.7 with an anti-human SOD1 antibody which also cross-reacts with murine SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153922 15850589 203954 20996 11179 SOD1 SOD1 SOD1s 3 2.4 In SDS-PAGE human SOD1s migrate at a slower rate than mouse SOD1 18 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153923 15850589 203954 20996 11179 SOD1 SOD1 SOD1 11 5.7 SDS-PAGE human SOD1s migrate at a slower rate than mouse SOD1 18 and accordingly two bands were detected with mouse SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153924 15850589 203954 20996 11179 SOD1 SOD1 SOD1 21 5.7 SOD1 18 and accordingly two bands were detected with mouse SOD1 being the band with the lower molecular weight 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153925 15850589 203955 20996 11179 SOD1 SOD1 SOD1 2 5.7 No human SOD1 expression is seen in cells transfected with empty vector 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153926 15850589 203956 20996 11179 SOD1 SOD1 SOD1 22 5.7 in this study was about 30% of the endogenous mouse SOD1 as measured by densitometry ( Fig 1 C 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153927 15850589 203960 18723 10261 ROS1 ROS ROS 8 0.0 Effect of G93ASOD1 on cell proliferation and viability ROS formation and MMP of motor neuron-like NSC-34 cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153928 15850589 203970 18723 10261 ROS1 ROS ROS 26 0.0 transfected with the mutant protein had a different level of ROS an effector of cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153929 15850589 203972 20996 11179 SOD1 SOD1 SOD1 25 5.7 observed in NSC-34 cells transfected with the wt form of SOD1 while a shift towards a higher DCF fluorescence level was 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153930 15850589 203972 20996 11179 SOD1 SOD1 SOD1 44 5.7 level was observed in NSC-34 cells transfected with the mutant SOD1 protein ( Fig 3 A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153931 15850589 203973 20996 11179 SOD1 SOD1 SOD1 13 5.7 quantified measuring the average DCF fluorescence of living untransfected wt SOD1 and G93ASOD1 transfected cells ( Fig 3 B 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153932 15850589 203974 20996 11179 SOD1 SOD1 SOD1 22 5.7 the G93ASOD1 cells while it was lower in the wt SOD1 cells 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 153933 15850589 203976 20996 11179 SOD1 SOD1 SOD1 6 5.7 This suggests the two forms of SOD1 handle free radicals differently 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153934 15850589 203977 18723 10261 ROS1 ROS ROS 6 0.0 A cell death pathway mediated by ROS might involve some alteration of MMP 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153935 15850589 203981 20996 11179 SOD1 SOD1 SOD1 29 5.7 of cells with depolarized mitochondria compared to untransfected or wt SOD1 transfected cell lines ( Fig 4 A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153936 15850589 203989 20996 11179 SOD1 SOD1 SOD1 19 5.7 3 days limited the MTT reduction in NSC-34 expressing mutant SOD1 protein more than in NSC-34 expressing wt SOD1 or untransfected 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153937 15850589 203989 20996 11179 SOD1 SOD1 SOD1 27 5.7 expressing mutant SOD1 protein more than in NSC-34 expressing wt SOD1 or untransfected cells ( Fig 5 A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153938 15850589 203989 7361 20442 FBRS FBS FBS 7 0.0 Growth in a culture medium not containing FBS for 3 days limited the MTT reduction in NSC-34 expressing 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 153939 15850589 203992 20996 11179 SOD1 SOD1 SOD1 25 5.7 h caused preferential toxicity towards cells transfected with the mutant SOD1 (about about 35% decrease Fig 5 C 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153940 15850589 203996 20996 11179 SOD1 SOD1 SOD1 10 5.7 NaB did not affect MTT conversion of untransfected or wt SOD1 cells 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 153941 15850589 203999 20996 11179 SOD1 ALS ALS 0 2.4 ALS is a pathology of motor neurons 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0011578060308504<>ScoreDetail__5468|IGFALS|0.000250260688216893__11179|SOD1|0.0011578060308504__ 0 0 0 0 0 153942 15850589 204000 20996 11179 SOD1 SOD1 SOD1 22 5.7 (NSC-34) NSC-34 stably expressing the human mutant G93A form of SOD1 as representative of the SOD1 mutant forms seen in about 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153943 15850589 204000 20996 11179 SOD1 SOD1 SOD1 27 5.7 human mutant G93A form of SOD1 as representative of the SOD1 mutant forms seen in about 20% of FALS patients 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153944 15850589 204001 20996 11179 SOD1 SOD1 SOD1 13 5.7 containing G93ASOD1 had a lower viability than those expressing wt SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153945 15850589 204002 20996 11179 SOD1 SOD1 SOD1 20 5.7 though it was expressed at a lower level than normal SOD1 a condition similar to FALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153946 15850589 204003 20996 11179 SOD1 SOD1 SOD1s 5 2.4 Apoptotic cell death by mutant SOD1s was shown in other cellular models but in these studies 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153947 15850589 204003 20996 11179 SOD1 SOD1 SOD1 27 5.7 was not investigated whether the expression level of the mutant SOD1 proteins was comparable to the level observed in the FALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153948 15850589 204006 20996 11179 SOD1 SOD1 SOD1 4 5.7 The effect of mutant SOD1 on viability appeared when motor neurons were in the growth 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153949 15850589 204011 20996 11179 SOD1 SOD1 SOD1 12 5.7 event is the enhanced ROS formation in cells containing mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153950 15850589 204011 18723 10261 ROS1 ROS ROS 6 0.0 One such event is the enhanced ROS formation in cells containing mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153951 15850589 204012 20996 11179 SOD1 SOD1 SOD1 8 5.7 This effect is peculiar to G93ASOD1 and wt SOD1 might in fact afford protection since it lowered intracellular ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153952 15850589 204012 18723 10261 ROS1 ROS ROS 18 0.0 SOD1 might in fact afford protection since it lowered intracellular ROS even in comparison with untransfected NSC-34 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153953 15850589 204013 18723 10261 ROS1 ROS ROS 1 0.0 Enhanced ROS formation might come from the _amp_#x201c gain of function_amp_#x201d attributed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153954 15850589 204014 20996 11179 SOD1 ALS ALS 37 2.4 in vivo it could activate neuro-inflammatory processes also documented in ALS (for for a review see Ref 22 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0011578060308504<>ScoreDetail__5468|IGFALS|0.000250260688216893__11179|SOD1|0.0011578060308504__ 0 0 0 0 0 153955 15850589 204014 18723 10261 ROS1 ROS ROS 4 0.0 The higher production of ROS might directly damage the motor neuron cells in which they 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153956 15850589 204017 20221 10990 SLC25A4 ANT ANT 30 0.0 particularly in MPTP components such as adenine nucleotide translocator (ANT) ANT 1 JUMiner_v2.2 1 1 adenine nucleotide translocator 0 0 0 0 0 0 0 0 153957 15850589 204018 18723 10261 ROS1 ROS ROS 7 0.0 Together with the reduced viability and increased ROS formation in G93ASOD1 cells this initial permeabilization might be the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153958 15850589 204019 20996 11179 SOD1 SOD1 SOD1 11 5.7 was also reduced in human neuroblastoma SH-SY5Y cells expressing mutant SOD1 in a ratio of 1 1 with the endogenous SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153959 15850589 204019 20996 11179 SOD1 SOD1 SOD1 20 5.7 SOD1 in a ratio of 1 1 with the endogenous SOD1 protein 24 and in primary motor neurons from G93A mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153960 15850589 204021 20996 11179 SOD1 SOD1 SOD1 4 5.7 The presence of mutant SOD1 in our cellular model caused the appearance of a population 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153961 15850589 204023 20996 11179 SOD1 SOD1 SOD1 3 5.7 Mitochondria of mutant SOD1 transgenic mice are also swollen and in addition abnormally vacuolated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153962 15850589 204024 20996 11179 SOD1 SOD1 SOD1 25 5.7 damage with some relationship with the high content of mutant SOD1 in some of these in vivo experimental models 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153963 15850589 204025 20996 11179 SOD1 ALS ALS 20 2.4 observed in motor nerve terminals 28 and liver 29 of ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0011578060308504<>ScoreDetail__5468|IGFALS|0.000250260688216893__11179|SOD1|0.0011578060308504__ 0 0 0 0 0 153964 15850589 204027 20996 11179 SOD1 SOD1 SOD1 19 5.7 more affected in these cells than in NSC-34 expressing wt SOD1 after exposure to rotenone EA or serum withdrawal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153965 15850589 204029 18723 10261 ROS1 ROS ROS 9 0.0 Rotenone a specific mitochondrial complex I inhibitor boosts mitochondrial ROS production 30 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153966 15850589 204031 18723 10261 ROS1 ROS ROS 3 0.0 EA increases intracellular ROS and causes mitochondrial dysfunction and death in NSC-34 cells 17 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153967 15850589 204032 20996 11179 SOD1 SOD1 SOD1 9 5.7 Altered ETC activities were shown in FALS patients with SOD1 mutations (for for a review see Ref 9 in mutant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153968 15850589 204032 20996 11179 SOD1 SOD1 SOD1 20 5.7 mutations (for for a review see Ref 9 in mutant SOD1 transgenic mice 31 and 32 and in a cell culture 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153969 15850589 204033 18723 10261 ROS1 ROS ROS 8 0.0 ETC components can be inactivated by exposure to ROS or to peroxynitrite 33 and 34 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153970 15850589 204034 18723 10261 ROS1 ROS ROS 5 0.0 ETC impairment could cause further ROS production and oxidative damage setting up a vicious circle with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153971 15850589 204036 20996 11179 SOD1 ALS ALS 3 2.4 Also relevant to ALS is the notion that mitochondrial dysfunction increases the sensitivity of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0011578060308504<>ScoreDetail__5468|IGFALS|0.000250260688216893__11179|SOD1|0.0011578060308504__ 0 0 0 0 0 153972 15850589 204036 20996 11179 SOD1 SOD1 SOD1 24 5.7 motor neurons to excitotoxicity 36 and motor neurons containing mutant SOD1 were more vulnerable to glutamate 25 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153973 15850589 204038 18723 10261 ROS1 ROS ROS 12 0.0 did not investigate the intracellular source of the excess of ROS in viable G93ASOD1 cells although it is tempting to speculate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153974 15850589 204039 18723 10261 ROS1 ROS ROS 15 0.0 ETC these organelles are considered the main source of intracellular ROS including superoxide 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153975 15850589 204041 20996 11179 SOD1 SOD1 SOD1 3 5.7 A fraction of SOD1 is located in this space with the putative function to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153976 15850589 204042 20996 11179 SOD1 SOD1 SOD1 4 5.7 The presence of mutant SOD1 in the intermembrane space of FALS mitochondria might however be 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153977 15850589 204042 20996 11179 SOD1 SOD1 SOD1-associated 21 2.4 mitochondria might however be critical in the pathogenesis of mutant SOD1-associated FALS 32 38 and 39 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153978 15850589 204043 20996 11179 SOD1 SOD1 SOD1 7 5.7 Our study shows that overexpression of wt SOD1 did indeed reduce the ROS level in viable motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153979 15850589 204043 18723 10261 ROS1 ROS ROS 12 0.0 shows that overexpression of wt SOD1 did indeed reduce the ROS level in viable motor neurons while the opposite effect was 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153980 15850589 204044 18723 10261 ROS1 ROS ROS 8 0.0 Assuming that mitochondria were the main source of ROS the increased ROS formation in G93ASOD1 mitochondria is one possible 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153981 15850589 204044 18723 10261 ROS1 ROS ROS 11 0.0 that mitochondria were the main source of ROS the increased ROS formation in G93ASOD1 mitochondria is one possible mechanism through which 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153982 15850589 204045 20997 11180 SOD2 MnSOD MnSOD 6 1.9 In agreement with this overexpression of MnSOD attenuates neuronal death in cellular models of FALS 12 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153983 15850589 204046 20996 11179 SOD1 SOD1 SOD1 31 5.7 disease onset and prolonged survival in transgenic mice with mutant SOD1 42 43 and 44 and rendered cells transfected with mutant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153984 15850589 204046 20996 11179 SOD1 SOD1 SOD1 43 5.7 42 43 and 44 and rendered cells transfected with mutant SOD1 more resistant to apoptosis 45 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153985 15850589 204046 1576 990 BCL2 BCL2 bcl2 9 0.0 Treatment with inhibitors of MPTP opening and overexpression of bcl2 which inhibits the opening of MPTP under stressful conditions delayed 14 JUMiner_v2.2 1 1 bcl2; 0 0 0 0 0 0 0 0 153986 15850589 204047 20996 11179 SOD1 SOD1 SOD1 13 5.7 scavengers reversed mitochondrial dysfunction and cell death due to mutant SOD1 in cell culture models of FALS 12 and 35 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153987 15850589 204048 20996 11179 SOD1 SOD1 SOD1 10 5.7 In conclusion this study found that motor neurons containing mutant SOD1 in amounts comparable to FALS patients are in a condition 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153988 15850589 204049 20996 11179 SOD1 SOD1 SOD1 17 5.7 determining the cell destiny in the presence of the mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153989 15850589 204051 20996 11179 SOD1 SOD1 SOD1 9 5.7 Fig 1._amp_#xa0 Morphology and transfection of NSC-34 cells with human SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153990 15850589 204053 20996 11179 SOD1 SOD1 SOD1 9 5.7 Panels B and C show the expression of human SOD1 after transient or stable transfection of NSC-34 cells with empty 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153991 15850589 204053 20996 11179 SOD1 SOD1 SOD1 27 5.7 cells with empty vector wild type or G93A mutant human SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153992 15850589 204054 20996 11179 SOD1 SOD1 SOD1 16 5.7 upper and lower bands correspond to the human and murine SOD1 respectively 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153993 15850589 204062 18723 10261 ROS1 ROS ROS 6 0.0 Fig 3._amp_#xa0 Effect of G93ASOD1 on cellular ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153994 15850589 204063 18723 10261 ROS1 ROS ROS 11 0.0 5 days in culture without any change of medium intracellular ROS were measured from the conversion of H 2 DCFDA to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153995 15850589 204074 7361 20442 FBRS FBS FBS 14 0.0 and transfected NSC-34 cells was evaluated in cells grown without FBS (Panel Panel A or after exposure to 100 _amp_#x3bc M 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 153996 15850589 204077 20996 11179 SOD1 SOD1 SOD1 9 5.7 Fig 6._amp_#xa0 Effect of sodium butyrate on expression of human SOD1 and mitochondrial function 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 153997 15850589 204078 20996 11179 SOD1 SOD1 SOD1 12 5.7 shows the Western blot analysis of human wt or G93A SOD1 expression after 24 h treatment with sodium butyrate (NaB; NaB 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142715 15863242 187979 20996 11179 SOD1 SOD1 SOD1 3 2.5 Cu/Zn-superoxide Cu Zn-superoxide dismutase 1 (SOD1), SOD1 encoded on chromosome 21 is a key enzyme in metabolism 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142716 15863242 187980 20996 11179 SOD1 SOD1 SOD1 4 2.5 Transgenic mice overexpressing human SOD1 (Tg-hSOD1) Tg-hSOD1 are useful model for Down syndrome (trisomy trisomy 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142717 15863242 187980 20996 11179 SOD1 ALS ALS 19 1.7 syndrome (trisomy trisomy 21 and familial amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000845010227974227<>ScoreDetail__5468|IGFALS|0.000599878681251777__11179|SOD1|0.000845010227974227__ 0 0 0 0 0 142718 15863242 187984 20996 11179 SOD1 SOD1 SOD1 5 2.5 Our findings suggest that overexpressed SOD1 directly or by generating reactive oxygen species may lead to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142719 15863242 187987 20996 11179 SOD1 SOD1 hSOD1 6 3.0 The human Cu/Zn-superoxide Cu Zn-superoxide dismutase 1 gene (hSOD1) hSOD1 was the first chromosome 21 gene to be characterised ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142720 15863242 187988 20996 11179 SOD1 SOD1 SOD1 5 2.5 Later studies revealed overexpression of SOD1 mRNA protein and increased activity was detected in brains of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142721 15863242 187989 20996 11179 SOD1 SOD1 SOD1 6 2.5 Moreover transgenic mice expressing wild-type human SOD1 (Tg-hSOD1 Tg-hSOD1 mice were the first model for DS ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142722 15863242 187991 20996 11179 SOD1 SOD1 SOD1 16 2.5 deficit in DS no proof for a pathogenetic role of SOD1 in DS exists 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142723 15863242 187992 20996 11179 SOD1 SOD1 SOD1 2 2.5 Although increased SOD1 may lead to generation of reactive oxygen species and thus 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142724 15863242 187992 20996 11179 SOD1 SOD1 SOD1 37 2.5 role in neurodegenerative mechanisms it was demonstrated that overexpression of SOD1 may be protective against apoptosis for hippocampal neurons ( Korenberg 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142725 15863242 188002 20996 11179 SOD1 SOD1 hSOD1 7 3.0 Transgenic mice about 3-month-old male harbouring the hSOD1 gene were obtained from Dr Jacqueline London University of Paris 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142726 15863242 188003 20996 11179 SOD1 SOD1 hSOD1 3 3.0 Generation of the hSOD1 transgenic line KT has been described previously ( Paris et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142727 15863242 188004 20996 11179 SOD1 SOD1 hSOD1 14 3.0 by injecting an 11.5 kb EcoRI_amp_#x2013 BamH1 fragment containing the hSOD1 gene into fertilised eggs from FVB/N FVB N mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142728 15863242 188013 20996 11179 SOD1 SOD1 SOD1 2 2.5 Measurement of SOD1 activity and immunostaining in WT and Tg-hSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142729 15863242 188014 20996 11179 SOD1 SOD1 hSOD1 1 3.0 For hSOD1 activity measurements hippocampal extracts of WT and Tg-hSOD1 mice were 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142730 15863242 188015 20996 11179 SOD1 SOD1 SOD1 2 2.5 Activity of SOD1 was assayed photochemically by measuring inhibition of nitroblue tetrazolium reduction 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142731 15863242 188016 20996 11179 SOD1 SOD1 hSOD1 5 3.0 In Tg-hSOD1 mice immunostaining for hSOD1 was strong in the brain and no immunostaining occurred in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142732 15863242 188016 20996 11179 SOD1 SOD1 hSOD1 26 3.0 the CNS of WT indicating that labeling was specific for hSOD1 ( Jaarsma et al. 2000 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142733 15863242 188037 15911 8524 OVGP1 OGP OGP 24 0.0 (consisting consisting of 5 mM octyl _amp_#x3b2 -d -glucopyranoside (OGP) OGP and 10 mM ammonium bicarbonate and incubated for 4 h 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142734 15863242 188038 6883 3541 F3 TFA TFA 9 0.0 Peptide extraction was performed with 10 _amp_#x3bc l of 1% TFA in 5 mM OGP and directly applied onto a target 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142735 15863242 188038 15911 8524 OVGP1 OGP OGP 13 0.0 with 10 _amp_#x3bc l of 1% TFA in 5 mM OGP and directly applied onto a target (AnchorChip_amp_#x2122;, AnchorChip_amp_#x2122 Bruker Daltonics 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142736 15863242 188039 7509 13506 FEZF2 TOF TOF 10 0.0 mass spectrometer used in this work was an Ultraflex_amp_#x2122 TOF/TOF TOF TOF (Bruker Bruker Daltonics Germany operated in the reflector mode 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142737 15863242 188039 7509 13506 FEZF2 TOF TOF 10 0.0 spectrometer used in this work was an Ultraflex_amp_#x2122 TOF/TOF TOF TOF (Bruker Bruker Daltonics Germany operated in the reflector mode 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142738 15863242 188058 20996 11179 SOD1 SOD1 SOD1 3 2.5 Increased activity of SOD1 in hippocampus of Tg-hSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142739 15863242 188059 20996 11179 SOD1 SOD1 SOD1 2 2.5 Overexpression of SOD1 in hippocampus was evaluated by enzymatic activity using the classic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142740 15863242 188059 20996 11179 SOD1 SOD1 SOD1 21 2.5 the classic test of inhibition of nitroblue tetrazolium reduction by SOD1 and automatically assayed using a Ransod kit 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142741 15863242 188060 20996 11179 SOD1 SOD1 SOD1 1 2.5 The SOD1 activity was increased by factor 5 in blood 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142742 15863242 188061 20996 11179 SOD1 SOD1 SOD1 11 2.5 in hippocampus of 3-month-old Tg-SOD1 showed large increases in total SOD1 activity WT (2.5 2.5 _amp_#xb1 0.17 U/mg), U mg hemizygotes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142743 15863242 188061 20996 11179 SOD1 SOD1 hSOD1 19 3.0 WT (2.5 2.5 _amp_#xb1 0.17 U/mg), U mg hemizygotes (hSOD1/+, hSOD1 38.87 _amp_#xb1 2.04 U/mg) U mg and homozygotes (hSOD1/hSOD1, hSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142744 15863242 188061 20996 11179 SOD1 SOD1 hSOD1 26 3.0 hSOD1 38.87 _amp_#xb1 2.04 U/mg) U mg and homozygotes (hSOD1/hSOD1, hSOD1 hSOD1 47.79 _amp_#xb1 1.69 U/mg) U mg 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142745 15863242 188061 20996 11179 SOD1 SOD1 hSOD1 26 3.0 38.87 _amp_#xb1 2.04 U/mg) U mg and homozygotes (hSOD1/hSOD1, hSOD1 hSOD1 47.79 _amp_#xb1 1.69 U/mg) U mg 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142746 15863242 188066 20996 11179 SOD1 SOD1 hSOD1 11 3.0 large series of proteins were successfully represented and even transgenic hSOD1 was detected in 2-DE gels of Tg-hSOD1 mice ( Fig 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142747 15863242 188079 20996 11179 SOD1 SOD1 SOD1 8 2.5 Antioxidant proteins showed no different expression except mouse SOD1 (mSOD1) mSOD1 (Unpublished Unpublished data Shin et al. 2003 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142748 15863242 188079 20996 11179 SOD1 SOD1 mSOD1 9 1.7 Antioxidant proteins showed no different expression except mouse SOD1 (mSOD1) mSOD1 (Unpublished Unpublished data Shin et al. 2003 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142749 15863242 188080 20996 11179 SOD1 SOD1 mSOD1 4 1.7 In addition spots of mSOD1 and hSOD1 showing high similarity ( Fig 3 (A)) A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142750 15863242 188080 20996 11179 SOD1 SOD1 hSOD1 6 3.0 In addition spots of mSOD1 and hSOD1 showing high similarity ( Fig 3 (A)) A were detected 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142751 15863242 188081 20996 11179 SOD1 SOD1 hSOD1 6 3.0 We observed that expression level of hSOD1 in hippocampus of homozygotes was significantly higher than that in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142752 15863242 188081 20996 11179 SOD1 SOD1 mSOD1 29 1.7 _amp_#xb1 1.804 versus 12.244 _amp_#xb1 2.259 P = 0.0259 while mSOD1 was significantly decreased in hippocampus of Tg-hSOD1 mice (Unpublished Unpublished 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142753 15863242 188086 2578 23512 C10orf28 PSORT PSORT 9 1.3 Putative cellular localizations of hypothetical proteins were determined by PSORT II using of k-nearest neighbor (k-NN) k-NN algorithm for assessing 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 142754 15863242 188090 20996 11179 SOD1 SOD1 SOD1-dependent 20 1.7 in hemizygous or homozygous Tg-hSOD1 mice revealing directly or indirectly SOD1-dependent alterations of several protein pathways and cascades systems that are 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142755 15863242 188092 21932 11655 TCP1 TCP1 TCP-1 4 1.3 Eight t-complex 1 proteins (TCP-1) TCP-1 were studied in DS brain the TCP-1 epsilon ( Yoo 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142756 15863242 188092 21932 11655 TCP1 TCP1 TCP-1 11 1.3 1 proteins (TCP-1) TCP-1 were studied in DS brain the TCP-1 epsilon ( Yoo et al. 2001a as well as alpha 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142757 15863242 188092 20996 11179 SOD1 SOD1 SOD1 54 2.5 the gamma subunit was here observed in hippocampus in the SOD1 overexpression animal model of DS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142758 15863242 188094 21932 11655 TCP1 TCP1 TCP-1 3 1.3 Alterations of the TCP-1 system are of particular interest as some subunits are chaperones 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142759 15863242 188099 6372 3189 EEF1A1 EF-Tu EF-Tu-like 34 2.1 of translation reflected by reduced expression of translation elongation factor EF-Tu-like protein P43 ( Table 2 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142760 15863242 188099 23430 12420 TUFM P43 P43 36 1.4 reflected by reduced expression of translation elongation factor EF-Tu-like protein P43 ( Table 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142761 15863242 188099 18723 10261 ROS1 ROS ROS 10 0.0 underlying cause may be activation of reactive oxygen species (ROS) ROS with subsequent oxidation and modification of transcription neurodegeneration per se 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142762 15863242 188108 20996 11179 SOD1 SOD1 SOD1-mediated 22 2.0 catalyzing covalent attachment of ubiquitin to other proteins may reflect SOD1-mediated impaired protein handling in terms of ubiquitination 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142763 15863242 188114 20996 11179 SOD1 SOD1 SOD1 9 2.5 Multiple protein derangement may directly or indirectly depend on SOD1 overexpression impairment of translation (translation translation elongation or simply reflect 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142764 15863242 188123 20996 11179 SOD1 SOD1 mSOD1 2 1.7 Spots of mSOD1 and hSOD1 were demonstrated in hippocampus of Tg-hSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142765 15863242 188123 20996 11179 SOD1 SOD1 hSOD1 4 3.0 Spots of mSOD1 and hSOD1 were demonstrated in hippocampus of Tg-hSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142766 15863242 188124 20996 11179 SOD1 SOD1 hSOD1 3 3.0 Fig 3._amp_#xa0 Comparison of hSOD1 with mSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142767 15863242 188124 20996 11179 SOD1 SOD1 mSOD1 5 1.7 Fig 3._amp_#xa0 Comparison of hSOD1 with mSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142768 15863242 188125 20996 11179 SOD1 SOD1 hSOD1 3 3.0 (A) A Alignment of hSOD1 (P00441) P00441 with mSOD1 ( P08228 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142769 15863242 188125 20996 11179 SOD1 SOD1 mSOD1 6 1.7 (A) A Alignment of hSOD1 (P00441) P00441 with mSOD1 ( P08228 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142770 15863242 188127 20996 11179 SOD1 SOD1 hSOD1 7 3.0 This sequence alignment with CLUSTALW showed that hSOD1 has high similarity to mSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142771 15863242 188127 20996 11179 SOD1 SOD1 mSOD1 12 1.7 alignment with CLUSTALW showed that hSOD1 has high similarity to mSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142772 15863242 188128 20996 11179 SOD1 SOD1 mSOD1 3 1.7 MALDI-TOF spectrum of mSOD1 (B) B and hSOD1 (C) C 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 142773 15863242 188128 20996 11179 SOD1 SOD1 hSOD1 6 3.0 MALDI-TOF spectrum of mSOD1 (B) B and hSOD1 (C) C 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144555 15896810 189879 7975 3951 FXN FRDA FRDA 18 4.3 neurodegenerative diseases including Parkinson's disease Alzheimer's disease Friedreich's ataxia (FRDA), FRDA multiple sclerosis and amyotrophic lateral sclerosis may involve the generation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144556 15896810 189879 6981 22140 FAM20C RNS RNS 38 0.6 species (ROS) ROS and/or and or reactive nitrogen species (RNS) RNS associated with mitochondrial dysfunction 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 144557 15896810 189879 18723 10261 ROS1 ROS ROS 33 0.0 sclerosis may involve the generation of reactive oxygen species (ROS) ROS and/or and or reactive nitrogen species (RNS) RNS associated with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144558 15896810 189882 7975 3951 FXN FRDA FRDA 6 4.3 The precise sequence of events in FRDA pathogenesis is uncertain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144559 15896810 189884 7975 3951 FXN FRDA FRDA 29 4.3 addition that decreased expression of frataxin protein is associated with FRDA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144560 15896810 189884 18723 10261 ROS1 ROS ROS 7 0.0 Recent evidence suggests that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144561 15896810 189885 7975 3951 FXN FRDA FRDA 7 4.3 Many approaches have been undertaken to understand FRDA but the heterogeneity of the etiologic factors makes it difficult 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144562 15896810 189886 7975 3951 FXN FRDA FRDA 24 4.3 and their interaction in a vicious cycle are central to FRDA pathogenesis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144563 15896810 189887 7975 3951 FXN FRDA FRDA 2 4.3 Brains of FRDA patients undergo many changes such as disruption of protein synthesis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144564 15896810 189889 9691 5232 HSPA1A HSP HSP 8 3.4 In the central nervous system heat shock protein (HSP) HSP synthesis is induced not only after hyperthermia but also following 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144565 15896810 189890 20996 11179 SOD1 ALS ALS 13 1.4 (AD), AD Parkinson's disease (PD), PD amyotrophic lateral sclerosis (ALS), ALS multiple sclerosis (MS), MS Huntington's disease (HD) HD and FRDA 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000583925481347638<>ScoreDetail__5468|IGFALS|0.000392536404970433__11179|SOD1|0.000583925481347638__ 0 0 0 0 0 144566 15896810 189890 7975 3951 FXN FRDA FRDA 21 4.3 ALS multiple sclerosis (MS), MS Huntington's disease (HD) HD and FRDA are all associated with the presence of abnormal proteins 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144567 15896810 189891 9691 5232 HSPA1A HSP HSPs 3 3.7 Among the various HSPs HSP32 also known as heme oxygenase I (HO-1), HO-1 has 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144568 15896810 189891 9462 5013 HMOX1 HO-1 HO-1 11 2.9 various HSPs HSP32 also known as heme oxygenase I (HO-1), HO-1 has received considerable attention as it has been recently demonstrated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144569 15896810 189891 9462 5013 HMOX1 HO-1 HO-1 23 2.9 received considerable attention as it has been recently demonstrated that HO-1 induction by generating the vasoactive molecule carbon monoxide and the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144570 15896810 189897 20996 11179 SOD1 ALS ALS 15 1.4 mitochondrial involvement in neurodegenerative diseases including Alzheimer's and Parkinson's diseases ALS MS and FRDA 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000583925481347638<>ScoreDetail__5468|IGFALS|0.000392536404970433__11179|SOD1|0.000583925481347638__ 0 0 0 0 0 144571 15896810 189897 7975 3951 FXN FRDA FRDA 18 4.3 neurodegenerative diseases including Alzheimer's and Parkinson's diseases ALS MS and FRDA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144572 15896810 189901 10824 6204 JUN AP-1 AP-1 25 1.8 and/or and or DNA binding of numerous transcription factors including AP-1 fos jun myc erg-1 SAPK and NFkB 3 1 JUMiner_v2.2 1 0 0 2 6204 TotalCon:5<>3796|FOS|2353|Complete__3797|FOSB|2354|Complete__6204|JUN|3725|Complete__6205|JUNB|3726|Complete__6206|JUND|3727|Complete__<>AvaiableGeneRif=5<>BEST:6204|JUN|0.000551219090590182<>ScoreDetail__3796|FOS|0.000471461547043793__3797|FOSB|0.000441056650528258__6205|JUNB|0.000443975420090924__6204|JUN|0.000551219090590182__6206|JUND|0.000488816935939566__ 0 0 0 0 0 144573 15896810 189901 13925 7553 MYC MYC myc 28 0.3 DNA binding of numerous transcription factors including AP-1 fos jun myc erg-1 SAPK and NFkB 3 14 JUMiner_v2.2 1 0 0 2 7869 TotalCon:2<>7553|MYC|4609|Complete__7869|NOL3|8996|Complete__<>AvaiableGeneRif=2<>BEST:7869|NOL3|0.000550074040109986<>ScoreDetail__7553|MYC|0.000539740047168336__7869|NOL3|0.000550074040109986__ 0 0 0 0 0 144574 15896810 189901 12354 6886 MAPK9 SAPK SAPK 30 1.3 of numerous transcription factors including AP-1 fos jun myc erg-1 SAPK and NFkB 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144575 15896810 189901 14352 7794 NFKB1 NFKB NFkB 32 0.3 transcription factors including AP-1 fos jun myc erg-1 SAPK and NFkB 3 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144576 15896810 189905 9691 5232 HSPA1A HSP HSP 9 3.4 the central nervous system (CNS), CNS heat shock protein (HSP) HSP synthesis is induced not only after hyperthermia but also following 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144577 15896810 189906 9691 5232 HSPA1A HSP HSP 18 3.4 is harmful and can lead to cell death induction of HSP synthesis can result in stress tolerance and cytoprotection in a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144578 15896810 189908 1576 990 BCL2 Bcl-2 Bcl-2 23 1.0 as increased expression of heat shock proteins antioxidant enzymes and Bcl-2 may be triggered to withstand all the above mentioned pathogenic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144579 15896810 189911 7975 3951 FXN FRDA FRDA 20 4.3 may play an essential role in neurodegenerative diseases such as FRDA 9 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144580 15896810 189915 7975 3951 FXN FRDA FRDA 6 4.3 The precise sequence of events in FRDA pathogenesis is uncertain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144581 15896810 189917 7975 3951 FXN FRDA FRDA 33 4.3 addition that decreased expression of frataxin protein is associated with FRDA 11 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144582 15896810 189917 18723 10261 ROS1 ROS ROS 10 0.0 There is now evidence to suggest that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols 10 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144583 15896810 189919 7975 3951 FXN FRDA FRDA 35 4.3 the oxidative stress hypothesis which may underlie the pathogenesis of FRDA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144584 15896810 189924 7975 3951 FXN FRDA FRDA 0 4.3 FRDA is an autosomal recessive degenerative disorder characterized by progressive gait 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144585 15896810 189925 7975 3951 FXN FRDA FRDA 2 4.3 Neuropathology in FRDA is characterized by early degeneration of large sensory neurons in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144586 15896810 189926 7975 3951 FXN FRDA FRDA 7 4.3 Hypertrophic cardiomyopathy is present in large proportion FRDA patients 12 and 13 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144587 15896810 189927 7975 3951 FXN FRDA FRDA 4 4.3 The causative mutation of FRDA is an abnormally expanded GAA triplet repeat in the first 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144588 15896810 189927 8012 4065 GAA GAA GAA 9 0.3 The causative mutation of FRDA is an abnormally expanded GAA triplet repeat in the first intron of the FRDA gene 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144589 15896810 189927 7975 3951 FXN FRDA FRDA 18 4.3 expanded GAA triplet repeat in the first intron of the FRDA gene on chromosome 9q13 14 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144590 15896810 189928 7975 3951 FXN FRDA FRDA 3 4.3 Ninety-eight percent of FRDA patients are homozygous for the GAA expansion the remainder carrying 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144591 15896810 189928 8012 4065 GAA GAA GAA 9 0.3 Ninety-eight percent of FRDA patients are homozygous for the GAA expansion the remainder carrying a repeat expansion in one FRDA 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144592 15896810 189928 7975 3951 FXN FRDA FRDA 19 4.3 GAA expansion the remainder carrying a repeat expansion in one FRDA allele and a point mutation in the other 12 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144593 15896810 189929 8012 4065 GAA GAA GAA 4 0.3 The size of the GAA expansion in FRDA patients ranges from about 100 repeats to 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144594 15896810 189929 7975 3951 FXN FRDA FRDA 7 4.3 The size of the GAA expansion in FRDA patients ranges from about 100 repeats to 1700 12 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144595 15896810 189930 7975 3951 FXN FRDA FRDA 8 4.3 The expression of a number of symptoms/signs symptoms signs in FRDA is dependent upon the length of the GAA repeat expansion 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144596 15896810 189930 8012 4065 GAA GAA GAA 16 0.3 signs in FRDA is dependent upon the length of the GAA repeat expansion in the smaller allele 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144597 15896810 189931 8012 4065 GAA GAA GAA 24 0.3 of progression of the disease positively with the number of GAA repeats in the smaller allele 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144598 15896810 189932 8012 4065 GAA GAA GAA 13 0.3 severity of hypertrophic cardiomyopathy increases with the size of the GAA expansion in the smaller allele 12 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144599 15896810 189933 7975 3951 FXN FRDA FRDA 3 4.3 Mutations in the FRDA gene either GAA expansions or point mutations result in reduced 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144600 15896810 189933 8012 4065 GAA GAA GAA 6 0.3 Mutations in the FRDA gene either GAA expansions or point mutations result in reduced expression of a 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144601 15896810 189934 7975 3951 FXN FRDA FRDA 10 4.3 In normal subjects the highest level of expression of the FRDA gene has been found in the heart and spinal cord 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144602 15896810 189935 7975 3951 FXN FRDA FRDA 10 4.3 The amount of residual frataxin in lymphoblastoid cell lines from FRDA patients correlates with the GAA expansion size in the smaller 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144603 15896810 189935 8012 4065 GAA GAA GAA 15 0.3 in lymphoblastoid cell lines from FRDA patients correlates with the GAA expansion size in the smaller allele 16 and likely represents 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144604 15896810 189935 8012 4065 GAA GAA GAA 33 0.3 and likely represents the molecular basis of the relationship between GAA expansion size and phenotypic expression of the disease 12 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144605 15896810 189938 6981 22140 FAM20C RNS RNS 36 0.6 of reactive oxygen species (ROS), ROS reactive nitrogen species (RNS) RNS and mitochondrial dysfunction 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 144606 15896810 189938 18723 10261 ROS1 ROS ROS 32 0.0 sclerosis may involve the generation of reactive oxygen species (ROS), ROS reactive nitrogen species (RNS) RNS and mitochondrial dysfunction 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144607 15896810 189940 18723 10261 ROS1 ROS ROS 25 0.0 10-fold increase in iron within the mitochondria along with increased ROS production 17 and 20 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144608 15896810 189942 166 118 ACO2 aconitase aconitase 17 1.6 mitochondrial respiratory chain complexes I and II/III II III and aconitase activities have been demonstrated in post-mortem cardiac muscle samples from 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144609 15896810 189942 7975 3951 FXN FRDA FRDA 30 4.3 been demonstrated in post-mortem cardiac muscle samples from patients with FRDA associated with reduced levels of mitochondrial DNA and with increased 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144610 15896810 189944 18723 10261 ROS1 ROS ROS 7 0.0 Recent evidence suggests that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols 10 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144611 15896810 189945 18723 10261 ROS1 ROS ROS 28 0.0 thiols thereby reducing the incidence of malignant transformation induced by ROS as observed by soft agar assays and tumour formation in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144612 15896810 189946 20997 11180 SOD2 MnSOD MnSOD 6 1.9 Up-regulation of protein manganese superoxide dismutase (MnSOD) MnSOD fails to occur in FRDA fibroblasts exposed to iron 25 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144613 15896810 189946 7975 3951 FXN FRDA FRDA 11 4.3 protein manganese superoxide dismutase (MnSOD) MnSOD fails to occur in FRDA fibroblasts exposed to iron 25 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144614 15896810 189947 14352 7794 NFKB1 NFKB NFkB 13 0.3 with the observation of absent activation of the redox-sensitive factor NFkB suggest that a NFkB-independent pathway that may not require free 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144615 15896810 189947 14352 7794 NFKB1 NFKB NFkB-independent 17 0.3 absent activation of the redox-sensitive factor NFkB suggest that a NFkB-independent pathway that may not require free radical signaling is responsible 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144616 15896810 189947 20997 11180 SOD2 MnSOD MnSOD 33 1.9 free radical signaling is responsible for the reduced induction of MnSOD 26 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144617 15896810 189954 8012 4065 GAA GAA GAA 15 0.3 of wild type frataxin levels by virtue of a (GAA) GAA 230 expansion inserted in the first intron of the mouse 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144618 15896810 189955 7975 3951 FXN FRDA FRDA 9 4.3 Cardiac and skeletal muscle bioenergetics was investigated directly in FRDA patients using in vivo 31 P-MRS 41 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144619 15896810 189959 24185 29175 WDTC1 ADP ADP 3 0.0 Free (metabolically metabolically active ADP the major regulator of the oxidative phosphorylation can be calculated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144620 15896810 189960 7975 3951 FXN FRDA FRDA 7 4.3 Cardiac bioenergetics was assessed in vivo in FRDA patients with and without left ventricular hypertrophy 43 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144621 15896810 189961 7975 3951 FXN FRDA FRDA 7 4.3 Cardiac PCr to ATP ratios in the FRDA group as a whole were reduced by about 40% 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144622 15896810 189962 7975 3951 FXN FRDA FRDA 13 4.3 were significantly reduced compared to controls in both groups of FRDA patients with normal and hypertrophic heart 43 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144623 15896810 189964 7975 3951 FXN FRDA FRDA 1 4.3 In FRDA the hypertrophic process may be compensatory and caused or contributed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144624 15896810 189966 7975 3951 FXN FRDA FRDA 19 4.3 have shown a reduced rate of mitochondrial ATP synthesis in FRDA patients 46 and 47 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144625 15896810 189968 7975 3951 FXN FRDA FRDA 7 4.3 Mitochondrial V max for ATP production in FRDA patients was also significantly lower than in a group of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144626 15896810 189968 7975 3951 FXN FRDA FRDA 48 4.3 se did not account for the reduced mitochondrial function in FRDA patients 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144627 15896810 189969 8012 4065 GAA GAA GAA 23 0.3 synthesis rate was strongly dependent on the size of the GAA repeats in the smaller allele the higher the number of 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144628 15896810 189969 8012 4065 GAA GAA GAA 34 0.3 repeats in the smaller allele the higher the number of GAA repeats the lower the mitochondrial ATP synthesis rate 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144629 15896810 189970 8012 4065 GAA GAA GAA 6 0.3 This is compelling evidence that the GAA expansion is the cause of the mitochondrial deficit and suggests 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144630 15896810 189971 8012 4065 GAA GAA GAA 4 0.3 The length of the GAA expansion has been shown to determine the amount of frataxin 3 JUMiner_v2.2 1 2 gaa triplet 0 0 0 0 0 0 0 0 144631 15896810 189973 7975 3951 FXN FRDA FRDA 26 4.3 utilization of oxygen in response to exercise showed in several FRDA patients features related to inadequate oxygen utilization by muscle 48 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144632 15896810 190043 8306 4268 GIF INF INF-_amp_#x3b3 1 0.0 Cytokines (INF-_amp_#x3b3;) INF-_amp_#x3b3 which are present in normal brain are elevated in numerous 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144633 15896810 190044 14533 7872 NOS1 NOS NOS 7 2.7 Accordingly as cytokines promote the induction of NOS in brain a possible role for a glial-derived NO_amp_#xb7 in 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.00100561390883972<>ScoreDetail__7873|NOS2A|0.000992779045329277__7872|NOS1|0.00100561390883972__ 0 0 0 0 0 144634 15896810 190045 14533 7872 NOS1 NOS NOS 21 2.7 study in which NADPH diaphorase (a a cytochemical marker of NOS activity positive glial cells have been identified in the substantia 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.00100561390883972<>ScoreDetail__7873|NOS2A|0.000992779045329277__7872|NOS1|0.00100561390883972__ 0 0 0 0 0 144635 15896810 190048 14533 7872 NOS1 nNOS nNOS 14 2.7 this it has been reported that the selective inhibition of nNOS prevents 1-methyl-4-phenyl-1 2 3 6-tetrahydropyridine (MPTP)-induced MPTP -induced Parkinsonism in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144636 15896810 190050 14533 7872 NOS1 NOS NOS 2 2.7 Role of NOS and NO in brain pathophysiology 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.00100561390883972<>ScoreDetail__7873|NOS2A|0.000992779045329277__7872|NOS1|0.00100561390883972__ 0 0 0 0 0 144637 15896810 190054 14533 7872 NOS1 NOS NOS 11 2.7 responsible for NO synthesis is the nitric oxide synthase (NOS) NOS family of enzymes which catalyse the conversion of arginine to 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.00100561390883972<>ScoreDetail__7873|NOS2A|0.000992779045329277__7872|NOS1|0.00100561390883972__ 0 0 0 0 0 144638 15896810 190055 14533 7872 NOS1 NOS NOS 0 2.7 NOS localized in the CNS and in the periphery 91 is 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.00100561390883972<>ScoreDetail__7873|NOS2A|0.000992779045329277__7872|NOS1|0.00100561390883972__ 0 0 0 0 0 144639 15896810 190055 14533 7872 NOS1 NOS NOS 20 2.7 is present in three well characterized isoforms (a) a neuronal NOS (nNOS, nNOS type I (b) b endothelial NOS (eNOS; eNOS 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.00100561390883972<>ScoreDetail__7873|NOS2A|0.000992779045329277__7872|NOS1|0.00100561390883972__ 0 0 0 0 0 144640 15896810 190055 14533 7872 NOS1 nNOS nNOS 21 2.7 in three well characterized isoforms (a) a neuronal NOS (nNOS, nNOS type I (b) b endothelial NOS (eNOS; eNOS type III 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144641 15896810 190055 14533 7872 NOS1 NOS NOS 26 2.7 a neuronal NOS (nNOS, nNOS type I (b) b endothelial NOS (eNOS; eNOS type III and (c) c inducible NOS (iNOS, 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.00100561390883972<>ScoreDetail__7873|NOS2A|0.000992779045329277__7872|NOS1|0.00100561390883972__ 0 0 0 0 0 144642 15896810 190055 14538 7876 NOS3 eNOS eNOS 27 2.2 NOS (nNOS, nNOS type I (b) b endothelial NOS (eNOS; eNOS type III and (c) c inducible NOS (iNOS, iNOS type 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144643 15896810 190055 14533 7872 NOS1 NOS NOS 33 2.7 endothelial NOS (eNOS; eNOS type III and (c) c inducible NOS (iNOS, iNOS type II 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.00100561390883972<>ScoreDetail__7873|NOS2A|0.000992779045329277__7872|NOS1|0.00100561390883972__ 0 0 0 0 0 144644 15896810 190055 14535 7873 NOS2A iNOS iNOS 34 2.7 (eNOS; eNOS type III and (c) c inducible NOS (iNOS, iNOS type II 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144645 15896810 190056 14533 7872 NOS1 NOS NOS 5 2.7 Activation of different isoforms of NOS requires various factors and co-factors 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.00100561390883972<>ScoreDetail__7873|NOS2A|0.000992779045329277__7872|NOS1|0.00100561390883972__ 0 0 0 0 0 144646 15896810 190057 14533 7872 NOS1 NOS NOS 13 2.7 complexes is a prerequisite before the functional active dimer exhibits NOS activity which depends also on cofactors such as tetrahydrobiopterin (BH 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.00100561390883972<>ScoreDetail__7873|NOS2A|0.000992779045329277__7872|NOS1|0.00100561390883972__ 0 0 0 0 0 144647 15896810 190057 17461 9508 PSEN1 FAD FAD 26 0.3 depends also on cofactors such as tetrahydrobiopterin (BH BH 4 FAD FMN and NADPH 92 1 JUMiner_v2.2 1 2 nadph 0 2 3585 TotalCon:3<>1101|BRCA2|675|Complete__3585|FANCD2|2177|Complete__9508|PSEN1|5663|Complete__<>AvaiableGeneRif=3<>BEST:3585|FANCD2|0.00060856279987548<>ScoreDetail__1101|BRCA2|0.000299281490752651__9508|PSEN1|0.000575250281324742__3585|FANCD2|0.00060856279987548__ 0 0 0 0 0 144648 15896810 190057 7638 3768 FMN1 FMN FMN 27 0.2 also on cofactors such as tetrahydrobiopterin (BH BH 4 FAD FMN and NADPH 92 5 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144649 15896810 190058 14533 7872 NOS1 nNOS nNOS 3 2.7 In contrast to nNOS and eNOS iNOS can bind to calmodulin even at very 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144650 15896810 190058 14538 7876 NOS3 eNOS eNOS 5 2.2 In contrast to nNOS and eNOS iNOS can bind to calmodulin even at very low concentration 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144651 15896810 190058 14535 7873 NOS2A iNOS iNOS 6 2.7 In contrast to nNOS and eNOS iNOS can bind to calmodulin even at very low concentration of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144652 15896810 190058 14535 7873 NOS2A iNOS iNOS 20 2.7 calmodulin even at very low concentration of intracellular calcium thus iNOS can exert its activity in a calcium-independent manner 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144653 15896810 190059 14535 7873 NOS2A iNOS iNOS 3 2.7 The levels of iNOS in the CNS are generally fairly low 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144654 15896810 190060 14535 7873 NOS2A iNOS iNOS 5 2.7 However an increased expression of iNOS in astrocytes and microglia occurs following viral infection and trauma 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144655 15896810 190061 14535 7873 NOS2A iNOS iNOS 2 2.7 Activation of iNOS requires gene transcription and the induction can be influenced by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144656 15896810 190062 16440 8884 PGA PGA PGA 14 0.3 drugs (dexamethasone), dexamethasone inhibitory cytokines (interleukin-4, interleukin-4 interleukin-10 prostaglandins (PGA PGA 2 tissue growth factors or inhibitors of protein synthesis e.g. 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 144657 15896810 190066 20996 11179 SOD1 SOD SOD 15 1.4 three times faster than the rate of superoxide dismutase (SOD) SOD in catalyzing the dismutation of the superoxide anion to hydrogen 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144658 15896810 190067 20996 11179 SOD1 SOD SOD 10 1.4 Therefore when present at appropriate concentrations NO effectively competes with SOD for O 2 _amp_#x2212 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144659 15896810 190074 8118 4141 GAPDH GAPDH GAPDH 12 1.6 demonstrated to stimulate the auto-ADP ribosylation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) GAPDH by reacting with a critical cysteine with resulting binding of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144660 15896810 190074 8118 4141 GAPDH GAPDH GAPDH 30 1.6 resulting binding of NAD to the catalytic cysteine inhibition of GAPDH activity and depression of glycolysis 104 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144661 15896810 190078 9038 4827 HBB hemoglobin hemoglobin 11 1.0 Other heme protein targets for NO are catalase cytochrome c hemoglobin and peroxidase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144662 15896810 190079 166 118 ACO2 aconitase aconitase 18 1.6 sulfur cluster present in numerous enzymes including NADH-ubiquinone oxidoreductase cis -aconitase and NADH succinate oxidoreductase 108 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144663 15896810 190082 166 118 ACO2 aconitase aconitase 14 1.6 iron metabolism at the post-transcriptional level by interacting with cytosolic aconitase which after binding NO functions as iron responsive binding protein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144664 15896810 190082 166 118 ACO2 aconitase aconitase 27 1.6 binding NO functions as iron responsive binding protein diminishing its aconitase activity 109 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144665 15896810 190104 926 620 APP amyloid amyloid 5 1.0 Accordingly the recent finding that _amp_#x3b2 -amyloid fragment 25_amp_#x2013 35 selectively decreases complex IV activity in isolated 11 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 144666 15896810 190111 18723 10261 ROS1 ROS ROS 9 0.0 Glutathione is the predominant defense against reactive oxygen species (ROS), ROS which are reduced by GSH in the presence of GSH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144667 15896810 190118 18723 10261 ROS1 ROS ROS 5 0.0 In addition to protection against ROS glutathione is an excellent scavenger of lipid peroxidation products such 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144668 15896810 190118 6554 3309 ELA2 HNE HNE 17 0.0 is an excellent scavenger of lipid peroxidation products such as HNE and acrolein both of which have been found to bind 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144669 15896810 190126 6554 3309 ELA2 HNE HNE 30 0.0 peroxynitrite and reactive aldehydic products of lipid peroxidation 4-hydroxy-2-nonenal (HNE) HNE or 2-propenal (acrolein) acrolein 119 120 121 122 and 123 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144670 15896810 190127 6554 3309 ELA2 HNE HNE 0 0.0 HNE and acrolein are increased in AD brain 124 and 125 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144671 15896810 190127 6554 3309 ELA2 HNE HNE 13 0.0 acrolein are increased in AD brain 124 and 125 and HNE is covalently bound in excess to the glutamate transporter in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144672 15896810 190130 7975 3951 FXN FRDA FRDA 39 4.3 glutathione bound to haemoglobin in erythrocytes have been demonstrated in FRDA patients 128 also associated with a significant elevation in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144673 15896810 190136 9691 5232 HSPA1A HSP HSP 3 3.4 In mammalian cells HSP synthesis is induced not only after hyperthermia but also following 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144674 15896810 190137 9691 5232 HSPA1A HSP HSP 18 3.4 is harmful and can lead to cell death induction of HSP synthesis can result in stress tolerance and cytoprotection against stress-induced 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144675 15896810 190142 9691 5232 HSPA1A HSP HSPs 4 3.7 Some of the known HSPs include ubiquitin HSP10 HSP27 HSP32 (or or HO-1 HSP47 HSP60 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144676 15896810 190142 9726 5269 HSPE1 HSP10 HSP10 7 1.9 Some of the known HSPs include ubiquitin HSP10 HSP27 HSP32 (or or HO-1 HSP47 HSP60 HSC70 HSP70 (or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144677 15896810 190142 9708 5247 HSPB2 HSP27 HSP27 8 1.9 Some of the known HSPs include ubiquitin HSP10 HSP27 HSP32 (or or HO-1 HSP47 HSP60 HSC70 HSP70 (or or 1 JUMiner_v2.2 1 0 0 2 5246 TotalCon:2<>5246|HSPB1|3315|Complete__5247|HSPB2|3316|Complete__<>AvaiableGeneRif=2<>BEST:5246|HSPB1|0.000727030772142085<>ScoreDetail__5246|HSPB1|0.000727030772142085__5247|HSPB2|0.000567495945077214__ 0 0 0 0 0 144678 15896810 190142 9462 5013 HMOX1 HO-1 HO-1 11 2.9 the known HSPs include ubiquitin HSP10 HSP27 HSP32 (or or HO-1 HSP47 HSP60 HSC70 HSP70 (or or HSP72 HSP90 and HSP100/105 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144679 15896810 190142 19730 1546 SERPINH1 HSP47 HSP47 12 1.3 known HSPs include ubiquitin HSP10 HSP27 HSP32 (or or HO-1 HSP47 HSP60 HSC70 HSP70 (or or HSP72 HSP90 and HSP100/105 HSP100 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144680 15896810 190142 9718 5261 HSPD1 HSP60 HSP60 13 1.9 HSPs include ubiquitin HSP10 HSP27 HSP32 (or or HO-1 HSP47 HSP60 HSC70 HSP70 (or or HSP72 HSP90 and HSP100/105 HSP100 105 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144681 15896810 190142 9700 5241 HSPA8 HSC70 HSC70 14 1.9 include ubiquitin HSP10 HSP27 HSP32 (or or HO-1 HSP47 HSP60 HSC70 HSP70 (or or HSP72 HSP90 and HSP100/105 HSP100 105 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144682 15896810 190142 9691 5232 HSPA1A HSP70 HSP70 15 5.5 ubiquitin HSP10 HSP27 HSP32 (or or HO-1 HSP47 HSP60 HSC70 HSP70 (or or HSP72 HSP90 and HSP100/105 HSP100 105 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144683 15896810 190142 9691 5232 HSPA1A HSP72 HSP72 17 3.4 HSP32 (or or HO-1 HSP47 HSP60 HSC70 HSP70 (or or HSP72 HSP90 and HSP100/105 HSP100 105 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144684 15896810 190144 9691 5232 HSPA1A HSP70 HSP70 0 5.5 HSP70 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144685 15896810 190146 9700 5241 HSPA8 HSC70 HSC70 5 1.9 Included in this family are HSC70 (heat heat shock cognate the constitutive form HSP70 (the the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144686 15896810 190146 9691 5232 HSPA1A HSP70 HSP70 12 5.5 family are HSC70 (heat heat shock cognate the constitutive form HSP70 (the the inducible form also referred to as HSP72 GRP75 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144687 15896810 190146 9691 5232 HSPA1A HSP72 HSP72 20 3.4 form HSP70 (the the inducible form also referred to as HSP72 GRP75 (a a constitutively expressed glucose-regulated protein found in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144688 15896810 190146 9701 5244 HSPA9 GRP75 GRP75 21 2.2 HSP70 (the the inducible form also referred to as HSP72 GRP75 (a a constitutively expressed glucose-regulated protein found in the endoplasmic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144689 15896810 190147 9691 5232 HSPA1A HSP70 HSP70 9 5.5 After a variety of central nervous system (CNS) CNS insults HSP70 is synthesized at high levels and is present in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144690 15896810 190149 10463 6018 IL6 HSF HSFs 7 0.6 These denaturated proteins activate heat shock factors (HSFs) HSFs within the cytosol by dissociating other HSPs that are normally 13 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 144691 15896810 190149 9691 5232 HSPA1A HSP HSPs 14 3.7 shock factors (HSFs) HSFs within the cytosol by dissociating other HSPs that are normally bound to HSF 132 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144692 15896810 190149 10463 6018 IL6 HSF HSF 20 0.6 cytosol by dissociating other HSPs that are normally bound to HSF 132 13 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 144693 15896810 190150 10463 6018 IL6 HSF HSF 1 0.6 Freed HSF is phosphorylated and forms trimers which enter the nucleus and 13 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 144694 15896810 190150 9652 23316 HSD17B6 HSE HSE 17 0.3 enter the nucleus and bind to heat shock elements (HSE) HSE within the promoters of different heat shock genes leading to 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 144695 15896810 190150 9691 5232 HSPA1A HSP HSPs 32 3.7 different heat shock genes leading to transcription and synthesis of HSPs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144696 15896810 190151 9691 5232 HSPA1A HSP70 HSP70 8 5.5 After heat shock for instance the synthesis of HSP70 increases to a point to where it becomes the most 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144697 15896810 190152 9691 5232 HSPA1A HSP70 HSP70 2 5.5 Once synthesized HSP70 binds to denaturated proteins in an ATP-dependent manner 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144698 15896810 190155 9691 5232 HSPA1A HSP HSPs 4 3.7 In the nervous system HSPs are induced in a variety of pathological conditions including cerebral 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144699 15896810 190156 9691 5232 HSPA1A HSP HSPs 5 3.7 Expression of the gene encoding HSPs has been found in various cell populations within the nervous 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144700 15896810 190157 9691 5232 HSPA1A HSP HSPs 0 3.7 HSPs consist of both stress-inducible and constitutive family members 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144701 15896810 190159 9691 5232 HSPA1A HSP70 HSP70 20 5.5 gene transfer has become possible to overexpress the gene encoding HSP70 to test directly the hypothesis that stress proteins protects cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144702 15896810 190159 9691 5232 HSPA1A HSP70 HSP70 41 5.5 from injury and it has been demonstrated that overproduction of HSP70 leads to protection in several different models of nervous system 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144703 15896810 190160 9691 5232 HSPA1A HSP70 HSP70 6 5.5 Following focal cerebral ischemia mRNA encoding HSP70 is synthesized in most ischemic cells except in areas of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144704 15896810 190161 9691 5232 HSPA1A HSP70 HSP70 0 5.5 HSP70 proteins is produced mainly in endothelial cells in the core 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144705 15896810 190162 9691 5232 HSPA1A HSP70 HSP70 9 5.5 It has been suggested that this neuronal expression of HSP70 outside an infarct can be used to define the ischemic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144706 15896810 190163 9691 5232 HSPA1A HSP HSP 12 3.4 of in vitro studies show that both heat shock and HSP overproduction protect CNS cells against both necrosis and apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144707 15896810 190165 9691 5232 HSPA1A HSP70 HSP70 5 5.5 Transfection of cultured astrocytes with HSP70 protects them from ischemia or glucose deprivation 140 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144708 15896810 190166 9691 5232 HSPA1A HSP70 HSP70 0 5.5 HSP70 has been demonstrated to inhibit caspase-3 activation caused by ceramide 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144709 15896810 190166 10824 6204 JUN JUN JUN 14 1.8 to inhibit caspase-3 activation caused by ceramide and also affect JUN kinase and p38-kinase activation 141 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144710 15896810 190166 12359 6876 MAPK14 p38 p38-kinase 17 0.3 activation caused by ceramide and also affect JUN kinase and p38-kinase activation 141 11 JUMiner_v2.2 1 0 0 2 6878 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6878|MAPK4|0.000678050449441697<>ScoreDetail__1189|AHSA1|0.000428187822048044__6878|MAPK4|0.000678050449441697__6871|MAPK1|0.000563140228061107__6876|MAPK14|0.000537517353429365__ 0 0 0 0 0 144711 15896810 190167 9691 5232 HSPA1A HSP70 HSP70 2 5.5 In addition HSP70 binds to and modulates the function of BAG-1 the bcl-2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144712 15896810 190167 1495 937 BAG1 BAG1 BAG-1 10 0.0 In addition HSP70 binds to and modulates the function of BAG-1 the bcl-2 binding protein 142 thus modulating some type of 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144713 15896810 190168 9691 5232 HSPA1A HSP HSP 17 3.4 between mechanisms of oxidative and/or and or nitrosative stress and HSP induction 143 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144714 15896810 190169 14352 7794 NFKB1 NFKB NFkB 19 0.3 shock response can exert its protective effects through inhibition of NFkB signaling pathway 132 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144715 15896810 190170 9691 5232 HSPA1A HSP70 Hsp70 18 5.5 cytokine-induced nitrosative stress is associated with an increased synthesis of Hsp70 stress proteins 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144716 15896810 190171 9691 5232 HSPA1A HSP70 Hsp70 2 5.5 Increase in Hsp70 protein expression was also found after treatment of cells with 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144717 15896810 190171 9691 5232 HSPA1A hsp70 hsp70 28 5.5 (SNP), SNP thus suggesting a role for NO in inducing hsp70 proteins 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144718 15896810 190173 9691 5232 HSPA1A HSP HSPs 6 3.7 Ubiquitin is one of the smallest HSPs and is expressed throughout brain in response to ischemia 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144719 15896810 190174 14352 7794 NFKB1 NFKB NFKB 14 0.3 targeting and chaperoning of proteins degraded in proteasomes which include NFKB cyclins HSFs hypoxia-inducible factor some apoptosis-related proteins tumor necrosis factor 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144720 15896810 190174 10463 6018 IL6 HSF HSFs 16 0.6 chaperoning of proteins degraded in proteasomes which include NFKB cyclins HSFs hypoxia-inducible factor some apoptosis-related proteins tumor necrosis factor and erythropoietin 13 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 144721 15896810 190175 9708 5247 HSPB2 HSP27 HSP27 0 1.9 HSP27 is synthesized mainly in astrocytes in response to ischemic situations 1 JUMiner_v2.2 1 0 0 2 5246 TotalCon:2<>5246|HSPB1|3315|Complete__5247|HSPB2|3316|Complete__<>AvaiableGeneRif=2<>BEST:5246|HSPB1|0.000727030772142085<>ScoreDetail__5246|HSPB1|0.000727030772142085__5247|HSPB2|0.000567495945077214__ 0 0 0 0 0 144722 15896810 190177 22551 11892 TNF TNF TNF 6 1.2 It also protects against Fas-Apo-1 staurosporine TNF and etoposside-induced apoptotic cell death as well as H 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144723 15896810 190178 19730 1546 SERPINH1 HSP47 HSP47 0 1.3 HSP47 is synthesized mainly in microglia following cerebral ischemia and subarachnoid 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144724 15896810 190179 9718 5261 HSPD1 HSP60 HSP60 0 1.9 HSP60 glucose-regulated protein 75 (GRP75) GRP75 and HSP10 chaperone proteins within 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144725 15896810 190179 9701 5244 HSPA9 GRP75 GRP75 4 2.2 HSP60 glucose-regulated protein 75 (GRP75) GRP75 and HSP10 chaperone proteins within mitochondria 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144726 15896810 190179 9726 5269 HSPE1 HSP10 HSP10 6 1.9 HSP60 glucose-regulated protein 75 (GRP75) GRP75 and HSP10 chaperone proteins within mitochondria 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144727 15896810 190180 9701 5244 HSPA9 GRP75 GRP75 0 2.2 GRP75 and GRP78 also called oxygen-regulated proteins (ORPs) ORPs are produced 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144728 15896810 190180 9697 5238 HSPA5 GRP78 GRP78 0 1.9 GRP75 and GRP78 also called oxygen-regulated proteins (ORPs) ORPs are produced 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144729 15896810 190180 9697 5238 HSPA5 GRP78 GRP78 2 1.9 GRP75 and GRP78 also called oxygen-regulated proteins (ORPs) ORPs are produced by low 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144730 15896810 190183 9462 5013 HMOX1 HO-1 HO-1 7 2.9 There are three isoforms of heme oxygenase HO-1 or inducible isoform HO-2 or constitutive isoform and the recently 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144731 15896810 190183 9463 5014 HMOX2 HO-2 HO-2 11 1.9 are three isoforms of heme oxygenase HO-1 or inducible isoform HO-2 or constitutive isoform and the recently discovered HO-3 149 150 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144732 15896810 190183 9027 4817 HARS2 HO3 HO-3 19 0.3 inducible isoform HO-2 or constitutive isoform and the recently discovered HO-3 149 150 151 152 153 and 154 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144733 15896810 190187 9462 5013 HMOX1 HO-1 HO-1 4 2.9 The iron released by HO-1 is bound by ferritin perhaps via a HO-1 chaperone function 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144734 15896810 190187 9462 5013 HMOX1 HO-1 HO-1 12 2.9 released by HO-1 is bound by ferritin perhaps via a HO-1 chaperone function 155 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144735 15896810 190189 9462 5013 HMOX1 HO-1 HO-1 5 2.9 Increasing evidence suggests that the HO-1 gene is redox regulated and contains in its promoter region 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144736 15896810 190190 926 620 APP amyloid amyloid 13 1.0 of heat shock proteins is closely related to that of amyloid precursor protein (APP), APP heat-shock proteins have been studied in 11 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 144737 15896810 190190 926 620 APP APP APP 16 0.3 is closely related to that of amyloid precursor protein (APP), APP heat-shock proteins have been studied in brains of patients with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144738 15896810 190191 9462 5013 HMOX1 HO-1 HO-1 6 2.9 Significant increases in the levels of HO-1 have been observed in AD brains in association with neurofibrillary 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144739 15896810 190191 9462 5013 HMOX1 HO-1 HO-1 21 2.9 in AD brains in association with neurofibrillary tangles 157 and HO-1 mRNA was found to be increased in AD neocortex and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144740 15896810 190192 9462 5013 HMOX1 HO-1 HO-1 0 2.9 HO-1 increase was not only in association with neurofibrillary tangles but 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144741 15896810 190193 9462 5013 HMOX1 HO-1 HO-1 8 2.9 It is conceivable that the dramatic increase in HO-1 in AD may be a direct response to increased free 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144742 15896810 190203 14352 7794 NFKB1 NFKB NFkB 15 0.3 cell line it has recently been shown that curcumin inhibits NFkB activation effectively preventing neuronal cell death 159 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144743 15896810 190204 9462 5013 HMOX1 HO-1 HO-1 12 2.9 evidence has demonstrated that curcumin is a potent inducer of HO-1 in vascular endothelial cells 7 and 167 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144744 15896810 190205 20455 14011 SMC2 CAPE CAPE 15 1.3 astroglial cells the role of caffeic acid phenylethyl ester (CAPE), CAPE an active component of propolis as a novel HO-1 inducer 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 144745 15896810 190205 9462 5013 HMOX1 HO-1 HO-1 24 2.9 (CAPE), CAPE an active component of propolis as a novel HO-1 inducer 162 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144746 15896810 190206 20455 14011 SMC2 CAPE CAPE 3 1.3 The similarity of CAPE to curcumin is striking because CAPE is also a Michael 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 144747 15896810 190206 20455 14011 SMC2 CAPE CAPE 9 1.3 The similarity of CAPE to curcumin is striking because CAPE is also a Michael reaction acceptor endowed with anti-inflammatory antioxidant 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 144748 15896810 190211 7975 3951 FXN FRDA FRDA 3 4.3 Therapy advances in FRDA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144749 15896810 190212 7975 3951 FXN FRDA FRDA 6 4.3 The precise sequence of events in FRDA pathogenesis is uncertain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144750 15896810 190215 7975 3951 FXN FRDA FRDA 0 4.3 FRDA offers a unique opportunity to intervene with _amp_#x201c neuroprotective_amp_#x201d therapy 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144751 15896810 190216 7975 3951 FXN FRDA FRDA 33 4.3 in the presence of advanced disease and established pathogenetic mechanisms FRDA patients can be diagnosed by genetic analysis either presymptomatically or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144752 15896810 190217 7975 3951 FXN FRDA FRDA 12 4.3 free radical production and deficit of oxidative phosphorylation shown in FRDA suggests that the mitochondrial respiration deficit may be amenable to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144753 15896810 190218 7975 3951 FXN FRDA FRDA 1 4.3 Three FRDA patients were treated for 4 to 9 months with idebenone 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144754 15896810 190220 7975 3951 FXN FRDA FRDA 27 4.3 equal or more than 20% in 17 out of 38 FRDA patients 173 and by two more recent idebenone trials 174 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144755 15896810 190221 7975 3951 FXN FRDA FRDA 13 4.3 daily also resulted in decreased markers of oxidative stress in FRDA patients 176 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144756 15896810 190222 7975 3951 FXN FRDA FRDA 37 4.3 hypertrophy (LVH) LVH and ataxia has been evaluated in ten FRDA patients 177 After 6 months of therapy cardiac PCr to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144757 15896810 190225 7975 3951 FXN FRDA FRDA 0 4.3 FRDA patients assessed neurologically using the semi-quantitative International Cooperative Ataxia Rating 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144758 15896810 190227 4772 26515 COQ10A Q10 Q10 14 1.2 the efficacy of mitochondria-targeted and untargeted antioxidants derived from coenzyme Q10 and from vitamin E at preventing cell death due to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144759 15896810 190227 7975 3951 FXN FRDA FRDA 36 4.3 oxidative stress has been recently investigated in cultured fibroblasts from FRDA patients in which glutathione synthesis have been blocked 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144760 15896810 190231 7975 3951 FXN FRDA FRDA 7 4.3 Targeted antioxidants may have therapeutic potential in FRDA and in other disorders involving mitochondrial oxidative damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144761 15896810 190237 7975 3951 FXN FRDA FRDA 6 4.3 Given the physiopathological mechanisms responsible for FRDA selenium administration could represent another therapy strategy 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144762 15896810 190244 7975 3951 FXN FRDA FRDA 33 4.3 address the toxicity of GPX mimetics in humans before human FRDA trials can be considered 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144763 15896810 190246 7975 3951 FXN FRDA FRDA 18 4.3 screening of compounds that have potential in the treatment of FRDA 183 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144764 15896810 190249 7975 3951 FXN FRDA FRDA 8 4.3 Since the discovery of the genetic basis of FRDA only few years ago the progress made in our understanding 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144765 15896810 190249 7975 3951 FXN FRDA FRDA 24 4.3 progress made in our understanding of the pathogenic mechanisms underlying FRDA has been remarkable 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144766 15896810 190250 7975 3951 FXN FRDA FRDA 11 4.3 the precise function of frataxin still remains to be defined FRDA has clearly been identified as a nuclear encoded mitochondrial disorder 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 144767 15896810 190251 7975 3951 FXN FRDA FRDA 39 4.3 randomised trials which will confirm whether an early diagnosis of FRDA can be exploited to initiate antioxidant treatment and prevent the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 147176 15964487 194014 20996 11179 SOD1 ALS ALS 12 1.4 AD Parkinson (PD) PD diseases and amyotrophic lateral sclerosis (ALS), ALS are one of the main causes of death in Western 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000456571993222906<>ScoreDetail__5468|IGFALS|0.000248253897132062__11179|SOD1|0.000456571993222906__ 0 0 0 0 0 147177 15964487 194016 7333 11920 FAS FAS Fas-ligand 24 0.3 pathways initiated by several apoptotic stimuli including receptor activation by Fas-ligand ( Kavurma and Khachigian 2003 or glutamate ( Stout et 11 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000396558866669676<>ScoreDetail__11920|FAS|0.000396558866669676__3594|FASN|0.000367853204232248__ 0 0 0 0 0 147178 15964487 194017 17686 9683 PTPRU PTP PTP 6 0.3 Opening of a permeability transition pore (PTP) PTP leads to mitochondrial swelling and the release of intramitochondrial proteins 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9951 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9951|REG1A|0.000357540123947243<>ScoreDetail__9951|REG1A|0.000357540123947243__9683|PTPRU|0.000257334019557386__ 0 0 0 0 0 147179 15964487 194018 17686 9683 PTPRU PTP PTP 7 0.3 Indeed drugs with the ability to block PTP formation are cytoprotective against a variety of toxic stimuli ( 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9951 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9951|REG1A|0.000357540123947243<>ScoreDetail__9951|REG1A|0.000357540123947243__9683|PTPRU|0.000257334019557386__ 0 0 0 0 0 147180 15964487 194019 17686 9683 PTPRU PTP PTP 21 0.3 membrane potential (_amp_#x394;_amp_#x3c8;m), _amp_#x394 _amp_#x3c8 m the opening of the PTP and the release of proapoptotic factors ( Kristal and Dubinsky 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9951 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9951|REG1A|0.000357540123947243<>ScoreDetail__9951|REG1A|0.000357540123947243__9683|PTPRU|0.000257334019557386__ 0 0 0 0 0 147181 15964487 194023 20996 11179 SOD1 SOD1 SOD1 10 1.4 its administration in mice expressing a mutant superoxide dismutase (SOD1(G37R)) SOD1 G37R at late presymptomatic stage delayed the onset of motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 147182 15964487 194023 20996 11179 SOD1 SOD1 SOD1 31 1.4 and muscle strength decline and increased the longevity of SOD1(G37R) SOD1 G37R mice ( Kriz et al. 2002 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 147183 15964487 194028 14535 7873 NOS2A iNOS iNOS 24 2.2 expression of cycloxygenase-2 caspase-1 and inducible nitric oxide synthase (iNOS) iNOS mRNA have been described ( Chen et al. 2000 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 147184 15964487 194059 17686 9683 PTPRU PTP PTP 0 0.3 PTP activity 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9951 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9951|REG1A|0.000357540123947243<>ScoreDetail__9951|REG1A|0.000357540123947243__9683|PTPRU|0.000257334019557386__ 0 0 0 0 0 147185 15964487 194060 17686 9683 PTPRU PTP PTP 0 0.3 PTP opening was assayed spectrophotometrically as previously described ( Kristal et 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9951 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9951|REG1A|0.000357540123947243<>ScoreDetail__9951|REG1A|0.000357540123947243__9683|PTPRU|0.000257334019557386__ 0 0 0 0 0 147186 15964487 194062 17686 9683 PTPRU PTP PTP 13 0.3 at 540nm (A A 540 indicating mitochondrial swelling due to PTP opening were followed after addition of different compounds using a 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9951 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9951|REG1A|0.000357540123947243<>ScoreDetail__9951|REG1A|0.000357540123947243__9683|PTPRU|0.000257334019557386__ 0 0 0 0 0 147187 15964487 194090 8255 4236 GFER HPO HPO 17 0.0 were resuspended in media containing 125mM KCl 2mM K 2 HPO 4 1mM MgCl 2 20mM HEPES 5_amp_#x3bc M EGTA 1_amp_#x3bc 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 147188 15964487 194103 17686 9683 PTPRU PTP PTP 13 0.3 in cellular death programs associated to some pathological situations is PTP formation ( Hirsch et al. 1998 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9951 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9951|REG1A|0.000357540123947243<>ScoreDetail__9951|REG1A|0.000357540123947243__9683|PTPRU|0.000257334019557386__ 0 0 0 0 0 147189 15964487 194104 20247 20116 SLC25A29 CACL CaCl 19 1.3 swelling by following 540nm absorbance (A A 540 decrease using CaCl 2 and KO 2 as inductors 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 147190 15964487 194119 17686 9683 PTPRU PTP PTP 17 0.3 of cytoplasmic free Ca 2 levels ( Skulachev 1999 and PTP is triggered by intramitochondrial Ca 2 accumulation we were interested 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9951 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9951|REG1A|0.000357540123947243<>ScoreDetail__9951|REG1A|0.000357540123947243__9683|PTPRU|0.000257334019557386__ 0 0 0 0 0 147191 15964487 194120 20247 20116 SLC25A29 CACL CaCl 33 1.3 2 from media following the addition of known pulses of CaCl 2 using Calcium Green-5N fluorescence tracing 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 147192 15964487 194121 20247 20116 SLC25A29 CACL CaCl 4 1.3 A fixed amount of CaCl 2 (4nmol) 4nmol was added repeatedly every 60 s until 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 147193 15964487 194143 17686 9683 PTPRU PTP PTP 7 0.3 Mitochondrial swelling might be a consequence of PTP formation which leads to a massive water influx into mitochondria 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9951 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9951|REG1A|0.000357540123947243<>ScoreDetail__9951|REG1A|0.000357540123947243__9683|PTPRU|0.000257334019557386__ 0 0 0 0 0 147194 15964487 194145 17686 9683 PTPRU PTP PTP 6 0.3 In fact drugs able to block PTP formation afford complete or partial neuroprotection against a broad type 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9951 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9951|REG1A|0.000357540123947243<>ScoreDetail__9951|REG1A|0.000357540123947243__9683|PTPRU|0.000257334019557386__ 0 0 0 0 0 147195 15964487 194153 22000 11730 TERT TERT tert 20 0.0 where minocycline has distinct mechanisms of action against oxidative ( tert -butyl hydroperoxide phenylarsine oxide and nonoxidative (Ca/Pi, Ca Pi t-Bid 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 147196 15964487 194170 14535 7873 NOS2A iNOS iNOS 20 2.2 death by other mechanisms such as inhibition of methaloproteases or iNOS expression ( Chen et al 2000 and Sadowski and Steinmeyer 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 147197 15964487 194174 17686 9683 PTPRU PTP PTP 17 0.3 dissipation and blocking both mitochondrial Ca 2 accumulation and subsequent PTP opening 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9951 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9951|REG1A|0.000357540123947243<>ScoreDetail__9951|REG1A|0.000357540123947243__9683|PTPRU|0.000257334019557386__ 0 0 0 0 0 147198 15964487 194175 17686 9683 PTPRU PTP PTP 1 0.3 Since PTP might play a key role in the development of a 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9951 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9951|REG1A|0.000357540123947243<>ScoreDetail__9951|REG1A|0.000357540123947243__9683|PTPRU|0.000257334019557386__ 0 0 0 0 0 147199 15964487 194185 20247 20116 SLC25A29 CACL CaCl 16 1.3 A 540 indicating mitochondrial swelling were followed after addition of CaCl 2 (75_amp_#x3bc;M, 75_amp_#x3bc M panel A and KO 2 (5_amp_#x3bc;M, 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 147200 15964487 194186 9701 5244 HSPA9 CSA CsA 19 0.3 Red (RR, RR 5 _amp_#x3bc M and cyclosporin A (CsA, CsA 10 _amp_#x3bc M was measured 14 JUMiner_v2.2 1 2 UserEdit 0 2 5244 TotalCon:3<>3439|ERCC8|1161|Complete__2440|CSH1|1442|Complete__5244|HSPA9|3313|Complete__<>AvaiableGeneRif=3<>BEST:5244|HSPA9|0.000505687193139817<>ScoreDetail__3439|ERCC8|0.000220871142763688__2440|CSH1|0.000339353719693828__5244|HSPA9|0.000505687193139817__ 1 1 0 0 0 147201 15964487 194193 20247 20116 SLC25A29 CACL CaCl 3 1.3 Pulses of 4nmol CaCl 2 (100_amp_#x3bc;M) 100_amp_#x3bc M were added every 60 s 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 136102 16026864 180215 20996 11179 SOD1 ALS ALS 3 2.2 Amyotrophic lateral sclerosis (ALS) ALS is a neurodegenerative disease clinically characterized by progressive loss of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136103 16026864 180216 20996 11179 SOD1 ALS ALS 0 2.2 ALS is sporadic in 90% of cases the remaining 10% are 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136104 16026864 180216 20996 11179 SOD1 SOD1 SOD1 27 2.2 induced by mutations in the enzyme superoxide dismutase 1 (SOD1) SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136105 16026864 180217 20996 11179 SOD1 ALS ALS 14 2.2 apparent differences in onset or progression of sporadic and familial ALS which has led researchers to hypothesize that the two forms 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136106 16026864 180218 20996 11179 SOD1 ALS ALS 9 2.2 Corresponding to the clinical picture the characteristic hallmark of ALS pathology is the progressive and highly selective loss of cortical 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136107 16026864 180220 18723 10261 ROS1 ROS ROS 17 0.0 including glutamate excitotoxicity 2 production of reactive oxygen species (ROS) ROS 3 Ca 2 -dependent formation of protein aggregates 4 axonal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136108 16026864 180222 20996 11179 SOD1 ALS ALS 5 2.2 Increasing evidence also suggests that ALS pathogenesis is not confined to motoneurons but rather develops as 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136109 16026864 180223 20996 11179 SOD1 ALS ALS 9 2.2 According to the selective pattern of motoneuron loss in ALS it is generally believed that unique properties of affected motoneurons 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136110 16026864 180223 20996 11179 SOD1 ALS ALS-associated 26 2.2 properties of affected motoneurons are responsible for their vulnerability during ALS-associated injury 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136111 16026864 180224 8790 4572 GRIA2 GLUR2 GluR2 25 1.3 of highly Ca 2 -permeable AMPA receptors which lack the GluR2 unit 4 14 15 and 16 a high neurofilament content 14 JUMiner_v2.2 1 0 0 2 4594 TotalCon:2<>4572|GRIA2|2891|Complete__4594|GRM2|2912|Complete__<>AvaiableGeneRif=2<>BEST:4594|GRM2|0.000802375888497567<>ScoreDetail__4594|GRM2|0.000802375888497567__4572|GRIA2|0.000640558482989497__ 0 0 0 0 0 136112 16026864 180225 20996 11179 SOD1 ALS ALS 31 2.2 will also address their involvement during pathological states such as ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136113 16026864 180226 18723 10261 ROS1 ROS ROS 15 0.0 integrative hypothesis for the role of Ca 2 mitochondria and ROS in selective motoneuron vulnerability 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136114 16026864 180231 20996 11179 SOD1 ALS ALS 11 2.2 of the cellular and molecular event initiating motoneuron degeneration in ALS disruption of intracellular Ca 2 homeostasis is thought to have 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136115 16026864 180232 20996 11179 SOD1 ALS ALS 30 2.2 and parvalbumin were absent in motoneuron populations lost early in ALS (cortical, cortical spinal and lower cranial nerve motoneurons whereas motoneurons 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136116 16026864 180235 20996 11179 SOD1 ALS ALS 14 2.2 Ca 2 homeostasis ultimately lead to degeneration of motoneurons in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136117 16026864 180237 20996 11179 SOD1 ALS ALS 23 2.2 strategy that has proven beneficial in slowing disease progression in ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136118 16026864 180238 20996 11179 SOD1 ALS ALS 7 2.2 The presumed mechanisms of glutamate-mediated toxicity in ALS have been reviewed recently and are therefore only briefly outlined 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136119 16026864 180239 20017 10940 SLC1A2 EAAT2 EAAT2 22 1.0 can be caused by oxidative damage to the glutamate transporter EAAT2 or by aberrant RNA processing 22 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136120 16026864 180240 20996 11179 SOD1 ALS ALS-resistant 35 2.2 2 concentration ([Ca Ca 2 i in motoneurons than in ALS-resistant neurons 23 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136121 16026864 180242 20996 11179 SOD1 ALS ALS 6 2.2 For the well-studied familial form of ALS induced by mutant SOD1 the involvement of Ca 2 has 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136122 16026864 180242 20996 11179 SOD1 SOD1 SOD1 10 2.2 For the well-studied familial form of ALS induced by mutant SOD1 the involvement of Ca 2 has been demonstrated in cell 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136123 16026864 180243 20996 11179 SOD1 SOD1 SOD1 20 2.2 given by the inhibition of glial glutamate transport by mutant SOD1 and the consecutive disturbance of Ca 2 homeostasis by excitotoxic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136124 16026864 180243 20996 11179 SOD1 ALS ALS 38 2.2 homeostasis by excitotoxic mechanisms similar to those proposed for sporadic ALS 27 and 28 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136125 16026864 180244 20996 11179 SOD1 SOD1 SOD1-related 16 2.2 the importance of Ca 2 -permeable AMPA receptors in mutant SOD1-related ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136126 16026864 180244 20996 11179 SOD1 ALS ALS 17 2.2 importance of Ca 2 -permeable AMPA receptors in mutant SOD1-related ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136127 16026864 180245 20996 11179 SOD1 SOD1 SOD1 27 2.2 Ca 2 -permeable AMPA receptors and survival times of transgenic SOD1 mice were significantly increased following chronic treatment with AMPA receptor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136128 16026864 180246 20996 11179 SOD1 SOD1 SOD1 33 2.2 addition to glutamate receptors in mediating the toxicity of mutant SOD1 in motoneurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136129 16026864 180247 20996 11179 SOD1 SOD1 SOD1 17 2.2 -permeable AMPA receptors was further underlined by cross-breeding of transgenic SOD1 mice with mice that showed markedly reduced Ca 2 permeability 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136130 16026864 180247 8790 4572 GRIA2 GLUR2 GluR2 33 1.3 Ca 2 permeability of AMPA/kainate AMPA kainate receptors due to GluR2 overexpression 14 JUMiner_v2.2 1 0 0 2 4594 TotalCon:2<>4572|GRIA2|2891|Complete__4594|GRM2|2912|Complete__<>AvaiableGeneRif=2<>BEST:4594|GRM2|0.000802375888497567<>ScoreDetail__4594|GRM2|0.000802375888497567__4572|GRIA2|0.000640558482989497__ 0 0 0 0 0 136131 16026864 180250 20996 11179 SOD1 ALS ALS 7 2.2 In both sporadic and familial forms of ALS there is increasing evidence for crucial involvement of mitochondria 30 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136132 16026864 180251 20996 11179 SOD1 ALS ALS 22 2.2 swelling as some of the earliest signs of pathology in ALS mouse models and in human ALS 32 33 and 34 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136133 16026864 180251 20996 11179 SOD1 ALS ALS 28 2.2 signs of pathology in ALS mouse models and in human ALS 32 33 and 34 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136134 16026864 180252 20996 11179 SOD1 ALS ALS 20 2.2 but were also detected in muscle and liver biopsies from ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136135 16026864 180253 18723 10261 ROS1 ROS ROS 20 0.0 altered activity of the respiratory chain and increased production of ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136136 16026864 180254 20996 11179 SOD1 ALS ALS 2 2.2 In sporadic ALS altered electron transport chain activity most often a decrease in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136137 16026864 180255 20996 11179 SOD1 ALS ALS 23 2.2 in cell function has been addressed by transferring mtDNA from ALS subjects to mtDNA-depleted human neuroblastoma cells 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136138 16026864 180256 20996 11179 SOD1 ALS ALS 33 2.2 a pathological role for mtDNA mutations in some forms of ALS 38 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136139 16026864 180257 18723 10261 ROS1 ROS ROS 8 0.0 Other studies pointed out the increased production of ROS by mitochondria in motoneurons as a result of mitochondrial Ca 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136140 16026864 180258 18723 10261 ROS1 ROS ROS 3 0.0 Evidence suggests that ROS generated in motoneurons can cross the plasma membrane and cause 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136141 16026864 180260 18723 10261 ROS1 ROS ROS 22 0.0 exact mechanisms of how mitochondrial Ca 2 uptake would increase ROS production are still unclear 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136142 16026864 180261 20996 11179 SOD1 ALS ALS 2 2.2 In mutant-SOD1-related ALS the importance of mitochondrial mechanisms was indicated not only by 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136143 16026864 180263 20996 11179 SOD1 SOD1 SOD1 3 2.2 Aggregates containing mutant SOD1 have been found within the mitochondrial matrix 42 43 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136144 16026864 180264 20996 11179 SOD1 SOD1 SOD1 8 2.2 Most interestingly recent work provided evidence that mutant SOD1 might disrupt association of complex IV (cytochrome cytochrome c with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136145 16026864 180265 18723 10261 ROS1 ROS ROS 14 0.0 such disturbed mitochondrial respiration seems to be increased production of ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136146 16026864 180266 20996 11179 SOD1 SOD1 SOD1 9 2.2 This has been demonstrated for cultured motoneurons expressing mutant SOD1 49 and is in line with a study of motoneurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136147 16026864 180270 20996 11179 SOD1 ALS ALS-like 5 2.2 In line with these observations ALS-like symptoms and neuropathology can be produced in mice by a 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136148 16026864 180270 23910 12680 VEGFA VEGF VEGF 27 2.2 that eliminates the ability of vascular endothelial-cell growth factor (VEGF) VEGF to respond to tissue hypoxia 54 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136149 16026864 180271 20996 11179 SOD1 SOD1 SOD1 5 2.2 Cross-breeding these mice with the SOD1 mutants severely enhanced motoneuron degeneration 55 whereas treatment of SOD-transgenic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136150 16026864 180271 20996 11179 SOD1 SOD SOD-transgenic 16 2.2 SOD1 mutants severely enhanced motoneuron degeneration 55 whereas treatment of SOD-transgenic mice with VEGF delayed progression of symptoms and prolonged survival 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136151 16026864 180271 23910 12680 VEGFA VEGF VEGF 19 2.2 enhanced motoneuron degeneration 55 whereas treatment of SOD-transgenic mice with VEGF delayed progression of symptoms and prolonged survival 56 and 57 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136152 16026864 180272 23910 12680 VEGFA VEGF VEGF 5 2.2 Although direct neurotrophic effects of VEGF might contribute to these phenomena motoneurons seem selectively vulnerable to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136153 16026864 180274 20996 11179 SOD1 ALS ALS 23 2.2 of Ca 2 homeostasis and selective vulnerability of motoneurons during ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136154 16026864 180275 20996 11179 SOD1 ALS ALS-related 19 2.2 have proven valuable tools for physiological and biochemical characterization of ALS-related pathology over time and for testing for protective strategies 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136155 16026864 180285 20996 11179 SOD1 ALS ALS 37 2.2 with the selective vulnerability of a given cell type in ALS ( Figure 2 b 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136156 16026864 180287 20996 11179 SOD1 ALS ALS 24 2.2 and hippocampal cells 66 which are also hardly affected in ALS patients and corresponding mouse models 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136157 16026864 180295 20996 11179 SOD1 ALS ALS-related 31 2.2 but also enhance the selective vulnerability of hypoglossal motoneurons during ALS-related motoneuron degeneration 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136158 16026864 180298 20996 11179 SOD1 ALS ALS-resistant 12 2.2 mitochondrial Ca 2 uptake is comparably small in highly buffered ALS-resistant cells 39 and 70 suggesting that mitochondria partially compensate for 1 JUMiner_v2.2 1 2 32 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136159 16026864 180300 18723 10261 ROS1 ROS ROS-dependent 19 0.0 homeostasis in motoneurons not only by buffering but also by ROS-dependent regulation of excitability 18 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136160 16026864 180301 18723 10261 ROS1 ROS ROS 7 0.0 When respiration is inhibited by cyanide subsequent ROS formation induces opening of Na conductances increases action potential discharge 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136161 16026864 180302 20996 11179 SOD1 ALS ALS 6 2.2 This mechanism is potentially relevant for ALS because various studies have demonstrated mitochondrial inhibition and increased ROS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136162 16026864 180302 18723 10261 ROS1 ROS ROS 16 0.0 ALS because various studies have demonstrated mitochondrial inhibition and increased ROS production 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136163 16026864 180304 20996 11179 SOD1 ALS ALS 5 2.2 In conclusion it seems that ALS is a multifactorial disease where motoneuron degeneration can be initiated 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136164 16026864 180306 20996 11179 SOD1 SOD1 SOD1 9 2.2 Briefly mitochondrial respiration can be disturbed by mutations in SOD1 hypoxia Ca 2 overload or alterations in the mitochondrial genome 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136165 16026864 180307 18723 10261 ROS1 ROS ROS 16 0.0 to be worked-out these alterations seem to increase formation of ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136166 16026864 180308 18723 10261 ROS1 ROS ROS 4 0.0 It is hypothesized that ROS have a central role in propagating damage by targeting surrounding 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136167 16026864 180311 18723 10261 ROS1 ROS ROS 20 0.0 induction of apoptotic pathways could well be consequences of either ROS generation or a rise in Ca 2 i 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136168 16026864 180316 20996 11179 SOD1 ALS ALS 15 2.2 protecting mitochondrial function could be useful in various forms of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136169 16026864 180323 20996 11179 SOD1 ALS ALS 12 2.2 2 -buffering capacities correlate with the vulnerability of neurons in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136170 16026864 180329 20996 11179 SOD1 ALS ALS 16 2.2 between cells and that neurons that are typically damaged in ALS _amp_#x2013 hypoglossal spinal and facial motoneurons (MN) MN _amp_#x2013 display 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136171 16026864 180329 20996 11179 SOD1 ALS ALS 39 2.2 that are several times lower than cells usually resistant in ALS i.e oculomotor neurons and cerebellar (Cb) Cb Purkinje cells 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136172 16026864 180336 20996 11179 SOD1 ALS ALS 9 2.2 Figure 4._amp_#xa0 Ca 2 mitochondria and motoneuron degeneration in ALS _amp_#x2013 an integrative model that combines different aspects of ALS-related 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136173 16026864 180336 20996 11179 SOD1 ALS ALS-related 19 2.2 ALS _amp_#x2013 an integrative model that combines different aspects of ALS-related motoneuron degeneration 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136174 16026864 180337 20996 11179 SOD1 ALS ALS-related 0 2.2 ALS-related disturbance of mitochondrial respiration by mutant superoxide dismutase 1 (SOD1) 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000779631943122995<>ScoreDetail__5468|IGFALS|0.000282552389922298__11179|SOD1|0.000779631943122995__ 0 0 0 0 0 136175 16026864 180337 20996 11179 SOD1 SOD1 SOD1 10 2.2 disturbance of mitochondrial respiration by mutant superoxide dismutase 1 (SOD1) SOD1 or hypoxia results in increased formation of reactive oxygen species 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136176 16026864 180337 18723 10261 ROS1 ROS ROS 21 0.0 hypoxia results in increased formation of reactive oxygen species (ROS) ROS 48 and 49 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136177 16026864 180338 18723 10261 ROS1 ROS ROS 3 0.0 Evidence suggests that ROS formation enhances motoneuron excitability via induction of a Na current 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136178 16026864 180339 18723 10261 ROS1 ROS ROS 0 0.0 ROS are also suspected to leave the neuron and damage glial 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136179 16026864 180346 18723 10261 ROS1 ROS ROS 27 0.0 be integrated into the model as consequences of mitochondrial disturbance ROS formation or increased Ca 2 i 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136748 16043017 181168 20996 11179 SOD1 ALS ALS 3 2.2 Amyotrophic lateral sclerosis (ALS) ALS is a fatal motor neuron degenerative disease characterized by the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136749 16043017 181169 20996 11179 SOD1 ALS ALS 1 2.2 Familial ALS cases accounting for 10_amp_#x2013 15% of all ALS disease are 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136750 16043017 181169 20996 11179 SOD1 ALS ALS 8 2.2 Familial ALS cases accounting for 10_amp_#x2013 15% of all ALS disease are caused by a gain-of-function mutation in Cu Zn-superoxide 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136751 16043017 181169 20996 11179 SOD1 SOD1 SOD1 19 2.7 caused by a gain-of-function mutation in Cu Zn-superoxide dismutase (SOD1) SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136752 16043017 181170 20996 11179 SOD1 SOD SOD 14 1.9 proposed to explain the toxic gain of function of mutant SOD (mSOD) mSOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136753 16043017 181170 20996 11179 SOD1 SOD mSOD 15 1.9 explain the toxic gain of function of mutant SOD (mSOD) mSOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136754 16043017 181171 20996 11179 SOD1 SOD mSOD 3 1.9 One is that mSOD can directly promote reactive oxygen species and reactive nitrogen species 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136755 16043017 181173 20996 11179 SOD1 ALS ALS-like 21 1.9 spinal cord from 2 to 4 months and eventually develop ALS-like motor neuron disease and die within 5_amp_#x2013 6 months 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136756 16043017 181176 20996 11179 SOD1 SOD1 SOD1 3 2.7 These proteins are SOD1 translationally controlled tumor protein (TCTP), TCTP ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1), 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136757 16043017 181176 22727 12022 TPT1 TCTP TCTP 8 2.5 These proteins are SOD1 translationally controlled tumor protein (TCTP), TCTP ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1), UCH-L1 and possibly B-crystallin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136758 16043017 181176 23620 12513 UCHL1 UCHL1 UCH-L1 12 2.2 translationally controlled tumor protein (TCTP), TCTP ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1), UCH-L1 and possibly B-crystallin 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136759 16043017 181177 23620 12513 UCHL1 UCHL1 UCH-L1 19 2.2 activity decline our current study suggests that oxidative modification of UCH-L1 TCTP SOD1 and possibly B-crystallin may play an important role 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136760 16043017 181177 22727 12022 TPT1 TCTP TCTP 20 2.5 decline our current study suggests that oxidative modification of UCH-L1 TCTP SOD1 and possibly B-crystallin may play an important role in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136761 16043017 181177 20996 11179 SOD1 SOD1 SOD1 21 2.7 our current study suggests that oxidative modification of UCH-L1 TCTP SOD1 and possibly B-crystallin may play an important role in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136762 16043017 181177 20996 11179 SOD1 ALS ALS 34 2.2 B-crystallin may play an important role in the neurodegeneration of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136763 16043017 181178 20996 11179 SOD1 ALS ALS 3 2.2 Amyotrophic lateral sclerosis (ALS) ALS is a fatal motor neuron degenerative disease characterized by the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136764 16043017 181179 20996 11179 SOD1 ALS ALS 0 2.2 ALS typically presents in middle age and progresses rapidly 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136765 16043017 181180 20996 11179 SOD1 ALS ALS 5 2.2 Life expectancy of victims of ALS usually is 3_amp_#x2013 5 years after diagnosis 1 and 2 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136766 16043017 181181 20996 11179 SOD1 ALS ALS 1 2.2 Inherited ALS accounts for 10_amp_#x2013 15% of cases and among all of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136767 16043017 181181 20996 11179 SOD1 ALS ALS 13 2.2 10_amp_#x2013 15% of cases and among all of the familial ALS (FALS) FALS patients 20_amp_#x2013 30% of them are caused by 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136768 16043017 181181 20996 11179 SOD1 SOD1 SOD1 28 2.7 caused by a gain-of-function mutation in Cu Zn-superoxide dismutase (SOD1) SOD1 3 and 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136769 16043017 181182 20996 11179 SOD1 SOD1 SOD1 0 2.7 SOD1 catalyzes the disproportionation of superoxide anion radical to hydrogen peroxide 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136770 16043017 181183 20996 11179 SOD1 SOD1 SOD1 8 2.7 Over 100 different missense substitutions in the 153-amino-acid SOD1 have been described in individuals and kindreds affected by SOD1-linked 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136771 16043017 181183 20996 11179 SOD1 SOD1 SOD1-linked 18 1.9 SOD1 have been described in individuals and kindreds affected by SOD1-linked FALS 5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136772 16043017 181184 20996 11179 SOD1 SOD1 SOD1 7 2.7 One of the most common mutations of SOD1 is the substitution of glycine by alanine at residue 93 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136773 16043017 181185 20996 11179 SOD1 SOD SOD 15 1.9 proposed to explain the toxic gain of function of mutant SOD (mSOD) mSOD 6 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136774 16043017 181185 20996 11179 SOD1 SOD mSOD 16 1.9 explain the toxic gain of function of mutant SOD (mSOD) mSOD 6 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136775 16043017 181186 20996 11179 SOD1 SOD mSOD 3 1.9 One is that mSOD can directly promote reactive oxygen species and reactive nitrogen species 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136776 16043017 181190 20996 11179 SOD1 ALS ALS 7 2.2 The proteinaceous inclusions found in tissues from ALS patients 23 24 and 25 and mSOD transgenic mice 22 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136777 16043017 181190 20996 11179 SOD1 SOD mSOD 15 1.9 in tissues from ALS patients 23 24 and 25 and mSOD transgenic mice 22 and 26 reportedly are rich in mSOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136778 16043017 181190 20996 11179 SOD1 SOD mSOD 25 1.9 mSOD transgenic mice 22 and 26 reportedly are rich in mSOD ubiquitin and neurofilament proteins 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136779 16043017 181191 20996 11179 SOD1 ALS ALS 27 2.2 27 although the roles of oxidative stress and aggregation in ALS are highly controversial (recently recently reviewed in 18 28 and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136780 16043017 181192 20996 11179 SOD1 SOD1 SOD1-related 11 1.9 oxidative modification of macromolecules was demonstrated in neuronal tissues of SOD1-related FALS patients and transgenic mice 30 31 and 32 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136781 16043017 181193 20996 11179 SOD1 SOD1 mSOD1 7 1.9 Enhanced susceptibility of exogenous oxidative stress in mSOD1 cell cultures was also observed in in vitro studies 33 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136782 16043017 181194 20996 11179 SOD1 SOD mSOD 10 1.9 Exogenous oxidative stress can even inhibit the rapid degradation of mSOD 36 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136783 16043017 181195 20996 11179 SOD1 ALS ALS 15 2.2 the notion that oxidative stress plays an important role in ALS development 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136784 16043017 181197 20996 11179 SOD1 SOD1 SOD1 31 2.7 higher capacity to generate free radicals 9 compared to wild-type SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136785 16043017 181199 20996 11179 SOD1 ALS ALS-like 32 1.9 39 creating oxidative stress that may be responsible for the ALS-like syndrome observed in the G93A-SOD1 mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136786 16043017 181200 20996 11179 SOD1 SOD1 SOD1 11 2.7 of the oxidatively modified proteins in G93A-SOD1 transgenic mice is SOD1 32 indicating that oxidation of SOD1 is likely important to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136787 16043017 181200 20996 11179 SOD1 SOD1 SOD1 18 2.7 G93A-SOD1 transgenic mice is SOD1 32 indicating that oxidation of SOD1 is likely important to the development of this model of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136788 16043017 181200 20996 11179 SOD1 ALS ALS 29 2.2 is likely important to the development of this model of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136789 16043017 181203 20996 11179 SOD1 ALS ALS 13 2.2 better understand the role of oxidative modification of proteins in ALS we employed quantitative redox proteomic analysis to identify the specific 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136790 16043017 181206 20996 11179 SOD1 SOD1 SOD1 5 2.7 Transgenic mice expressing the human SOD1 gene with a G93A mutation strain B6SJL/TgN B6SJL TgN (SOD1-G93A)-2Gur) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136791 16043017 181206 22055 11764 TG TGN TgN 12 0.0 human SOD1 gene with a G93A mutation strain B6SJL/TgN B6SJL TgN (SOD1-G93A)-2Gur) SOD1-G93A -2Gur 37 were purchased from The Jackson Laboratory 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136792 16043017 181239 7509 13506 FEZF2 TOF TOF 22 0.3 Bruker Daltonics Billerica MA USA at the UKMSF or a TOF Spec 2E (Micromass, Micromass UK MALDI-TOF mass spectrometer at the 1 JUMiner_v2.2 1 2 maldi-tof 0 0 0 0 0 0 0 0 136793 16043017 181242 6883 3541 F3 TFA TFA 11 0.0 spot was washed with 1 _amp_#x3bc l of a 1% TFA solution for approximately 60 s 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136794 16043017 181243 6883 3541 F3 TFA TFA 1 0.0 The TFA droplet was gently blown off the sample spot with compressed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136795 16043017 181244 6883 3541 F3 TFA TFA 16 0.0 1 _amp_#x3bc l of a solution of ethanol acetone 0.1% TFA (6:3:1 6 3 1 ratio 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136796 16043017 181251 23620 12513 UCHL1 UCHL1 UCH-L1 4 2.2 Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) UCH-L1 assay 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136797 16043017 181252 23620 12513 UCHL1 UCHL1 UCH-L1 3 2.2 The activities of UCH-L1 in the spinal cord were measured by determining the rate 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136798 16043017 181252 646 456 AMCN AMC AMC 25 0.0 ubiquitin-C-terminal 7-amido-4-methylcoumarin (Ub-AMC) Ub-AMC (Calbiochem) Calbiochem to ubiquitin and free AMC 48 1 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 136799 16043017 181254 646 456 AMCN AMC AMC 16 0.0 Ub-AMC was added to the enzyme solution and cleavage of AMC from Ub-AMC was monitored at _amp_#x3bb ex 355 nm and 1 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 136800 16043017 181255 23620 12513 UCHL1 UCHL1 UCH-L1 0 2.2 UCH-L1 activities of each individual were assayed by the change of 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136801 16043017 181256 23620 12513 UCHL1 UCHL1 UCH-L1 2 2.2 The average UCH-L1 activities of six transgenic animals were compared to those of 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136802 16043017 181269 20996 11179 SOD1 SOD1 SOD1 5 2.7 These proteins were identified as SOD1 translationally controlled tumor protein (TCTP), TCTP UCH-L1 and B-crystallin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136803 16043017 181269 22727 12022 TPT1 TCTP TCTP 10 2.5 proteins were identified as SOD1 translationally controlled tumor protein (TCTP), TCTP UCH-L1 and B-crystallin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136804 16043017 181269 23620 12513 UCHL1 UCHL1 UCH-L1 11 2.2 were identified as SOD1 translationally controlled tumor protein (TCTP), TCTP UCH-L1 and B-crystallin 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136805 16043017 181274 20996 11179 SOD1 SOD1 SOD1 10 2.7 We report here that the specific carbonyl levels of human SOD1 TCTP UCH-L1 and possibly B-crystallin are significantly increased in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136806 16043017 181274 22727 12022 TPT1 TCTP TCTP 11 2.5 report here that the specific carbonyl levels of human SOD1 TCTP UCH-L1 and possibly B-crystallin are significantly increased in the spinal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136807 16043017 181274 23620 12513 UCHL1 UCHL1 UCH-L1 12 2.2 here that the specific carbonyl levels of human SOD1 TCTP UCH-L1 and possibly B-crystallin are significantly increased in the spinal cord 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136808 16043017 181275 20996 11179 SOD1 SOD1 SOD1 4 2.7 Spots close to human SOD1 are modified SOD1 possibly phosphorylated SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136809 16043017 181275 20996 11179 SOD1 SOD1 SOD1 7 2.7 Spots close to human SOD1 are modified SOD1 possibly phosphorylated SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136810 16043017 181275 20996 11179 SOD1 SOD1 SOD1 10 2.7 Spots close to human SOD1 are modified SOD1 possibly phosphorylated SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136811 16043017 181281 23620 12513 UCHL1 UCHL1 UCH-L1 15 2.2 oxidative modification inactivated protein activity we compared the activity of UCH-L1 in the G93A-SOD1 transgenic mice to that in the control 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136812 16043017 181282 23620 12513 UCHL1 UCHL1 UCH-L1 20 2.2 of activity of oxidatively modified proteins 49 50 and 51 UCH-L1 activity was significantly decreased (29%) 29% in the G93A-SOD1 transgenic 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136813 16043017 181285 20996 11179 SOD1 SOD SOD 15 1.9 provide insight into the mechanisms of the neurotoxicity of mutant SOD in vivo 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136814 16043017 181286 20996 11179 SOD1 SOD1 SOD1 6 2.7 It is well established that mutant SOD1 enhances oxidative activity by acting as a peroxidase 9 11 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136815 16043017 181289 20996 11179 SOD1 SOD1 SOD1 21 2.7 carbonyl levels compared to those of the nontransgenic mice as SOD1 TCTP UCH-L1 and B-crystallin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136816 16043017 181289 22727 12022 TPT1 TCTP TCTP 22 2.5 levels compared to those of the nontransgenic mice as SOD1 TCTP UCH-L1 and B-crystallin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136817 16043017 181289 23620 12513 UCHL1 UCHL1 UCH-L1 23 2.2 compared to those of the nontransgenic mice as SOD1 TCTP UCH-L1 and B-crystallin 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136818 16043017 181290 20996 11179 SOD1 SOD1 SOD1 0 2.7 SOD1 previously was identified immunochemically as one of the oxidatively modified 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136819 16043017 181291 20996 11179 SOD1 SOD1 SOD1 15 2.7 proteomics approach to confirm that the specific carbonyl level of SOD1 is increased in the spinal cords of G93A-SOD1 transgenic mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136820 16043017 181292 20996 11179 SOD1 SOD1 SOD1 10 2.7 Although G93A-SOD1 shows dismutation activity identical to that of wild-type SOD1 the activity of SOD1 in FALS patients with mutations is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136821 16043017 181292 20996 11179 SOD1 SOD1 SOD1 14 2.7 activity identical to that of wild-type SOD1 the activity of SOD1 in FALS patients with mutations is decreased 50% in motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136822 16043017 181293 20996 11179 SOD1 SOD1 SOD1 12 2.7 radical production in the G93A-SOD1 transgenic animals is induced by SOD1 mutation 32 alteration of tumor necrosis factor TNF- and TNF--modulating 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136823 16043017 181293 22551 11892 TNF TNF TNF- 21 1.2 induced by SOD1 mutation 32 alteration of tumor necrosis factor TNF- and TNF--modulating cytokines 38 and 46 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136824 16043017 181293 22551 11892 TNF TNF TNF--modulating 24 1.2 SOD1 mutation 32 alteration of tumor necrosis factor TNF- and TNF--modulating cytokines 38 and 46 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136825 16043017 181294 20996 11179 SOD1 ALS ALS 12 2.2 issue of whether oxidative stress plays an early role in ALS remains unclear our current study is consistent with the notion 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136826 16043017 181294 20996 11179 SOD1 SOD1 SOD1 27 2.7 study is consistent with the notion that oxidative modification of SOD1 plays a role in the neurotoxicity of mutant SOD1 in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136827 16043017 181294 20996 11179 SOD1 SOD1 SOD1 36 2.7 of SOD1 plays a role in the neurotoxicity of mutant SOD1 in the disease 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136828 16043017 181295 22727 12022 TPT1 TCTP TCTP 12 2.5 modified protein in G93A-SOD1 transgenic mice identified by proteomics was TCTP 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136829 16043017 181296 22727 12022 TPT1 TCTP TCTP 0 2.5 TCTP processes calcium-binding activity (reviewed reviewed in 55 and has a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136830 16043017 181297 22727 12022 TPT1 TCTP TCTP 2 2.5 Overexpression of TCTP stabilizes microtubules and alters cell morphology 57 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136831 16043017 181298 22727 12022 TPT1 TCTP TCTP 4 2.5 Other molecular interactions of TCTP include self-interaction 58 and the interaction with myeloid cell leukemia 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136832 16043017 181299 22727 12022 TPT1 TCTP TCTP 0 2.5 TCTP levels are highly regulated in response to various stress conditions 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136833 16043017 181300 22727 12022 TPT1 TCTP TCTP 20 2.5 characterization as an antiapoptotic protein 67 these observations suggest that TCTP may exert a cytoprotective function for cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136834 16043017 181301 22727 12022 TPT1 TCTP TCTP 5 2.5 The current study showed that TCTP was oxidatively modified in the spinal cord of G93A-SOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136835 16043017 181301 22727 12022 TPT1 TCTP TCTP 28 2.5 the putative cytoprotective function and the calcium binding affinity of TCTP are impaired in G93A-SOD1 mice because oxidative modification alters the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136836 16043017 181302 20996 11179 SOD1 ALS ALS 12 2.2 this notion free cytosolic calcium was increased in lymphocytes from ALS patients 70 suggesting that oxidative modification of TCTP may also 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136837 16043017 181302 22727 12022 TPT1 TCTP TCTP 21 2.5 lymphocytes from ALS patients 70 suggesting that oxidative modification of TCTP may also play an important role in neurotoxicity of G93A-SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136838 16043017 181303 23620 12513 UCHL1 UCHL1 UCH-L1 0 2.2 UCH-L1 belongs to a family of ubiquitin carboxyl-terminal hydrolases that play 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136839 16043017 181307 23620 12513 UCHL1 UCHL1 UCH-L1 2 2.2 Loss of UCH-L1 function causes neuroaxonal dystrophy 74 75 and 76 significant protein 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136840 16043017 181308 23620 12513 UCHL1 UCHL1 UCH-L1 2 2.2 Similarly decreased UCH-L1 activity by mutation also enhances protein aggregation in Escherichia coli 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136841 16043017 181309 23620 12513 UCHL1 UCHL1 UCH-L1 9 2.2 Therefore based on the prior literature oxidative inactivation of UCH-L1 presented in the current study possibly contributes to both the 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136842 16043017 181309 20996 11179 SOD1 ALS ALS 32 2.2 and the oxidative stress observed in G93A-SOD1 transgenic mice and ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136843 16043017 181310 23620 12513 UCHL1 UCHL1 UCH-L1 14 2.2 notion and consistent with our finding ( Fig 4 that UCH-L1 activity is decreased in G93A-SOD1 mouse spinal cord the inclusions 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136844 16043017 181310 20996 11179 SOD1 ALS ALS 27 2.2 decreased in G93A-SOD1 mouse spinal cord the inclusions of human ALS and mSOD1 (including including G93A mice are excessively ubiquitinated 79 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136845 16043017 181310 20996 11179 SOD1 SOD1 mSOD1 29 1.9 G93A-SOD1 mouse spinal cord the inclusions of human ALS and mSOD1 (including including G93A mice are excessively ubiquitinated 79 80 81 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136846 16043017 181312 9691 5232 HSPA1A HSP HSPs 0 1.2 HSPs are cellular constituents synthesized by living organisms under stress conditions 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136847 16043017 181313 9691 5232 HSPA1A HSP HSPs 16 1.2 to stabilize other proteins under stress conditions whereas the high-molecular-weight HSPs normally play roles in protein folding during biosynthesis 83 and 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136848 16043017 181319 20996 11179 SOD1 ALS ALS 6 2.2 Consistent with this notion inclusions in ALS patients contain B-crystallin metallothionein glutamine synthetase and tubulin immunoreactivities 90 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136849 16043017 181320 22727 12022 TPT1 TCTP TCTP 10 2.5 remarkable feature of the oxidatively modified proteins (except except for TCTP in G93A-SOD1 transgenic mice is that they are involved in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136850 16043017 181320 20996 11179 SOD1 ALS ALS 26 2.2 that they are involved in the formation of inclusions in ALS patients or ALS models 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136851 16043017 181320 20996 11179 SOD1 ALS ALS 29 2.2 involved in the formation of inclusions in ALS patients or ALS models 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136852 16043017 181321 20996 11179 SOD1 ALS ALS 16 2.2 found in fibrillar neuronal inclusions in the cortex of sporadic ALS patients 79 80 81 and 91 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136853 16043017 181322 20996 11179 SOD1 SOD1 SOD1 4 2.7 Aberrant accumulation of mutant SOD1 is demonstrated in Caenorhabditis elegans expressing human mutant SOD1 36 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136854 16043017 181322 20996 11179 SOD1 SOD1 SOD1 13 2.7 mutant SOD1 is demonstrated in Caenorhabditis elegans expressing human mutant SOD1 36 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136855 16043017 181323 20996 11179 SOD1 SOD1 SOD1 10 2.7 Based on our current observations the increased oxidative modification of SOD1 UCH-L1 and B-crystallin plays a significant role in the protein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136856 16043017 181323 23620 12513 UCHL1 UCHL1 UCH-L1 11 2.2 on our current observations the increased oxidative modification of SOD1 UCH-L1 and B-crystallin plays a significant role in the protein aggregation 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136857 16043017 181324 22727 12022 TPT1 TCTP TCTP 23 2.5 involves oxidative modification of a Ca 2 regulating protein (TCTP) TCTP and proteins involved in inclusion formation (SOD1, SOD1 UCH-L1 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136858 16043017 181324 20996 11179 SOD1 SOD1 SOD1 30 2.7 protein (TCTP) TCTP and proteins involved in inclusion formation (SOD1, SOD1 UCH-L1 and B-crystallin suggesting a potential relationship between protein oxidation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136859 16043017 181324 23620 12513 UCHL1 UCHL1 UCH-L1 31 2.2 (TCTP) TCTP and proteins involved in inclusion formation (SOD1, SOD1 UCH-L1 and B-crystallin suggesting a potential relationship between protein oxidation protein 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136860 16043017 181324 20996 11179 SOD1 ALS ALS 48 2.2 between protein oxidation protein aggregation and Ca 2 regulation in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136861 16043017 181325 22727 12022 TPT1 TCTP TCTP 19 2.5 proteins impairs protein stability ( B-crystallin Ca 2 binding (TCTP), TCTP protein degradation (UCH-L1), UCH-L1 and antioxidant capacity (SOD1) SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136862 16043017 181325 23620 12513 UCHL1 UCHL1 UCH-L1 22 2.2 ( B-crystallin Ca 2 binding (TCTP), TCTP protein degradation (UCH-L1), UCH-L1 and antioxidant capacity (SOD1) SOD1 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136863 16043017 181325 20996 11179 SOD1 SOD1 SOD1 26 2.7 (TCTP), TCTP protein degradation (UCH-L1), UCH-L1 and antioxidant capacity (SOD1) SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136864 16043017 181326 20996 11179 SOD1 ALS ALS 17 2.2 modifications could also play a role in the pathogenesis of ALS involving other proteins 92 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158256424889225<>ScoreDetail__5468|IGFALS|0.000797990940455794__11179|SOD1|0.00158256424889225__ 0 0 0 0 0 136865 16043017 181340 23620 12513 UCHL1 UCHL1 UCH-L1 3 2.2 Fig 4._amp_#xa0 Activity of UCH-L1 in G93A-SOD1 transgenic mice as a percentage of the nontransgenic 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 136866 16043017 181341 23620 12513 UCHL1 UCHL1 UCH-L1 3 2.2 The activity of UCH-L1 is significantly decreased in the spinal cord of G93A-SOD1 transgenic 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137129 16046141 181619 20996 11179 SOD1 ALS ALS 23 1.7 neurons that constitute the hallmark of amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137130 16046141 181620 20996 11179 SOD1 SOD1 SOD1 17 2.2 the expression of several mutant Cu Zn superoxide dismutases (SOD1) SOD1 typical of familial ALS is mediated by Apaf1 a scaffold 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137131 16046141 181620 20996 11179 SOD1 ALS ALS 21 1.7 mutant Cu Zn superoxide dismutases (SOD1) SOD1 typical of familial ALS is mediated by Apaf1 a scaffold protein involved in neural 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137132 16046141 181620 864 576 APAF1 APAF1 Apaf1 25 2.1 dismutases (SOD1) SOD1 typical of familial ALS is mediated by Apaf1 a scaffold protein involved in neural development 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137133 16046141 181621 20996 11179 SOD1 SOD1 SOD1s 14 1.7 of neuronal origin and modulating the expression of both mutant SOD1s and Apaf1 we show that the removal of Apaf1 prevents 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137134 16046141 181621 864 576 APAF1 APAF1 Apaf1 16 2.1 origin and modulating the expression of both mutant SOD1s and Apaf1 we show that the removal of Apaf1 prevents cells death 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137135 16046141 181621 864 576 APAF1 APAF1 Apaf1 23 2.1 mutant SOD1s and Apaf1 we show that the removal of Apaf1 prevents cells death 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137136 16046141 181625 18723 10261 ROS1 ROS ROS 33 0.6 imbalance between generation and removal of reactive oxygen species (ROS) ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 137137 16046141 181626 20996 11179 SOD1 ALS ALS 17 1.7 as Alzheimer's disease Parkinson's disease and amyotrophic lateral sclerosis (ALS) ALS ( Andersen 2004 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137138 16046141 181627 20996 11179 SOD1 ALS ALS 1 1.7 In ALS that is the most frequent paralytic disease in adults symptoms 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137139 16046141 181628 18723 10261 ROS1 ROS ROS 16 0.6 respiratory complexes cytochrome c release and oxidative stress (increased increased ROS flux oxidatively modified proteins seem likely candidates to explain many 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 137140 16046141 181628 20996 11179 SOD1 ALS ALS 29 1.7 modified proteins seem likely candidates to explain many facets of ALS because of their early occurrence in experimental models and in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137141 16046141 181629 20996 11179 SOD1 ALS ALS 0 1.7 ALS occurs both as a sporadic and as a familial dominantly 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137142 16046141 181629 20996 11179 SOD1 SOD1 SOD1 33 2.2 gene coding for the enzyme Cu Zn superoxide dismutase (SOD1) SOD1 ( Rosen et al. 1993 fALS-SOD1 mutations cause the appearance 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137143 16046141 181630 20996 11179 SOD1 ALS ALS 12 1.7 only mechanical ventilation and treatment with riluzole prolong survival in ALS patients to some extent 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137144 16046141 181631 20996 11179 SOD1 ALS ALS 20 1.7 knowledge of the actual mechanisms by which neurons die in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137145 16046141 181632 20996 11179 SOD1 SOD1 SOD1 17 2.2 paradigms (post-mortem post-mortem samples from patients mice transgenic for mutant SOD1 and cell cultures 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137146 16046141 181633 20996 11179 SOD1 SOD1 SOD1-mediated 13 1.7 often yielded conflicting results converging evidence indicates that the mutant SOD1-mediated cell death observed in ALS is apoptotic in nature (reviewed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137147 16046141 181633 20996 11179 SOD1 ALS ALS 18 1.7 evidence indicates that the mutant SOD1-mediated cell death observed in ALS is apoptotic in nature (reviewed reviewed by Gu_amp_#xe9 gan and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137148 16046141 181634 20996 11179 SOD1 ALS ALS 16 1.7 show altered expression in post-mortem samples from sporadic and familial ALS patients and in experimental models as well ( Mu et 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137149 16046141 181634 1576 990 BCL2 Bcl2 Bcl2 36 1.5 Mu et al. 1996 and Vukosavic et al. 1999 and Bcl2 prevents death of cells expressing fALS-SOD1 ( Ghadge et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137150 16046141 181634 20996 11179 SOD1 ALS ALS 94 1.7 and caspase-9 is activated in spinal motor neurons of human ALS subjects ( Inoue et al. 2003 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137151 16046141 181635 20996 11179 SOD1 SOD1 SOD1 15 2.2 significantly extend the lifespan of transgenic mice overexpressing a fALS-linked SOD1 mutant ( Li et al. 2000 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137152 16046141 181636 20996 11179 SOD1 SOD1 SOD1 48 2.2 role in the initiation of motor neuron death by mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137153 16046141 181637 20996 11179 SOD1 ALS ALS 6 1.7 In spinal cord specimens of both ALS patients and in the mice model for fALS evidence of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137154 16046141 181638 20996 11179 SOD1 SOD1 SOD1 13 2.2 to be crucial targets of the toxic function of mutant SOD1 ( Mattiazzi et al. 2002 Liu et al. 2004 Pasinelli 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137155 16046141 181638 20996 11179 SOD1 ALS ALS 53 1.7 exact role played by these organelles in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137156 16046141 181639 864 576 APAF1 APAF1 Apaf1 15 2.1 c becomes part of the apoptosome a complex in which Apaf1 serves as a scaffold protein also for the binding of 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137157 16046141 181641 864 576 APAF1 APAF1 Apaf1 10 2.1 In this study we have investigated on the role of Apaf1 and the apoptosome in the induction of death in cell 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137158 16046141 181642 864 576 APAF1 APAF1 Apaf1 6 2.1 Our data demonstrate that removal of Apaf1 prevents cell death and mitochondrial damage by intercepting activation of 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137159 16046141 181645 20996 11179 SOD1 SOD1 SOD1 12 2.2 coding for wt or G93A G37R G85R and I113T mutant SOD1 were described elsewhere ( Carr_amp_#xec et al. 1997 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137160 16046141 181645 17196 30025 PPRC1 PRC pRc 0 0.0 pRc/CMV pRc CMV plasmids coding for wt or G93A G37R G85R and 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137161 16046141 181647 864 576 APAF1 APAF1 Apaf1 0 2.1 Apaf1 expression plasmid was created by cloning of Apaf1 cDNA ( 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137162 16046141 181647 864 576 APAF1 APAF1 Apaf1 8 2.1 Apaf1 expression plasmid was created by cloning of Apaf1 cDNA ( Cecconi et al. 1998 under control of the 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137163 16046141 181649 6895 3530 F12 F12 F12 19 0.0 of Cell Culture and grown in Dulbecco's modified Eagle's/F12 Eagle's F12 medium supplemented with 15% fetal calf serum (FCS) FCS at 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137164 16046141 181650 17196 30025 PPRC1 PRC pRc 11 0.0 expression of wt- or fALS-SOD1s was obtained by transfecting pRc/CMV-wtSOD1 pRc CMV-wtSOD1 or pRc/CMV-fALS-SOD1 pRc CMV-fALS-SOD1 plasmids in SH-SY5Y neuroblastoma cell 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137165 16046141 181650 17196 30025 PPRC1 PRC pRc 13 0.0 fALS-SOD1s was obtained by transfecting pRc/CMV-wtSOD1 pRc CMV-wtSOD1 or pRc/CMV-fALS-SOD1 pRc CMV-fALS-SOD1 plasmids in SH-SY5Y neuroblastoma cell using LipofectAMINE 2000 (Invitrogen), 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137166 16046141 181652 20996 11179 SOD1 SOD1 SOD1 11 2.2 lines transfected for the transient expression of human wild type SOD1 (named named wt or mutant fALS-SOD1 G93A G37R G85R and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137167 16046141 181653 864 576 APAF1 APAF1 Apaf1 3 2.1 Embryonic Telencefalic Naive Apaf1 (ETNA_amp_#x2212;/_amp_#x2212;) ETNA_amp_#x2212 _amp_#x2212 cell lines were obtained from e14 embryos 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137168 16046141 181653 14565 7896 NPAT E14 e14 10 0.3 Naive Apaf1 (ETNA_amp_#x2212;/_amp_#x2212;) ETNA_amp_#x2212 _amp_#x2212 cell lines were obtained from e14 embryos of Apaf1 knock-out mice as previously described ( Cozzolino 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137169 16046141 181653 864 576 APAF1 APAF1 Apaf1 13 2.1 ETNA_amp_#x2212 _amp_#x2212 cell lines were obtained from e14 embryos of Apaf1 knock-out mice as previously described ( Cozzolino et al. 2004 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137170 16046141 181654 5902 2903 DLG4 PSD95 PSD95 37 1.3 neural markers (NeuN, NeuN class III _amp_#x3b2 -tubulin choline acetyltransferase PSD95 and tau Cozzolino et al. 2004 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137171 16046141 181654 12369 6893 MAPT tau tau 39 0.3 (NeuN, NeuN class III _amp_#x3b2 -tubulin choline acetyltransferase PSD95 and tau Cozzolino et al. 2004 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137172 16046141 181661 646 456 AMCN AMC AMC 12 0.0 activities were determined by measuring the rates of 7-amido-4-methylcoumarin (AMC) AMC release from synthetic caspase substrates Ac-YVAD-AMC (for for caspase-1 and 1 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 137173 16046141 181664 646 456 AMCN AMC AMC 3 0.0 The amount of AMC release was quantified using a fluorescence plate reader (Wallac Wallac 1 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 137174 16046141 181671 19573 10691 SDS SDS SDS 23 0.0 50 mM Tris_amp_#x2013 HCl 0.5% Triton X-100 0.25% Na-deoxycholate 0.1% SDS 150 mM NaCl 1 mM EDTA 5 mM MgCl 2 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000322607838559905<>ScoreDetail__10691|SDS|0.000143876611418048__19440|SBDS|0.000322607838559905__ 0 0 0 0 0 137175 16046141 181674 480 8768 AIFM1 AIF AIF 4 0.6 For cytochrome c and AIF release experiments ETNA cells were harvested in hypotonic buffer (2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137176 16046141 181680 20996 11179 SOD1 SOD1 SOD1 1 2.2 Immunoreactive SOD1 was detected with a rabbit polyclonal antibody (Stratagene) Stratagene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137177 16046141 181681 864 576 APAF1 APAF1 Apaf1 0 2.1 Apaf1 was detected with a rat mAb anti-Apaf1 (clone clone 18H2 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137178 16046141 181688 19329 10524 SALL1 TBS TBS 5 0.0 After incubation in Tris-buffered saline (TBS) TBS solution containing 0.1% Tween 20 and 5% non-fat milk filters 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137179 16046141 181688 19329 10524 SALL1 TBS TBS 36 0.0 diluted in a 2% non-fat milk 0.1% Tween 20/TBS 20 TBS solution 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137180 16046141 181689 19329 10524 SALL1 TBS TBS 6 0.0 Following extensive washing in 0.1% Tween 20/TBS 20 TBS solution filters were incubated with the appropriated peroxidase-conjugated secondary antibodies 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137181 16046141 181690 19329 10524 SALL1 TBS TBS 6 0.0 Filters were washed in 0.1% Tween 20/TBS 20 TBS solution and developed using the POD chemiluminescence detection system (Roche) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137182 16046141 181691 20996 11179 SOD1 SOD1 SOD1 2 2.2 Measurement of SOD1 activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137183 16046141 181694 20996 11179 SOD1 SOD1 SOD1 0 2.2 SOD1 activity was detected as the achromatic band on the violet-colored 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137184 16046141 181698 19573 10691 SDS SDS SDS-polyacrylamide 5 0.0 Samples were resolved on 12% SDS-polyacrylamide gels and DNP-derivatized proteins were identified by immunoblotting with a 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000322607838559905<>ScoreDetail__10691|SDS|0.000143876611418048__19440|SBDS|0.000322607838559905__ 0 0 0 0 0 137185 16046141 181714 864 576 APAF1 APAF1 Apaf1 2 2.1 Overexpression of Apaf1 exacerbates apoptotic death induced by fALS-SOD1 in human neuroblastoma 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137186 16046141 181716 20996 11179 SOD1 SOD1 SOD1 14 2.2 1 A under this condition the total level of immunoreactive SOD1 is highly increased with respect to the parental line and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137187 16046141 181716 20996 11179 SOD1 SOD1 SOD1 33 2.2 line and 1 day after transfection all lines expressing mutant SOD1 show a remarkable decrease in mitochondrial metabolic activity as indicated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137188 16046141 181716 20996 11179 SOD1 SOD1 SOD1s 77 1.7 Materials and methods 48 h after transfection expression of mutant SOD1s induces activation of caspase-3 caspase-9 but not caspase-1 ( Fig 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137189 16046141 181718 20996 11179 SOD1 SOD1 SOD1 5 2.2 Cell death induced by mutant SOD1 is prevented by treatment both with pan-caspase inhibitor z-VAD and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137190 16046141 181719 864 576 APAF1 APAF1 Apaf1 3 2.1 To analyze whether Apaf1 is involved in mutant SOD1-induced apoptosis we stably transfected SH-SY5Y 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137191 16046141 181719 20996 11179 SOD1 SOD1 SOD1-induced 8 1.7 To analyze whether Apaf1 is involved in mutant SOD1-induced apoptosis we stably transfected SH-SY5Y neuroblastoma cells with a plasmid 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137192 16046141 181719 864 576 APAF1 APAF1 Apaf1 21 2.1 stably transfected SH-SY5Y neuroblastoma cells with a plasmid coding for Apaf1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137193 16046141 181720 864 576 APAF1 APAF1 Apaf1 17 2.1 C05 C19 and C20 were chosen for equivalent expression of Apaf1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137194 16046141 181721 864 576 APAF1 APAF1 Apaf1 12 2.1 results and data from clone C05 (named named SH/Apaf1) SH Apaf1 are shown 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137195 16046141 181722 864 576 APAF1 APAF1 Apaf1 8 2.1 Western blotting with specific anti-Apaf1 antibodies shows that SH/Apaf1 SH Apaf1 neuroblastoma cells express high levels of Apaf1 ( Fig 2 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137196 16046141 181722 864 576 APAF1 APAF1 Apaf1 15 2.1 that SH/Apaf1 SH Apaf1 neuroblastoma cells express high levels of Apaf1 ( Fig 2 A 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137197 16046141 181723 864 576 APAF1 APAF1 Apaf1 4 2.1 In this conditions no Apaf1 expression is detectable in total cell lysates from control cells 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137198 16046141 181723 864 576 APAF1 APAF1 Apaf1 19 2.1 total cell lysates from control cells although SH-SY5Y do express Apaf1 as assessed by us in immunoprecipitation experiments (not not shown 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137199 16046141 181724 864 576 APAF1 APAF1 Apaf1 7 2.1 Transient transfection of control SH cells or SH/Apaf1 SH Apaf1 cells with wtSOD1 or G93A-SOD1 mutant elicits high level comparable 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137200 16046141 181724 864 576 APAF1 APAF1 Apaf1 41 2.1 of caspase-3 is dramatically increased only in G93A-expressing SH/Apaf1 SH Apaf1 cells as compared to G93A-transfected SH cells ( Fig 2 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137201 16046141 181725 864 576 APAF1 APAF1 Apaf1 23 2.1 20-fold increase of apoptotic nuclei is observed in SH/Apaf1 SH Apaf1 cells expressing the mutant SOD1 with respect to untransfected control 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137202 16046141 181725 20996 11179 SOD1 SOD1 SOD1 28 2.2 is observed in SH/Apaf1 SH Apaf1 cells expressing the mutant SOD1 with respect to untransfected control SH cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137203 16046141 181727 864 576 APAF1 APAF1 Apaf1 2 2.1 Deletion of Apaf1 prevents apoptotic death induced by fALS-SOD1 in mouse neuronal cells 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137204 16046141 181728 864 576 APAF1 APAF1 Apaf1 11 2.1 order to establish an experimental system where the role of Apaf1 in fALS-SOD1-induced cell death could be thoroughly studied embryonal cortical 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137205 16046141 181728 864 576 APAF1 APAF1 Apaf1 27 2.1 thoroughly studied embryonal cortical cells from a control mouse (Apaf1+/+) Apaf1 or a mouse knocked-out for Apaf1 (Apaf1_amp_#x2212;/_amp_#x2212;) Apaf1_amp_#x2212 _amp_#x2212 have 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137206 16046141 181728 864 576 APAF1 APAF1 Apaf1 33 2.1 a control mouse (Apaf1+/+) Apaf1 or a mouse knocked-out for Apaf1 (Apaf1_amp_#x2212;/_amp_#x2212;) Apaf1_amp_#x2212 _amp_#x2212 have been isolated and immortalized by the 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137207 16046141 181729 17732 9717 PXMP3 PAF1 paf1 15 1.3 named ETNA ( E mbryonic T elencephalic N aive A paf1 ETNA+/+ ETNA and ETNA_amp_#x2212;/_amp_#x2212; ETNA_amp_#x2212 _amp_#x2212 cell lines have been 14 JUMiner_v2.2 1 2 UserEdit 0 2 9717 TotalCon:2<>25459|PAF1|54623|Complete__9717|PXMP3|5828|Complete__<>AvaiableGeneRif=2<>BEST:9717|PXMP3|0.000903102422439439<>ScoreDetail__9717|PXMP3|0.000903102422439439__25459|PAF1|0.000372564699040419__ 1 1 0 0 0 137208 16046141 181730 864 576 APAF1 APAF1 Apaf1 5 2.1 ETNA_amp_#x2212;/_amp_#x2212; ETNA_amp_#x2212 _amp_#x2212 cells do not express Apaf1 and the absence of this adapter provides them with a 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137209 16046141 181731 864 576 APAF1 APAF1 Apaf1 4 2.1 We have observed that Apaf1 deletion also provides these cells with a complete resistance to 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137210 16046141 181734 864 576 APAF1 APAF1 Apaf1 9 2.1 Cytochrome c release induced by fALS-SOD1 is independent of Apaf1 expression 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137211 16046141 181736 20996 11179 SOD1 SOD1 SOD1 12 2.2 cytochrome c release in cells expressing either fALS-SOD1s or wild-type SOD1 ETNA cells were transfected with cDNA coding for GFP-SOD1s fusion 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137212 16046141 181737 20996 11179 SOD1 SOD1 SOD1s 15 1.7 tag does not affect the dismutase activity of the various SOD1s ( Fig 4 A GFP-G93A and GFP-A4V mutants are similar 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137213 16046141 181738 20996 11179 SOD1 SOD1 SOD1s 9 1.7 As shown in Fig 4 C overexpression of mutant SOD1s causes the appearance of large intracellular aggregates (not not visible 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137214 16046141 181738 20996 11179 SOD1 SOD1 SOD1 23 2.2 large intracellular aggregates (not not visible in cells overexpressing wild-type SOD1 in ETNA cells as in various other experimental paradigms ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137215 16046141 181739 864 576 APAF1 APAF1 Apaf1 31 2.1 expressing different fALS-SOD1s display cytochrome c release independently from the Apaf1 genotype ( Figs 4 B_amp_#x2013 D 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137216 16046141 181740 480 8768 AIFM1 AIF AIF 28 0.6 that other mitochondrial factors involved in apoptotic pathways such as AIF ( Fig 4 and Fig 5 and EndoG (not not 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137217 16046141 181740 20996 11179 SOD1 SOD1 SOD1s 48 1.7 not shown are not affected by the expression of mutant SOD1s in this system 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137218 16046141 181740 6634 3346 ENDOG ENDOG EndoG 37 0.0 such as AIF ( Fig 4 and Fig 5 and EndoG (not not shown are not affected by the expression of 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137219 16046141 181742 18723 10261 ROS1 ROS ROS 17 0.6 on mitochondrial metabolic activity ATP synthesis and the generation of ROS since alteration of these factors is likely to contribute to 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 137220 16046141 181742 20996 11179 SOD1 ALS ALS 35 1.7 to contribute to the apoptotic death of neuronal cells in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137221 16046141 181743 864 576 APAF1 APAF1 Apaf1-deficient 6 1.1 As shown in Fig 6 A Apaf1-deficient ETNA cells are completely resistant to fALS-SOD1-induced mitochondrial impairment as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137222 16046141 181745 20996 11179 SOD1 SOD1 SOD1s 6 1.7 On the opposite cotransfection of mutant SOD1s with Apaf1 in ETNA_amp_#x2212;/_amp_#x2212; ETNA_amp_#x2212 _amp_#x2212 cells significantly restores the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137223 16046141 181745 864 576 APAF1 APAF1 Apaf1 8 2.1 On the opposite cotransfection of mutant SOD1s with Apaf1 in ETNA_amp_#x2212;/_amp_#x2212; ETNA_amp_#x2212 _amp_#x2212 cells significantly restores the toxic effect 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137224 16046141 181745 864 576 APAF1 APAF1 Apaf1 34 2.1 in these cells is exclusively due to the lack of Apaf1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137225 16046141 181747 20996 11179 SOD1 SOD1 SOD1-transfected 26 1.7 cells transfected with fALS-SOD1s as compared to untransfected or wild-type SOD1-transfected cells considering that the percentage of transfected cells was estimated 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 137226 16046141 181750 20996 11179 SOD1 SOD1 SOD1 6 2.2 Again protein oxidation induced by mutant SOD1 in ETNA+/+ ETNA cells is significantly reduced in cells lacking 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137227 16046141 181750 864 576 APAF1 APAF1 Apaf1 16 2.1 in ETNA+/+ ETNA cells is significantly reduced in cells lacking Apaf1 ( Fig 6 C 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137228 16046141 181755 20996 11179 SOD1 ALS ALS 23 1.7 al. 2000 Parkinson's disease ( Yang et al. 2004 and ALS ( Yuan and Yankner 2000 Gu_amp_#xe9 gan and Przedborski 2003 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137229 16046141 181756 20996 11179 SOD1 ALS ALS 1 1.7 In ALS activation of the apoptotic pathway in motor neurons may descend 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137230 16046141 181759 20996 11179 SOD1 ALS ALS 20 1.7 terminals of muscle biopsies from patients with early diagnosed sporadic ALS ( Siklos et al. 1996 and Beal 2000 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137231 16046141 181760 20996 11179 SOD1 SOD1 SOD1 20 2.2 has been suggested also by studies where targeting of mutant SOD1 specifically to the nucleus cytosol and in the mitochondrion matrix 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137232 16046141 181763 480 8768 AIFM1 AIF AIF 41 0.6 pore causing leakage of cytochrome c and apoptosis-inducing factor (AIF) AIF ( Friedlander 2003 were suggested to play a role in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137233 16046141 181764 20996 11179 SOD1 SOD1 SOD1 81 2.2 classic_amp_#x201d apoptosis is involved in the motor neuron death in SOD1 mutant mice and perhaps also in ALS patients 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137234 16046141 181764 20996 11179 SOD1 ALS ALS 88 1.7 neuron death in SOD1 mutant mice and perhaps also in ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137235 16046141 181765 20996 11179 SOD1 ALS ALS 13 1.7 knowledge of the mechanism of cell death of neurons in ALS may provide precious suggestions on new therapeutic strategies we have 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137236 16046141 181765 864 576 APAF1 APAF1 Apaf1 37 2.1 further insight in this process by studying the contribution of Apaf1 to cell death induced by different mutants SOD1s 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137237 16046141 181765 20996 11179 SOD1 SOD1 SOD1s 45 1.7 contribution of Apaf1 to cell death induced by different mutants SOD1s 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137238 16046141 181766 20996 11179 SOD1 SOD1 SOD1 44 2.2 loops (G37R, G37R I113T thus representing every class of mutant SOD1 found in patients except those truncated at the C-term end 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137239 16046141 181767 20996 11179 SOD1 SOD1 SOD1s 14 1.7 of neuronal origin and modulating the expression of both mutant SOD1s and Apaf1 we have observed that indeed Apaf1 is a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137240 16046141 181767 864 576 APAF1 APAF1 Apaf1 16 2.1 origin and modulating the expression of both mutant SOD1s and Apaf1 we have observed that indeed Apaf1 is a key factor 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137241 16046141 181767 864 576 APAF1 APAF1 Apaf1 22 2.1 both mutant SOD1s and Apaf1 we have observed that indeed Apaf1 is a key factor in the noxious function of fALS-SOD1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137242 16046141 181767 864 576 APAF1 APAF1 Apaf1 36 2.1 factor in the noxious function of fALS-SOD1 while overexpression of Apaf1 exacerbates the induction of apoptosis ( Fig 2 its removal 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137243 16046141 181770 19941 10876 SIGLEC7 p75 p75 29 0.3 critical caspase substrate in the mitochondria and that cleavage of p75 by caspases is responsible for disruption of electron transport leading 1 JUMiner_v2.2 1 0 0 2 10876 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:10876|SIGLEC7|0.000827123217268406<>ScoreDetail__9527|PSIP1|0.000508016350763939__2557|CUX1|0.000810621883843148__10876|SIGLEC7|0.000827123217268406__11917|TNFRSF1B|0.000411889766749005__ 0 0 0 0 0 137244 16046141 181770 18723 10261 ROS1 ROS ROS 44 0.6 for disruption of electron transport leading to increased generation of ROS loss of ATP production and mitochondrial damage ( Ricci et 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 137245 16046141 181770 14254 7707 NDUFS1 NDUFS1 NDUFS1 8 0.0 Interestingly Ricci et al have recently shown that NDUFS1 the 75 kDa subunit of respiratory complex I is a 1 JUMiner_v2.2 1 1 LongSymbol 0 0 0 0 0 0 0 0 137246 16046141 181771 20996 11179 SOD1 ALS ALS 17 1.7 in this work and in several other experimental paradigms of ALS may descend from mitochondria damage rather than a direct consequence 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137247 16046141 181771 20996 11179 SOD1 SOD1 SOD1 36 2.2 direct consequence of the postulated pro-oxidant toxic function of mutant SOD1 ( Valentine 2002 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137248 16046141 181772 20996 11179 SOD1 SOD1 SOD1 1 2.2 Mutant SOD1 may either exert some aberrant chemistry specifically inside (or or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137249 16046141 181773 20996 11179 SOD1 SOD1 SOD1 8 2.2 Indeed the intracellular localization of wild-type and mutant SOD1 has recently been questioned 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137250 16046141 181774 20996 11179 SOD1 SOD1 SOD1 13 2.2 previous studies reporting that a fraction of the normally cytosolic SOD1 protein is detected within the mitochondrion probably either at the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137251 16046141 181774 20996 11179 SOD1 SOD1 SOD1 66 2.2 al have reported that multiple disease-causing mutants but not wild-type SOD1 are recruited to mitochondria but only in affected tissues ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137252 16046141 181775 20996 11179 SOD1 SOD1 SOD1 13 2.2 of protein are successfully imported but nearly constant amounts of SOD1 mutants and covalently damaged adducts of them accumulate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137253 16046141 181776 20996 11179 SOD1 SOD1 SOD1 13 2.2 damage from action of spinal cord-specific factors that recruit mutant SOD1 to spinal mitochondria as the basis for their selective toxicity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137254 16046141 181776 20996 11179 SOD1 ALS ALS 25 1.7 spinal mitochondria as the basis for their selective toxicity in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137255 16046141 181777 20996 11179 SOD1 SOD1 SOD1 20 2.2 to being in the mitochondrial outer membrane and intermembrane space SOD1 is also localized in the mitochondrial matrix 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137256 16046141 181778 20996 11179 SOD1 SOD1 SOD1 2 2.2 Furthermore aberrant SOD1 macromolecular aggregates are formed in the matrix of brain mitochondria 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137257 16046141 181779 20996 11179 SOD1 SOD1 SOD1s 4 1.7 Aggregation of mitochondrial mutant SOD1s may also have a role in altering the functionality of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137258 16046141 181780 1576 990 BCL2 Bcl-2 Bcl-2 12 1.5 al have reported that both wt- and mutSOD1 bind to Bcl-2 an anti-apoptotic protein located on the cytoplasmic face of outer 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137259 16046141 181780 1576 990 BCL2 Bcl-2 Bcl-2 31 1.5 of outer mitochondria membranes and have suggested that entrapment of Bcl-2 by large mutSOD1 aggregates may deplete motor neurons of this 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137260 16046141 181782 20996 11179 SOD1 SOD1 SOD1 8 2.2 These results suggest a mechanism by which mutant SOD1 can disrupt the association of proteins involved in cell survival 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137261 16046141 181783 20996 11179 SOD1 ALS ALS 4 1.7 In this view sporadic ALS and non-SOD1-linked fALS may descend either from other (unknown) unknown 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137262 16046141 181783 20996 11179 SOD1 SOD1 SOD1 24 2.2 causes altering mitochondria functionality or from abnormal aggregation of wild-type SOD1 together with mitochondria proteins 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137263 16046141 181785 20996 11179 SOD1 ALS ALS 9 1.7 Because mitochondrial dysfunction occurs early in the course of ALS interception of Apaf1-mediated function may represent an important site for 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00124307451123221<>ScoreDetail__5468|IGFALS|0.000378242219879445__11179|SOD1|0.00124307451123221__ 0 0 0 0 0 137264 16046141 181787 20996 11179 SOD1 SOD1 SOD1 5 2.2 (A) A Western blot analysis of SOD1 expression in SH-SY5Y cells untransfected or transiently transfected for 48 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137265 16046141 181787 20996 11179 SOD1 SOD1 SOD1 26 2.2 h with wtSOD1 and G93A G37R G85R and I113T mutant SOD1 20 _amp_#x3bc g of total cell lysates was loaded 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137266 16046141 181791 646 456 AMCN AMC AMC 3 0.0 The amount of AMC release was quantified using a fluorescence plate reader 1 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 137267 16046141 181797 864 576 APAF1 APAF1 Apaf1 3 2.1 Fig 2._amp_#xa0 Overexpression of Apaf1 exacerbates apoptotic death induced by fALS-SOD1 in human neuroblastoma 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137268 16046141 181798 864 576 APAF1 APAF1 Apaf1 9 2.1 A Na_amp_#xef ve SH-SY5Y cells or SH-SY5Y cells stably overexpressing Apaf1 (SH/Apaf1) SH Apaf1 were transiently transfected with wtSOD1 or with 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137269 16046141 181798 864 576 APAF1 APAF1 Apaf1 10 2.1 SH-SY5Y cells or SH-SY5Y cells stably overexpressing Apaf1 (SH/Apaf1) SH Apaf1 were transiently transfected with wtSOD1 or with the G93A-SOD1 mutant 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137270 16046141 181799 20996 11179 SOD1 SOD1 SOD1 15 2.2 of total cell lysates was analyzed for the expression of SOD1 and Apaf1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137271 16046141 181799 864 576 APAF1 APAF1 Apaf1 17 2.1 cell lysates was analyzed for the expression of SOD1 and Apaf1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137272 16046141 181804 864 576 APAF1 APAF1 Apaf1 3 2.1 Fig 3._amp_#xa0 Deletion of Apaf1 prevents apoptotic death induced by fALS-SOD1 in mouse neuronal cells 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137273 16046141 181810 864 576 APAF1 APAF1 Apaf1 10 2.1 4._amp_#xa0 Cytochrome c release induced by fALS-SOD1 is independent of Apaf1 expression 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137274 16046141 181812 20996 11179 SOD1 SOD1 SOD1 3 2.2 After 24 h SOD1 activity was detected on 10% polyacrylamide gel by the NBT/riboflavin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137275 16046141 181818 480 8768 AIFM1 AIF AIF 28 0.6 mutants were assessed for the presence of cytochrome c and AIF by Western blot 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137276 16046141 181819 480 8768 AIFM1 AIF AIF 16 0.6 untransfected ETNA cells were used as a positive control for AIF and cytochrome c expression 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137277 16046141 181821 480 8768 AIFM1 AIF AIF 5 0.6 Fig 5._amp_#xa0 ETNA cells retain mitochondrial AIF upon fALS-SOD1 expression 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137278 16046141 181822 480 8768 AIFM1 AIF AIF 10 0.6 confocal immunofluorescence microscopy staining of cytochrome c (green) green and AIF (red) red in ETNA cells 48 h after transfection with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137279 16046141 181826 5131 2524 CTRL CTRL ctrl 17 0.0 G93A G37R G85R and I113T-SOD1 mutants in the absence (ctrl) ctrl or in the presence (zVAD) zVAD of 100 _amp_#x3bc M 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137280 16046141 181827 864 576 APAF1 APAF1 Apaf1 14 2.1 wtSOD1 or G93A G37R G85R and I113T-SOD1 mutants with (Apaf1) Apaf1 or without a plasmid coding for Apaf1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137281 16046141 181827 864 576 APAF1 APAF1 Apaf1 21 2.1 mutants with (Apaf1) Apaf1 or without a plasmid coding for Apaf1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137783 16050975 182083 20996 11179 SOD1 ALS ALS 15 1.7 is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137784 16050975 182085 20996 11179 SOD1 ALS ALS 11 1.7 and biochemical mitochondrial abnormalities have been described in sporadic human ALS cases but the implications of these findings in terminally ill 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137785 16050975 182086 20996 11179 SOD1 ALS ALS 14 1.7 have also been identified in transgenic mouse models of familial ALS expressing mutant Cu Zn superoxide dismutase (SOD1) SOD1 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137786 16050975 182086 20996 11179 SOD1 SOD1 SOD1 21 3.5 of familial ALS expressing mutant Cu Zn superoxide dismutase (SOD1) SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137787 16050975 182087 20996 11179 SOD1 ALS ALS 33 1.7 mitochondrial dysfunction may be causally involved in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137788 16050975 182088 20996 11179 SOD1 SOD1 SOD1 5 3.5 Although the mechanisms whereby mutant SOD1 damages mitochondria remain to be fully understood the finding that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137789 16050975 182088 20996 11179 SOD1 SOD1 SOD1 20 3.5 be fully understood the finding that a portion of mutant SOD1 is localized in mitochondria where it forms aberrant aggregates and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137790 16050975 182089 20996 11179 SOD1 SOD1 SOD1 14 3.5 to devise models to better understand the effects of mutant SOD1 in mitochondria and the relative contribution of mitochondrial dysfunction to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137791 16050975 182089 20996 11179 SOD1 ALS ALS 28 1.7 the relative contribution of mitochondrial dysfunction to the pathogenesis of ALS as well as to identify therapeutic approaches that target mitochondrial 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137792 16050975 182095 20996 11179 SOD1 ALS ALS 45 1.7 as a potentially important contributing factor to the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137793 16050975 182096 20996 11179 SOD1 ALS ALS 13 1.7 we will briefly describe the clinical and pathological characteristics of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137794 16050975 182097 20996 11179 SOD1 ALS ALS 13 1.7 examine the current evidence supporting the involvement of mitochondria in ALS and discuss its potential implications for the mechanism of pathogenesis 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137795 16050975 182102 20996 11179 SOD1 ALS ALS 0 1.7 ALS is a fatal neurodegenerative disorder that selectively affects neurons of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137796 16050975 182103 20996 11179 SOD1 ALS ALS 3 1.7 The prevalence of ALS is approximately 1_amp_#x2013 2 in 100 000 individuals ( Roman 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137797 16050975 182104 20996 11179 SOD1 ALS ALS 3 1.7 The onset of ALS is most common in the fourth and fifth decade of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137798 16050975 182108 20996 11179 SOD1 ALS ALS 1 1.7 Pathologically ALS is characterized by extensive loss of lower motor neurons in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137799 16050975 182110 20996 11179 SOD1 ALS ALS 16 1.7 incompletely defined etiology such as Alzheimer's disease and Parkinson's disease ALS appears to be a syndrome originating from diverse pathogenic processes 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137800 16050975 182111 20996 11179 SOD1 ALS ALS 0 1.7 ALS is predominantly a sporadic disorder (SALS), SALS but approximately 10% 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137801 16050975 182115 20996 11179 SOD1 ALS ALS 16 1.7 understanding the development and the role of mitochondrial dysfunction in ALS using these transgenic models 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137802 16050975 182118 20996 11179 SOD1 ALS ALS 1 1.7 Familial ALS due to SOD1 mutations and transgenic mouse models 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137803 16050975 182118 20996 11179 SOD1 SOD1 SOD1 4 3.5 Familial ALS due to SOD1 mutations and transgenic mouse models 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137804 16050975 182119 20996 11179 SOD1 SOD1 SOD1 16 3.5 to mutations in the gene encoding superoxide dismutase 1 (SOD1; SOD1 Cu Zn dismutase MIM147450 ( Rosen et al. 1993 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137805 16050975 182121 20996 11179 SOD1 SOD1 SOD1 0 3.5 SOD1 is a ubiquitous metalloprotein that prevents damage by oxygen-mediated free 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137806 16050975 182122 20996 11179 SOD1 SOD1 SOD1 8 3.5 The symptoms and pathology of FALS patients with SOD1 mutations closely resemble those of patients with SALS and the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137807 16050975 182122 20996 11179 SOD1 SOD1 SOD1 31 3.5 and pathologic alterations in motor neurons from mice expressing mutant SOD1 are also strikingly similar to those found in SALS patients 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137808 16050975 182123 20996 11179 SOD1 SOD1 SOD1 5 3.5 Since the initial report of SOD1 mutations ( Rosen et al. 1993 more than 100 different 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137809 16050975 182123 20996 11179 SOD1 SOD1 SOD1 21 3.5 al. 1993 more than 100 different mutated forms of the SOD1 gene most of which are missense mutations have been identified 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137810 16050975 182124 20996 11179 SOD1 SOD1 SOD1 7 3.5 Because several pathogenic mutations do not affect SOD1 activity significantly ( Borchelt et al. 1994 a toxic _amp_#x2018 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137811 16050975 182125 20996 11179 SOD1 SOD1 SOD1 14 3.5 confirmed by several transgenic studies in which mice expressing mutant SOD1 develop motor neuron degeneration despite an overall increase in their 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137812 16050975 182125 20996 11179 SOD1 SOD1 SOD1 25 3.5 develop motor neuron degeneration despite an overall increase in their SOD1 activity ( Xu 2000 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137813 16050975 182128 20996 11179 SOD1 SOD1 SOD1 1 3.5 Mutant SOD1 is expressed ubiquitously but the pathological process leading to the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137814 16050975 182129 20996 11179 SOD1 SOD1 SOD1 4 3.5 The tissue selectivity of SOD1 toxicity is a puzzling problem that has yet to be 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137815 16050975 182130 20996 11179 SOD1 SOD1 SOD1 6 3.5 While mouse models that express mutant SOD1 ubiquitously (similar similar to what happens in humans develop motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137816 16050975 182130 20996 11179 SOD1 ALS ALS 19 1.7 to what happens in humans develop motor neuron degeneration and ALS models that express mutant SOD1 exclusively either in the motor 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137817 16050975 182130 20996 11179 SOD1 SOD1 SOD1 24 3.5 develop motor neuron degeneration and ALS models that express mutant SOD1 exclusively either in the motor neurons or in astrocytes do 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137818 16050975 182131 20996 11179 SOD1 SOD1 SOD1 12 3.5 this view in chimeric mice that contain a mixture of SOD1 mutant and wild type cells motor neurons with wild type 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137819 16050975 182131 20996 11179 SOD1 SOD1 SOD1 23 3.5 mutant and wild type cells motor neurons with wild type SOD1 develop signs of degeneration whereas non-neuronal cells with wild type 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137820 16050975 182131 20996 11179 SOD1 SOD1 SOD1 46 3.5 to attenuate the degeneration of motor neurons with the mutant SOD1 gene ( Clement et al. 2003 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137821 16050975 182134 20996 11179 SOD1 ALS ALS 3 1.7 Mitochondrial involvement in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137822 16050975 182136 20996 11179 SOD1 ALS ALS 4 1.7 Mitochondrial involvement in sporadic ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137823 16050975 182140 20996 11179 SOD1 ALS ALS 16 1.7 levels within the mitochondria were found in muscle biopsies of ALS patients ( Siklos et al. 1996 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137824 16050975 182147 20996 11179 SOD1 ALS ALS 13 1.7 created cytoplasmic hybrid cells (cybrids) cybrids by fusing platelets from ALS patients (as as mitochondrial donor with neuroblastoma cells that have 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137825 16050975 182148 20996 11179 SOD1 ALS ALS 3 1.7 They showed that ALS cybrids have impaired respiratory chain function increased free radical production 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137826 16050975 182152 20996 11179 SOD1 SOD1 SOD1 8 3.5 However thanks to the availability of the mutant SOD1 transgenic mice that have provided an excellent platform to investigate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137827 16050975 182153 20996 11179 SOD1 ALS ALS 31 1.7 these studies have increased our understanding of mitochondrial involvement in ALS raised new questions and generated new hypotheses that can be 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137828 16050975 182154 20996 11179 SOD1 SOD1 SOD1 36 3.5 neuron degeneration in models of FALS caused by mutations in SOD1 gene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137829 16050975 182156 20996 11179 SOD1 ALS ALS 5 1.7 Mitochondrial involvement in models of ALS created by introduction of SOD1 mutants 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137830 16050975 182156 20996 11179 SOD1 SOD1 SOD1 10 3.5 Mitochondrial involvement in models of ALS created by introduction of SOD1 mutants 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137831 16050975 182157 20996 11179 SOD1 SOD1 SOD1 9 3.5 A striking pathological feature observed in transgenic mice expressing SOD1 mutants G93A or G37R is the presence of membrane bound 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137832 16050975 182164 20996 11179 SOD1 SOD1 SOD1 13 3.5 evidence obtained in cellular models indicate that expression of mutant SOD1 is not only associated with mitochondrial morphological changes but also 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137833 16050975 182165 20996 11179 SOD1 SOD1 SOD1 21 3.5 observed in neuroblastoma cells transfected with the mutated form of SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137834 16050975 182168 20996 11179 SOD1 SOD1 SOD1 48 3.5 found in cultured motor neuron-like cells expressing mutated forms of SOD1 ( Menzies et al. 2002 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137835 16050975 182169 20996 11179 SOD1 SOD1 SOD1 13 3.5 reported that mitochondrial bioenergetics is impaired in the G93A mutant SOD1 mouse model of FALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137836 16050975 182173 20996 11179 SOD1 SOD1 SOD1 10 3.5 Recently we have found that the bioenergetic failure in the SOD1 mutant mice causes an impairment of mitochondrial calcium loading capacity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137837 16050975 182175 20996 11179 SOD1 SOD1 SOD1 6 3.5 Impaired mitochondrial calcium loading capacity in SOD1 mutant mice may produce two consequences 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137838 16050975 182176 20996 11179 SOD1 ALS ALS 24 1.7 of the potential mechanisms for the motor neuron-selective toxicity in ALS ( Rothstein 1996 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137839 16050975 182178 8790 4572 GRIA2 GLUR2 gluR2 13 1.3 supported by the observation that overexpression of the calcium impermeable gluR2 subunit in motor neurons improves life span and motor functions 14 JUMiner_v2.2 1 0 0 2 4572 TotalCon:2<>4572|GRIA2|2891|Complete__4594|GRM2|2912|Complete__<>AvaiableGeneRif=2<>BEST:4572|GRIA2|0.000464718227958937<>ScoreDetail__4594|GRM2|0.000250035085568459__4572|GRIA2|0.000464718227958937__ 0 0 0 0 0 137840 16050975 182181 20996 11179 SOD1 SOD1 hSOD1 10 1.7 Consistent with this view antioxidant agents extended survival of mutant hSOD1 transgenic mice ( Jung et al. 2001 and Wu et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137841 16050975 182183 20996 11179 SOD1 ALS ALS 4 1.7 Mitochondria and apoptosis in ALS models 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137842 16050975 182185 20996 11179 SOD1 ALS ALS 9 1.7 Although the mechanisms leading to motor neuron death in ALS are still unclear several lines of evidence suggest that the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137843 16050975 182186 20996 11179 SOD1 SOD1 SOD1 4 3.5 The expression of mutant SOD1 predisposes cultured neuronal cells to activation of apoptosis in response 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137844 16050975 182187 20996 11179 SOD1 SOD1 SOD1 15 3.5 3 are activated sequentially in differentiated neuroblastoma cells expressing mutant SOD1 in response to oxidative stress ( Pasinelli et al. 1998 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137845 16050975 182190 1576 990 BCL2 Bcl-2 Bcl-2 19 1.8 al. 2000 and the overexpression of the mitochondrial anti-apoptotic protein Bcl-2 ( Kostic et al. 1997 slow motor neuron degeneration and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137846 16050975 182190 20996 11179 SOD1 SOD1 SOD1 35 3.5 1997 slow motor neuron degeneration and extend the survival of SOD1 mutant mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137847 16050975 182191 20996 11179 SOD1 ALS ALS 13 1.7 of caution should be said in regard to apoptosis in ALS motor neurons 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137848 16050975 182192 20996 11179 SOD1 SOD1 SOD1 3 3.5 For example mutant SOD1 mice genetically lacking caspase 11 an upstream regulator of the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137849 16050975 182193 20996 11179 SOD1 ALS ALS 15 1.7 of apoptotic cell death are difficult to detect both in ALS patients and in transgenic animals ( Migheli et al. 1999 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137850 16050975 182194 20996 11179 SOD1 ALS ALS 12 1.7 suggest that if the mitochondrially initiated apoptosis is occurring in ALS motor neurons it may follow an atypical course where the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137851 16050975 182195 480 8768 AIFM1 AIF AIF 23 0.6 pro-apoptotic factors such as cytochrome c apoptosis inducing factor (AIF), AIF and endoG from individual mitochondria perhaps in response to local 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137852 16050975 182195 6634 3346 ENDOG ENDOG endoG 25 0.1 such as cytochrome c apoptosis inducing factor (AIF), AIF and endoG from individual mitochondria perhaps in response to local calcium mediated 6 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137853 16050975 182198 20996 11179 SOD1 ALS ALS 5 1.7 Consistent with this scenario in ALS axons degenerate from the distal to the proximal direction (dying 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137854 16050975 182202 20996 11179 SOD1 SOD1 SOD1 5 3.5 Mechanisms of mitochondrial dysfunction in SOD1 FALS mitochondrial localization of SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137855 16050975 182202 20996 11179 SOD1 SOD1 SOD1 10 3.5 Mechanisms of mitochondrial dysfunction in SOD1 FALS mitochondrial localization of SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137856 16050975 182203 20996 11179 SOD1 SOD1 SOD1 15 3.5 changes and the biochemical abnormalities observed in mice expressing mutant SOD1 are still the object of intense investigation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137857 16050975 182204 20996 11179 SOD1 SOD1 SOD1 10 3.5 Two fundamental questions remain to be answered how is mutant SOD1 causing mitochondrial degeneration and dysfunction and is mitochondrial dysfunction necessary 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137858 16050975 182204 20996 11179 SOD1 SOD1 SOD1-induced 28 1.7 necessary and/or and or sufficient for the development of mutant SOD1-induced motor neuron degeneration 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137859 16050975 182205 20996 11179 SOD1 SOD1 SOD1 16 3.5 answering these questions is the finding that a portion of SOD1 (most most of which is cytosolic is actually localized in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137860 16050975 182206 20996 11179 SOD1 SOD1 SOD1 0 3.5 SOD1 enzymatic activity in rat liver mitochondria was first detected by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137861 16050975 182207 20996 11179 SOD1 SOD1 SOD1 4 3.5 Recently the existence of SOD1 in mitochondria of eukaryotic cells has been confirmed by several 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137862 16050975 182208 20996 11179 SOD1 SOD1 SOD1 7 3.5 By cell fractionation and mitochondrial purification techniques SOD1 was detected in the mitochondria of the yeast S cerevisiae 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137863 16050975 182209 20996 11179 SOD1 SOD1 SOD1 17 3.5 2001 and Higgins et al. 2002 have independently demonstrated that SOD1 localizes in the mitochondria of motor neurons in the spinal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137864 16050975 182210 20996 11179 SOD1 SOD1 SOD1 9 3.5 These investigators showed that both wild type and mutant SOD1 are localized in mitochondria 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137865 16050975 182211 20996 11179 SOD1 SOD1 SOD1 11 3.5 addition Field and colleagues have showed that the retention of SOD1 inside yeast mitochondria is dependent upon the interaction with its 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137866 16050975 182211 3838 1613 CCS CCS CCS 24 0.9 mitochondria is dependent upon the interaction with its copper chaperone CCS since SOD1 mutants that are unable to interact with CCS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137867 16050975 182211 20996 11179 SOD1 SOD1 SOD1 26 3.5 dependent upon the interaction with its copper chaperone CCS since SOD1 mutants that are unable to interact with CCS _amp_#x2018 leak 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137868 16050975 182211 3838 1613 CCS CCS CCS 34 0.9 CCS since SOD1 mutants that are unable to interact with CCS _amp_#x2018 leak out_amp_#x2019 of mitochondria ( Field et al. 2003 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137869 16050975 182212 20996 11179 SOD1 SOD1 SOD1 10 3.5 Based on mitochondrial fractionation experiments several groups have proposed that SOD1 concentrates mostly in the intermembrane space of mitochondria ( Okado-Matsumoto 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137870 16050975 182213 20996 11179 SOD1 SOD1 SOD1 9 3.5 Recent experiments suggest that in mice expressing transgenic human SOD1 a portion of mutant SOD1 may also localize in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137871 16050975 182213 20996 11179 SOD1 SOD1 SOD1 14 3.5 in mice expressing transgenic human SOD1 a portion of mutant SOD1 may also localize in the matrix space of mitochondria where 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137872 16050975 182213 20996 11179 SOD1 SOD1 SOD1 30 3.5 matrix space of mitochondria where it forms large aggregates containing SOD1 and possibly other mitochondrial matrix proteins ( Vijayvergiya and Manfredi 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137873 16050975 182214 20996 11179 SOD1 SOD1 SOD1 3 3.5 Although how mutant SOD1 damages mitochondria has not been unequivocally defined several non-mutually exclusive 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137874 16050975 182215 20996 11179 SOD1 SOD1 SOD1 6 3.5 Higgins and colleagues have observed that SOD1 and cytochrome c a resident protein of the intermembrane space 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137875 16050975 182215 20996 11179 SOD1 SOD1 SOD1 28 3.5 colocalize at the early stages of mitochondrial vacuolization in mutant SOD1 transgenic mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137876 16050975 182216 20996 11179 SOD1 SOD1 SOD1 6 3.5 They also observed large aggregates of SOD1 immunoreactive material within the vacuoles 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137877 16050975 182220 20996 11179 SOD1 SOD1 SOD1 11 3.5 and colleagues have recently reported that in transgenic mice mutant SOD1 but not wild type SOD1 associates preferentially with mitochondria of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137878 16050975 182220 20996 11179 SOD1 SOD1 SOD1 16 3.5 that in transgenic mice mutant SOD1 but not wild type SOD1 associates preferentially with mitochondria of the spinal cord 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137879 16050975 182221 20996 11179 SOD1 SOD1 SOD1 4 3.5 They proposed that mutant SOD1 progressively accumulates and aggregates on the outer membrane causing _amp_#x2018 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137880 16050975 182222 20996 11179 SOD1 SOD1 SOD1 40 3.5 of FALS it would suggest that mitochondrial localization of mutant SOD1 resulting in protein import impairment is an important contributor to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137881 16050975 182223 20996 11179 SOD1 SOD1 SOD1 23 3.5 mentioned above where both wild type and mutant transgenic human SOD1 were detected in the mitochondria of various tissues including brain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137882 16050975 182224 20996 11179 SOD1 SOD1 SOD1 10 3.5 Discrepancies in terms of the localization of the wild type SOD1 in these studies may be attributed to the differences in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137883 16050975 182224 20996 11179 SOD1 SOD1 SOD1 27 3.5 to the differences in the strategies for mitochondrial purification and SOD1 detection and will require further experiments to be reconciled 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137884 16050975 182225 20996 11179 SOD1 SOD1 SOD1 17 3.5 to clarify the specificity and the exact intramitochondrial localization of SOD1 there is general agreement that mutant SOD1 tends to form 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137885 16050975 182225 20996 11179 SOD1 SOD1 SOD1 24 3.5 intramitochondrial localization of SOD1 there is general agreement that mutant SOD1 tends to form aggregates in mitochondria with potential pathogenic effects 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137886 16050975 182227 20996 11179 SOD1 SOD1 SOD1 10 3.5 In particular it will be interesting to assess whether mutant SOD1 forms abnormal interactions with other mitochondrial proteins which may lead 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137887 16050975 182228 20996 11179 SOD1 SOD1 SOD1 13 3.5 such potentially harmful protein-protein interactions is the binding of mutant SOD1 with Bcl-2 ( Pasinelli et al. 2004 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137888 16050975 182228 1576 990 BCL2 Bcl-2 Bcl-2 15 1.8 harmful protein-protein interactions is the binding of mutant SOD1 with Bcl-2 ( Pasinelli et al. 2004 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137889 16050975 182229 20996 11179 SOD1 SOD1 SOD1 22 3.5 in protein import and energy metabolism may interact with mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137890 16050975 182231 20996 11179 SOD1 SOD1 SOD1 1 3.5 Because SOD1 is present both in the cytosol and in mitochondria it 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137891 16050975 182231 20996 11179 SOD1 SOD1 SOD1 27 3.5 mitochondrial dysfunction to a direct toxic effect of mitochondrial mutant SOD1 alone 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137892 16050975 182232 20996 11179 SOD1 SOD1 SOD1 16 3.5 mitochondrial dysfunction may arise as a consequence of cytosolic mutant SOD1 toxicity cannot be ruled out 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137893 16050975 182233 20996 11179 SOD1 SOD1 SOD1 4 3.5 For example mutant cytosolic SOD1 could promote aberrant production of reactive oxygen species ( Estevez 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137894 16050975 182236 20996 11179 SOD1 ALS ALS 13 1.7 a necessary step in motor neuron degeneration and development of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137895 16050975 182238 20996 11179 SOD1 SOD1 SOD1 19 3.5 are prominent pathological features in the G93A and the G37R SOD1 transgenic mice other mouse models such as those transgenic for 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137896 16050975 182240 20996 11179 SOD1 SOD1 SOD1 7 3.5 It remains to be tested whether some SOD1 mutants can affect mitochondrial functions without causing overt morphological changes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137897 16050975 182241 20996 11179 SOD1 SOD1 SOD1 9 3.5 Since most of the work on the bioenergetics of SOD1 mutant mitochondria has been done in the G93A model in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137898 16050975 182242 20996 11179 SOD1 SOD1 SOD1 34 3.5 function and protecting mitochondria from the pro-apoptotic effect of mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137899 16050975 182244 20996 11179 SOD1 SOD1 SOD1 31 3.5 of the mitochondrial apoptotic pathway extend the lifespan of mutant SOD1 transgenic mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137900 16050975 182247 20996 11179 SOD1 SOD1 SOD1 12 3.5 could be to generate cellular and animal models where mutant SOD1 is selectively localized in the mitochondria 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137901 16050975 182248 20996 11179 SOD1 SOD1 SOD1 3 3.5 Mitochondrial targeting of SOD1 could be achieved by appending specific mitochondrial targeting signals on 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137902 16050975 182250 20996 11179 SOD1 SOD1 SOD1 7 3.5 Conversely the identification of protein domains in SOD1 crucial for its mitochondrial import could allow for the generation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137903 16050975 182250 20996 11179 SOD1 SOD1 SOD1 26 3.5 the generation of models where the mitochondrial content of mutant SOD1 is drastically reduced or eliminated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137904 16050975 182251 20996 11179 SOD1 SOD1 SOD1 10 3.5 The comparison of these models with the ones where mutant SOD1 is expressed in both the cytosolic and mitochondrial compartments will 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137905 16050975 182251 20996 11179 SOD1 SOD1 SOD1 29 3.5 compartments will help us defining the role that mitochondrial mutant SOD1 plays in mitochondrial dysfunction and ultimately in the pathogenesis of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137906 16050975 182252 20996 11179 SOD1 SOD1 SOD1-related 9 1.7 Fig 1._amp_#xa0 Diagram of potential pathways of mitochondrial involvement in SOD1-related ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137907 16050975 182252 20996 11179 SOD1 ALS ALS 10 1.7 1._amp_#xa0 Diagram of potential pathways of mitochondrial involvement in SOD1-related ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00109460856319025<>ScoreDetail__5468|IGFALS|0.000256580402565804__11179|SOD1|0.00109460856319025__ 0 0 0 0 0 137908 16050975 182253 20996 11179 SOD1 SOD1 SOD1 1 3.5 Mutant SOD1 has been proposed to affect mitochondrial functions in several ways 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137909 16050975 182255 20996 11179 SOD1 SOD1 SOD1 1 3.5 Mutant SOD1 may affect mitochondria directly within the organelles or indirectly from 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137910 16050975 182256 20996 11179 SOD1 SOD1 SOD1 3 3.5 Within mitochondria mutant SOD1 may interfere with the anti-apoptotic function of Bcl-2 ( Pasinelli 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137911 16050975 182256 1576 990 BCL2 Bcl-2 Bcl-2 11 1.8 mitochondria mutant SOD1 may interfere with the anti-apoptotic function of Bcl-2 ( Pasinelli et al. 2004 affect mitochondrial import by interfering 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137912 16050975 182256 17370 15860 PRPF6 TOM TOM 27 0.0 affect mitochondrial import by interfering with the translocation machinery (TOM/TIM) TOM TIM ( Liu et al. 2004 generate toxic free radicals 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 137913 16050975 182256 1016 13209 ARHGEF5 TIM TIM 27 0.0 mitochondrial import by interfering with the translocation machinery (TOM/TIM) TOM TIM ( Liu et al. 2004 generate toxic free radicals (ROS) 1 JUMiner_v2.2 1 0 0 2 11813 TotalCon:2<>13209|ARHGEF5|7984|Complete__11813|TIMELESS|8914|Complete__<>AvaiableGeneRif=2<>BEST:11813|TIMELESS|0.000270112166006307<>ScoreDetail__13209|ARHGEF5|9.53538820949248e-05__11813|TIMELESS|0.000270112166006307__ 0 0 0 0 0 137914 16050975 182256 18723 10261 ROS1 ROS ROS 38 0.0 ( Liu et al. 2004 generate toxic free radicals (ROS) ROS via aberrant superoxide chemistry ( Estevez et al. 1999 accumulate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131705 16188953 173803 18723 10261 ROS1 ROS ROS 5 1.2 Detoxification of reactive oxygen species (ROS) ROS by pramipexole is shown in vitro and in vivo by 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131706 16188953 173803 18723 10261 ROS1 ROS ROS 18 1.2 is shown in vitro and in vivo by evaluating mitochondrial ROS release and aconitase-2 activity respectively 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131707 16188953 173805 18723 10261 ROS1 ROS ROS 21 1.2 the reactivity of the respective radical and the compartmentalization of ROS generation and ROS detoxification 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131708 16188953 173805 18723 10261 ROS1 ROS ROS 24 1.2 the respective radical and the compartmentalization of ROS generation and ROS detoxification 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131709 16188953 173808 18723 10261 ROS1 ROS ROS 30 1.2 to accumulate in brain cells and mitochondria where they detoxify ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131710 16188953 173811 17189 9319 PPP4C PPX PPX 1 0.3 Pramipexole (PPX) PPX - -2-amino-4 5 6 7-tetrahydro-6-D -propylamino-benzathiazole is a nonergot dopamine 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131711 16188953 173812 17189 9319 PPP4C PPX PPX 7 0.3 Preclinical studies show that nanomolar concentrations of PPX protect dopaminergic neurons in vitro (Ling Ling et al. 1999 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131712 16188953 173813 17189 9319 PPP4C PPX PPX 9 0.3 This is possibly mediated by the high selectivity of PPX for D3 receptors (Mierau Mierau et al. 1995 Ramirez et 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131713 16188953 173814 17189 9319 PPP4C PPX PPX 6 0.3 At higher concentrations (above above 10 microM PPX has been shown to be neuroprotective in vitro independent of 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131714 16188953 173815 17189 9319 PPP4C PPX PPX 6 0.3 In addition SND the (+)-enantiomer -enantiomer of PPX has been shown to be neuroprotective as well (Abramova Abramova 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131715 16188953 173815 17189 9319 PPP4C PPX PPX 37 0.3 affinity to dopamine receptors is approximately 100-fold less compared with PPX (Mierau, Mierau 1995 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131716 16188953 173819 17189 9319 PPP4C PPX PPX 4 0.3 However the concept that PPX and/or and or SND act intracellularly as mitochondrial-targeted antioxidants has 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131717 16188953 173821 20996 11179 SOD1 ALS ALS 26 2.2 of Alzheimer's diseases Parkinson's disease or amyotrophic lateral sclerosis (ALS) ALS (Andersen, Andersen 2004 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131718 16188953 173822 17189 9319 PPP4C PPX PPX 25 0.3 to enter neural cells and exert the same properties as PPX 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131719 16188953 173823 17189 9319 PPP4C PPX PPX 20 0.3 efficacy toward hydrogen peroxide and nitric oxide when compared with PPX and by equipotent efficacy of SND and PPX to prevent 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131720 16188953 173823 17189 9319 PPP4C PPX PPX 28 0.3 compared with PPX and by equipotent efficacy of SND and PPX to prevent cell death in glutathione-depleted neuroblastoma cells (Maher Maher 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131721 16188953 173824 17189 9319 PPP4C PPX PPX 7 0.3 This study addresses those neuroprotective properties of PPX and SND which are not mediated by stimulation of dopamine 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131722 16188953 173825 17189 9319 PPP4C PPX PPX 15 0.3 action is demonstrated by evaluating the uptake properties of H-labeled PPX 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131723 16188953 173826 17189 9319 PPP4C PPX PPX 7 0.3 We show for the first time that PPX enters neural cells and accumulates in mitochondria driven by mitochondrial 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131724 16188953 173827 17189 9319 PPP4C PPX PPX 2 0.3 In addition PPX detoxifies ROS within the mitochondria as shown by inhibition of 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131725 16188953 173827 18723 10261 ROS1 ROS ROS 4 1.2 In addition PPX detoxifies ROS within the mitochondria as shown by inhibition of mitochondrial hydrogen 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131726 16188953 173827 166 118 ACO2 aconitase aconitase 28 1.6 2 O 2 release and by an increase in mitochondrial aconitase activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131727 16188953 173828 20996 11179 SOD1 ALS ALS 0 2.2 ALS is a devastating disease progressing from mild motor symptoms to 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131728 16188953 173829 20996 11179 SOD1 ALS ALS 4 2.2 Twenty percent of familial ALS cases are caused by mutations in superoxide dismutase 1 (SOD1), 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131729 16188953 173829 20996 11179 SOD1 SOD1 SOD1 14 2.2 cases are caused by mutations in superoxide dismutase 1 (SOD1), SOD1 which expressed in mice result in a phenotype resembling the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131730 16188953 173830 20996 11179 SOD1 SOD1 SOD1 1 2.2 Transgenic SOD1 mice represent the predominant model to study ALS pathogenesis and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131731 16188953 173830 20996 11179 SOD1 ALS ALS 9 2.2 Transgenic SOD1 mice represent the predominant model to study ALS pathogenesis and therapy 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131732 16188953 173831 20996 11179 SOD1 ALS ALS 4 2.2 Neuronal cell death in ALS is at least in part associated with an increase in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131733 16188953 173832 20996 11179 SOD1 ALS ALS 11 2.2 dysfunction seems a likely candidate to explain many facets of ALS because it is the earliest reported pathologic event in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131734 16188953 173832 20996 11179 SOD1 ALS ALS 21 2.2 ALS because it is the earliest reported pathologic event in ALS mice (Bendotti Bendotti et al. 2001 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131735 16188953 173833 18723 10261 ROS1 ROS ROS 18 1.2 oxidative stress and indeed markers of oxidative damage (increased increased ROS flux oxidatively modified proteins have been found in cultured neuronal 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131736 16188953 173834 17189 9319 PPP4C PPX PPX 1 0.3 Furthermore PPX reduces oxidative stress in ALS patients (Pattee Pattee et al. 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131737 16188953 173834 20996 11179 SOD1 ALS ALS 6 2.2 Furthermore PPX reduces oxidative stress in ALS patients (Pattee Pattee et al. 2003 pointing to the necessity 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131738 16188953 173834 17189 9319 PPP4C PPX PPX 19 0.3 Pattee et al. 2003 pointing to the necessity to evaluate PPX and SND for their efficacy in an animal model for 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131739 16188953 173834 20996 11179 SOD1 ALS ALS 30 2.2 and SND for their efficacy in an animal model for ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131740 16188953 173835 17189 9319 PPP4C PPX PPX 5 0.3 To test for neuroprotection by PPX/SND PPX SND in vivo transgenic SOD1 mice were treated with both 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131741 16188953 173835 20996 11179 SOD1 SOD1 SOD1 9 2.2 test for neuroprotection by PPX/SND PPX SND in vivo transgenic SOD1 mice were treated with both compounds 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131742 16188953 173836 17189 9319 PPP4C PPX PPX 2 0.3 Treatment with PPX resulted in preonset motor hyperactivity SND was able to prolong 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131743 16188953 173837 17189 9319 PPP4C PPX PPX 7 0.3 This is the first report showing that PPX and SND are able to act as brain- and mitochondrial-targeted 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131744 16188953 173860 17189 9319 PPP4C PPX PPX 19 0.3 5 mM glutamate with or without the additional presence of PPX SND (both both 0.008-1 mM or EUK-134 (2-250 2-250 microM 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131745 16188953 173871 17189 9319 PPP4C PPX PPX 6 0.3 For analyzing the uptake of H PPX (69 69 mCi/mmol, mCi mmol GE Healthcare Little Chalfont Buckinghamshire 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131746 16188953 173871 20247 20116 SLC25A29 CACL CaCl 35 1.0 buffer (20 20 mM HEPES 145 mM NaCl 1.8 mM CaCl 2 5.4 mM KCl 1 mM MgCl 2 0.8 mM 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 131747 16188953 173871 8255 4236 GFER HPO HPO 50 0.0 mM KCl 1 mM MgCl 2 0.8 mM Na 2 HPO 4 and 5 mM glucose pH 7.4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131748 16188953 173873 17189 9319 PPP4C PPX PPX 3 0.3 Uptake of H PPX was started by the addition of 200 microl of H 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131749 16188953 173873 17189 9319 PPP4C PPX PPX 14 0.3 was started by the addition of 200 microl of H PPX (6 6 microCi/ml) microCi ml in incubation buffer with or 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131750 16188953 173873 17189 9319 PPP4C PPX PPX 24 0.3 microCi/ml) microCi ml in incubation buffer with or without unlabeled PPX (0-30 0-30 mM 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131751 16188953 173877 20247 20116 SLC25A29 CACL CaCl 25 1.0 buffer (20 20 mM HEPES 5.6 mM NaCl 1.8 mM CaCl 2 145 mM KCl 1 mM MgCl 2 0.8 mM 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 131752 16188953 173877 8255 4236 GFER HPO HPO 40 0.0 mM KCl 1 mM MgCl 2 0.8 mM Na 2 HPO 4 and 5 mM Glc pH 7.4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131753 16188953 173878 17189 9319 PPP4C PPX PPX 4 0.3 The uptake of H PPX was calculated by subtracting the obtained amount of radioactivity in 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131754 16188953 173879 17189 9319 PPP4C PPX PPX 4 0.3 The concentration of H PPX added to the incubation medium was 43.5 nM calculated by 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131755 16188953 173879 17189 9319 PPP4C PPX PPX 29 0.3 as well as the specific radioactivity of the used H PPX stock into account (1 1 mCi/ml, mCi ml 69 Ci/mmol) 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131756 16188953 173884 17189 9319 PPP4C PPX PPX 6 0.3 For measuring the uptake of H PPX 50 microl of mitochondria (0-1.6 0-1.6 mg/ml) mg ml were 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131757 16188953 173885 17189 9319 PPP4C PPX PPX 3 0.3 Uptake of H PPX was started by the addition of 200 microl of H 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131758 16188953 173885 17189 9319 PPP4C PPX PPX 14 0.3 was started by the addition of 200 microl of H PPX (6 6 microCi/ml) microCi ml in incubation buffer with or 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131759 16188953 173885 17189 9319 PPP4C PPX PPX 24 0.3 microCi/ml) microCi ml in incubation buffer with or without unlabeled PPX (0-30 0-30 mM 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131760 16188953 173889 17189 9319 PPP4C PPX PPX 5 0.3 The specific uptake of H PPX was determined as the amount of radioactivity in the presence 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131761 16188953 173896 17189 9319 PPP4C PPX PPX 3 0.3 In further conditions PPX (300 300 microM malonate (Malo, Malo 10 mM the SOD-catalase 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131762 16188953 173896 20996 11179 SOD1 SOD SOD-catalase 11 2.2 PPX (300 300 microM malonate (Malo, Malo 10 mM the SOD-catalase mimic EUK-134 (Melov Melov et al. 2001 EUK (30 30 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131763 16188953 173900 17189 9319 PPP4C PPX PPX 36 0.3 (0.1 0.1 mM (Fridovich, Fridovich 1970 in a solution containing PPX SND or EUK-134 at the indicated concentrations 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131764 16188953 173901 18723 10261 ROS1 ROS ROS 3 1.2 After 20 min ROS generation was stopped by the addition of allopurinol (1 1 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131765 16188953 173904 20996 11179 SOD1 SOD SOD 8 2.2 The specificity for hydrogen peroxide was verified with SOD (300 300 mU/ml), mU ml which did not affect the 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131766 16188953 173906 3897 2665 CD55 DAF DAF 35 1.2 to 100 microl of a solution containing 4 5-diaminofluorescein (DAF; DAF 5 microM and PPX or SND 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131767 16188953 173906 17189 9319 PPP4C PPX PPX 39 0.3 a solution containing 4 5-diaminofluorescein (DAF; DAF 5 microM and PPX or SND 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131768 16188953 173907 3897 2665 CD55 DAF DAF-triazole 3 1.2 The generation of DAF-triazole fluorescence was measured at room temperature every 30 s during 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131769 16188953 173908 17189 9319 PPP4C PPX PPX 9 0.3 The obtained slopes were plotted against the concentration of PPX 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131770 16188953 173918 17189 9319 PPP4C PPX PPX 9 0.3 Schedule for Plasma and Brain Levels of SND and PPX 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131771 16188953 173919 17189 9319 PPP4C PPX PPX 16 0.3 daily (7:00 7 00 AM and 7 00 PM with PPX or SND (four four in each group 200 mg/kg) mg 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131772 16188953 173924 17189 9319 PPP4C PPX PPX 16 0.3 injections (9:00 9 00 AM and 5 00 PM of PPX (30 30 mg/kg, mg kg n = 8 or vehicle 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131773 16188953 173927 17189 9319 PPP4C PPX PPX 8 0.3 Animals were treated by supplementing the diet with PPX or SND 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131774 16188953 173930 17189 9319 PPP4C PPX PPX 29 0.3 II (7 7 males 8 females received control diet and PPX in the drinking water (3 3 mg/kg/day), mg kg day 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131775 16188953 173945 23261 10539 TSPAN31 SAS SAS 9 0.0 The statistical evaluation was performed using the software package SAS version 8.2 (SAS SAS Institute Cary NC 1 JUMiner_v2.2 1 0 0 2 19237 TotalCon:2<>10539|TSPAN31|6302|Complete__19237|NANS|54187|Complete__<>AvaiableGeneRif=2<>BEST:19237|NANS|0.000547885163269779<>ScoreDetail__10539|TSPAN31|0__19237|NANS|0.000547885163269779__ 0 0 0 0 0 131776 16188953 173945 23261 10539 TSPAN31 SAS SAS 12 0.0 was performed using the software package SAS version 8.2 (SAS SAS Institute Cary NC 1 JUMiner_v2.2 1 0 0 2 19237 TotalCon:2<>10539|TSPAN31|6302|Complete__19237|NANS|54187|Complete__<>AvaiableGeneRif=2<>BEST:19237|NANS|0.000547885163269779<>ScoreDetail__10539|TSPAN31|0__19237|NANS|0.000547885163269779__ 0 0 0 0 0 131777 16188953 173947 17189 9319 PPP4C PPX PPX 5 0.3 Plasma and Brain Levels of PPX or SND 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131778 16188953 173948 17189 9319 PPP4C PPX PPX 3 0.3 For quantification of PPX or SND in brain the tissue was homogenized with 0.05 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131779 16188953 173949 22000 11730 TERT TERT tert 21 0.0 water and internal standard and then extracted two times with tert -butyl-methylether at pH 10 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131780 16188953 173950 22000 11730 TERT TERT tert 19 0.0 and an internal standard and then extracted two times with tert -butyl-methylether at pH 10 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131781 16188953 173954 17367 17348 PRPF3 RP18 RP18 6 1.0 Chromatography took place on a Kromasil RP18 column (2.1 2.1 mm i.d x 30 mm 5-microm particle 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131782 16188953 173960 166 118 ACO2 aconitase aconitase 1 1.6 Mitochondrial aconitase is reversibly inactivated by superoxide and has therefore been used 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131783 16188953 173965 166 118 ACO2 aconitase aconitase 14 1.6 against the 23 C-terminal amino acids of aconitase-2 (mitochondrial mitochondrial aconitase from rat (nanoTools; nanoTools Antik_amp_ouml rpertechnik Teningen Germany was used 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131784 16188953 173967 19573 10691 SDS SDS SDS 17 0.0 5 microg were reduced with dithiothreitol and subjected to SDS/polyacrylamide SDS polyacrylamide gel electrophoresis on a 10% polyacrylamide gel 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000215552942169049<>ScoreDetail__10691|SDS|0.000127839871429615__19440|SBDS|0.000215552942169049__ 0 0 0 0 0 131785 16188953 173976 17189 9319 PPP4C PPX PPX 12 0.3 for an intracellular site of action the uptake of H PPX into neural cells both cerebellar granule cells and astroglial cells 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131786 16188953 173977 17189 9319 PPP4C PPX PPX 3 0.3 The uptake of PPX increases with incubation time and reaches constant levels after incubation 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131787 16188953 173978 17189 9319 PPP4C PPX PPX 7 0.3 After reaching plateau the amount of H PPX obtained in the cell lysates does not differ significantly between 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131788 16188953 173979 17189 9319 PPP4C PPX PPX 15 0.3 cells converts to an intracellular concentration of 160 nM H PPX by taking the specific volume for astroglial cells (4 4 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131789 16188953 173980 17189 9319 PPP4C PPX PPX 0 0.3 PPX has been proposed to accumulate in mitochondria (Abramova Abramova et 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131790 16188953 173981 17189 9319 PPP4C PPX PPX 14 0.3 a prerequisite for penetration into mitochondria we show that H PPX enters astrocytes and neurons beyond nonspecific binding indicated by reduced 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131791 16188953 173982 17189 9319 PPP4C PPX PPX 2 0.3 Furthermore H PPX accumulates in astroglial cells as shown by the 3-fold intracellular 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131792 16188953 173983 17189 9319 PPP4C PPX PPX 17 0.3 and therefore diffusion-limited because of the nonsaturable rate of total PPX uptake (labeled labeled plus unlabeled which is proportional to the 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131793 16188953 173983 17189 9319 PPP4C PPX PPX 28 0.3 (labeled labeled plus unlabeled which is proportional to the total PPX concentration 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131794 16188953 173984 17189 9319 PPP4C PPX PPX 20 0.3 acidification might be explained by the p K values of PPX ( ~5 and 11 for the aminothiazole and propylamino group 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131795 16188953 173985 17189 9319 PPP4C PPX PPX 4 0.3 At pH 7.4 >98% PPX is protonated to the less permeable univalent cation a pH 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131796 16188953 173986 17189 9319 PPP4C PPX PPX 2 0.3 Mitochondrial H PPX uptake is proportional to mitochondrial amount and correlates with the 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131797 16188953 173987 17189 9319 PPP4C PPX PPX 7 0.3 The ability of mitochondria to retain H PPX is greatly affected by rupture of the mitochondrial membranes showing 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131798 16188953 173987 17189 9319 PPP4C PPX PPX 22 0.3 rupture of the mitochondrial membranes showing that nonspecific binding of PPX to mitochondrial proteins is low 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131799 16188953 173988 17189 9319 PPP4C PPX PPX 3 0.3 We conclude that PPX permeates the inner mitochondrial membrane and enters the matrix 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131800 16188953 173990 17189 9319 PPP4C PPX PPX 7 0.3 We show that in energized mitochondria H PPX influx is stimulated by a factor of two to six 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131801 16188953 173991 17189 9319 PPP4C PPX PPX 16 0.3 nM in energized mitochondria accounts for a 3-fold accumulation of PPX within mitochondria compared with incubation buffer 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131802 16188953 173992 17189 9319 PPP4C PPX PPX 15 0.3 pmol/mg) pmol mg most likely reflect the uniform distribution of PPX between incubation buffer and mitochondrial matrix (diffusion diffusion only whereas 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131803 16188953 173994 17189 9319 PPP4C PPX PPX 13 0.3 equal octanol/water octanol water partitioning (log log P = 0 PPX approximately -0.2 data not shown 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131804 16188953 173995 17189 9319 PPP4C PPX PPX 10 0.3 We conclude that apart from its binding to dopamine receptors PPX can accumulate within cells and mitochondria 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131805 16188953 173997 17189 9319 PPP4C PPX PPX 8 0.3 Although several studies addressed the antioxidative properties of PPX (e.g., e.g. Cassarino et al. 1998 Ferger et al. 2000 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131806 16188953 173998 17189 9319 PPP4C PPX PPX 7 0.3 Therefore we reevaluated the antioxidative properties of PPX and SND targeted toward different reactive species and compartments obtained 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131807 16188953 173998 20996 11179 SOD1 SOD SOD-catalase-mimetic 25 2.2 and compartments obtained efficacies were compared with EUK-134 a potent SOD-catalase-mimetic (Jung Jung et al. 2001 Melov et al. 2001 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131808 16188953 173999 17189 9319 PPP4C PPX PPX 3 0.3 We show that PPX and (the the equipotent SND are weak H 2 O 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131809 16188953 174000 18723 10261 ROS1 ROS ROS 6 1.2 In contrast EUK-134 detoxifies the generated ROS in the 5 microM range indicating a 100-fold higher efficacy 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131810 16188953 174000 17189 9319 PPP4C PPX PPX 19 0.3 5 microM range indicating a 100-fold higher efficacy compared with PPX or SND 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131811 16188953 174002 17189 9319 PPP4C PPX PPX 9 0.3 Importantly the loss of efficacy was not observed if PPX or SND was tested in these systems 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131812 16188953 174003 17189 9319 PPP4C PPX PPX 8 0.3 This is consistent with the uptake properties of PPX yielding cellular or mitochondrial accumulation thus bypassing competition with the 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131813 16188953 174004 17189 9319 PPP4C PPX PPX 7 0.3 The uptake properties and the efficacy of PPX to scavenge H 2 O 2 (accumulates accumulates 3-fold IC 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131814 16188953 174006 18723 10261 ROS1 ROS ROS 1 1.2 Mitochondrial ROS attenuation in HT22 cells is sufficient but not a prerequisite 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131815 16188953 174007 17189 9319 PPP4C PPX PPX 3 0.3 Therefore pathways by PPX/SND PPX SND other than antioxidative action located to mitochondria cannot be 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131816 16188953 174009 17189 9319 PPP4C PPX PPX 4 0.3 The low efficacy of PPX and SND toward H 2 O 2 might be the 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131817 16188953 174011 3897 2665 CD55 DAF DAF-triazole 3 1.2 The inhibition of DAF-triazole generation in the presence of a nitric oxide donor and 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131818 16188953 174011 17189 9319 PPP4C PPX PPX 25 0.3 (Nagata Nagata et al. 1999 was used to show that PPX and SND detoxify nitric oxide equipotently at the 15 microM 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131819 16188953 174012 17189 9319 PPP4C PPX PPX 7 0.3 We conclude that the antioxidative efficacy of PPX and SND in addition to the spatial issues discussed above 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131820 16188953 174013 17189 9319 PPP4C PPX PPX 3 0.3 We show that PPX treatment (2 2 x 30 mg/kg) mg kg results in 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131821 16188953 174013 166 118 ACO2 aconitase aconitase 15 1.6 30 mg/kg) mg kg results in an increase in mitochondrial aconitase activity in vivo indicating a reduction of the superoxide steady-state 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131822 16188953 174014 17189 9319 PPP4C PPX PPX 7 0.3 Because treatment of these mice with a PPX dose of 2 x 200 mg/kg mg kg results in 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131823 16188953 174014 166 118 ACO2 aconitase aconitase 30 1.6 12 h after the last treatment the increase in mitochondrial aconitase might result from total brain concentrations within the same order 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131824 16188953 174016 17189 9319 PPP4C PPX PPX 18 0.3 dopaminergic and nondopaminergic cells in the presence of 10 microM PPX or SND if added 48 h prior to complex I 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131825 16188953 174017 17189 9319 PPP4C PPX PPX 0 0.3 PPX causes a slight but not significant increase in total aconitase 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131826 16188953 174017 166 118 ACO2 aconitase aconitase 10 1.6 PPX causes a slight but not significant increase in total aconitase activity in 1-methyl-4-phenylpyridinium-treated SHSY-5Y cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131827 16188953 174020 17189 9319 PPP4C PPX PPX 7 0.3 The present results support the concept of PPX and SND as mitochondria-targeted antioxidants evidenced by equal antioxidative efficacy 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131828 16188953 174021 17189 9319 PPP4C PPX PPX 2 0.3 Targeting of PPX to mitochondria is supported by the membrane potential-dependent uptake process 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131829 16188953 174021 17189 9319 PPP4C PPX PPX 35 0.3 compared with direct scavenging and finally by the ability of PPX to lower mitochondrial superoxide levels in vivo 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131830 16188953 174022 17189 9319 PPP4C PPX PPX 9 0.3 We conclude that the in vitro neuroprotective properties of PPX are independent of the chiral 6-propylaminogroup in the molecule 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131831 16188953 174023 17189 9319 PPP4C PPX PPX 6 0.3 Therefore the (+)-enantiomer -enantiomer SND rather than PPX might permit a sufficiently high dosage regimen to exert antioxidative 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131832 16188953 174024 17189 9319 PPP4C PPX PPX 9 0.3 Therefore we tested SND (at at a high dose and PPX (at at a low dose in an animal model for 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131833 16188953 174024 20996 11179 SOD1 ALS ALS 20 2.2 at a low dose in an animal model for familial ALS the SOD1-G93A mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131834 16188953 174025 17189 9319 PPP4C PPX PPX 19 0.3 to achieve antioxidative action based on equipotent efficacy compared with PPX and the micromolar brain levels achieved in C57BL/6 C57BL 6 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131835 16188953 174026 17189 9319 PPP4C PPX PPX 2 0.3 The used PPX dose of 3 mg/kg/day mg kg day was chosen based 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131836 16188953 174027 17189 9319 PPP4C PPX PPX 6 0.3 Indeed we show that treatment with PPX does not increase survival time of the SOD1-G93A mice and 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131837 16188953 174028 17189 9319 PPP4C PPX PPX-treated 0 0.3 PPX-treated animals display an increase in presymptomatic running wheel activity probably 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131838 16188953 174032 20996 11179 SOD1 ALS ALS 16 2.2 mg/kg mg kg riluzole (the the only drug launched for ALS which prolongs survival time by 8 days in our laboratory 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131839 16188953 174035 17189 9319 PPP4C PPX PPX 10 0.3 Based on the high dose the equipotent antioxidative properties of PPX and SND and the lack of evidence for different distribution 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131840 16188953 174036 18723 10261 ROS1 ROS ROS 18 1.2 mouse needs to be confirmed by direct measurement of mitochondrial ROS attenuation in this model using specific endpoints such as modification 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131841 16188953 174036 166 118 ACO2 aconitase aconitase 34 1.6 specific endpoints such as modification of mitochondrial proteins or mitochondrial aconitase activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131842 16188953 174039 17189 9319 PPP4C PPX PPX 3 0.3 Uptake of H PPX in neural cells 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131843 16188953 174040 17189 9319 PPP4C PPX PPX 19 0.3 circles/bars) circles bars was started by the addition of H PPX (3 3 microCi/ml) microCi ml in incubation buffer containing 5 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131844 16188953 174041 5131 2524 CTRL CTRL Ctrl 13 0.0 at 37degreeC by using an incubating buffer pH 7.4 (Ctrl) Ctrl containing digitonin (Digi, Digi 100 microg/ml) microg ml or adjusting 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131845 16188953 174042 17189 9319 PPP4C PPX PPX 11 0.3 and D uptake was started by the addition of H PPX (3 3 microCi/ml) microCi ml and a variable concentration of 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131846 16188953 174042 17189 9319 PPP4C PPX PPX 20 0.3 3 microCi/ml) microCi ml and a variable concentration of unlabeled PPX (0-30 0-30 mM 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131847 16188953 174043 17189 9319 PPP4C PPX PPX 13 0.3 normalized on time and expressed as the rate of H PPX uptake 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131848 16188953 174044 17189 9319 PPP4C PPX PPX 6 0.3 D the specific rate of total PPX uptake was calculated by taking the excess of unlabeled PPX 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131849 16188953 174044 17189 9319 PPP4C PPX PPX 16 0.3 PPX uptake was calculated by taking the excess of unlabeled PPX into account and is shown as a function of total 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131850 16188953 174044 17189 9319 PPP4C PPX PPX 27 0.3 into account and is shown as a function of total PPX concentration in the incubation buffer * p _lt_ 0.05 ** 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131851 16188953 174044 17189 9319 PPP4C PPX PPX 66 0.3 or with C the incubation in the absence of unlabeled PPX respectively 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131852 16188953 174046 17189 9319 PPP4C PPX PPX 3 0.3 Uptake of H PPX in mitochondria 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131853 16188953 174048 17189 9319 PPP4C PPX PPX 8 0.3 Uptake was started by the addition of H PPX (3 3 microCi/ml) microCi ml and terminated at the indicated 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131854 16188953 174051 15869 8506 OSM OSM mOsm 12 0.0 were preincubated in buffer with increasing osmolarity (160-960 160-960 mOsm/l mOsm l adjusted with sucrose *** p _lt_ 0.001 compared with 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131855 16188953 174051 15869 8506 OSM OSM mOsm 25 0.0 *** p _lt_ 0.001 compared with incubation in 320 mOsm/l mOsm l incubation buffer 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131856 16188953 174052 17189 9319 PPP4C PPX PPX 6 0.3 D uptake was started by H PPX (3 3 microCi/ml), microCi ml which was diluted with unlabeled 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131857 16188953 174052 17189 9319 PPP4C PPX PPX 14 0.3 (3 3 microCi/ml), microCi ml which was diluted with unlabeled PPX (0-10 0-10 mM normalized on time and taking the excess 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131858 16188953 174052 17189 9319 PPP4C PPX PPX 26 0.3 mM normalized on time and taking the excess of unlabeled PPX into account 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131859 16188953 174053 17189 9319 PPP4C PPX PPX 5 0.3 The specific rate of total PPX uptake is shown as a function of the total PPX 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131860 16188953 174053 17189 9319 PPP4C PPX PPX 15 0.3 PPX uptake is shown as a function of the total PPX concentration 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131861 16188953 174055 20247 20116 SLC25A29 CACL CaCl 23 1.0 mM 1 microM valinomycin (Val), Val 100 nmol/mg nmol mg CaCl 2 1 mM phosphate 5 microM rotenone (Rot), Rot or 14 JUMiner_v2.2 1 2 cacl 0 0 0 0 0 0 0 0 131862 16188953 174055 24185 29175 WDTC1 ADP ADP 11 0.0 of mitochondrial membrane potential was induced by the addition of ADP plus phosphate (both both 1 mM 1 microM valinomycin (Val), 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131863 16188953 174057 17189 9319 PPP4C PPX PPX 3 0.3 Antioxidative effects of PPX and SND related to hydrogen peroxide 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131864 16188953 174058 18723 10261 ROS1 ROS ROS 1 1.2 A ROS were generated by xanthine oxidase in a solution containing EUK-134 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131865 16188953 174058 17189 9319 PPP4C PPX PPX 14 0.3 xanthine oxidase in a solution containing EUK-134 (black black bars PPX (light light gray bars or SND (dark dark gray bars 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131866 16188953 174059 18723 10261 ROS1 ROS ROS 10 1.2 To avoid competition of the compounds with the detection system ROS generation was stopped after 20 min by the addition of 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131867 16188953 174060 17189 9319 PPP4C PPX PPX 43 0.3 with the rate of AR oxidation in the presence of PPX (300 300 microM and EUK-134 (30 30 microM 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131868 16188953 174060 5131 2524 CTRL CTRL Ctrl 30 0.0 0.4 units/ml units ml HRP and 2.5 mM succinate (Ctrl) Ctrl and compared with the rate of AR oxidation in the 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131869 16188953 174064 17189 9319 PPP4C PPX PPX 4 0.3 Cells were treated with PPX (1 1 mM SND (1 1 mM and EUK-134 (250 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131870 16188953 174069 17189 9319 PPP4C PPX PPX 3 0.3 Antioxidative effects of PPX and SND related to nitric oxide generated by DETA 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131871 16188953 174070 3897 2665 CD55 DAF DAF 15 1.2 initiated by the addition of DETA to a solution containing DAF and PPX (filled filled circles or SND (open open circles 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131872 16188953 174070 17189 9319 PPP4C PPX PPX 17 0.3 the addition of DETA to a solution containing DAF and PPX (filled filled circles or SND (open open circles both 0-10 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131873 16188953 174071 3897 2665 CD55 DAF DAF-triazole 3 1.2 The generation of DAF-triazole fluorescence was measured at room temperature every 30 s during 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131874 16188953 174072 17189 9319 PPP4C PPX PPX 9 0.3 The obtained slopes were plotted against the concentration of PPX 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131875 16188953 174075 17189 9319 PPP4C PPX PPX 3 0.3 Antioxidative effect of PPX in vivo 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131876 16188953 174076 166 118 ACO2 aconitase aconitase 7 1.6 Activity (A) A and expression (B) B of mitochondrial aconitase after treatment of C57BL/6 C57BL 6 mice with PPX (2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131877 16188953 174076 17189 9319 PPP4C PPX PPX 14 0.3 mitochondrial aconitase after treatment of C57BL/6 C57BL 6 mice with PPX (2 2 x 30 mg/kg mg kg per day n 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131878 16188953 174076 5131 2524 CTRL CTRL Ctrl 26 0.0 mg kg per day n = 8 or vehicle (Ctrl, Ctrl n = 6 have been determined as described under Materials 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131879 16188953 174079 20996 11179 SOD1 SOD1 SOD1 2 2.2 Treatment of SOD1(G93A) SOD1 G93A transgenic mice with PPX and SND 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131880 16188953 174079 17189 9319 PPP4C PPX PPX 6 0.3 Treatment of SOD1(G93A) SOD1 G93A transgenic mice with PPX and SND 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131881 16188953 174080 17189 9319 PPP4C PPX PPX 18 0.3 SND (100 100 mg/kg mg kg p.o. black circles or PPX (3 3 mg/kg mg kg p.o. gray circles was measured 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131882 16188953 174080 5131 2524 CTRL CTRL Ctrl 8 0.0 A motor activity of mice treated with vehicle (Ctrl; Ctrl open circles SND (100 100 mg/kg mg kg p.o. black 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131883 16188953 174084 23261 10539 TSPAN31 SAS SAS 14 0.0 by a log rank Mantel-Cox test using the software package SAS version 8.2 1 JUMiner_v2.2 1 0 0 2 19237 TotalCon:2<>10539|TSPAN31|6302|Complete__19237|NANS|54187|Complete__<>AvaiableGeneRif=2<>BEST:19237|NANS|0.000547885163269779<>ScoreDetail__10539|TSPAN31|0__19237|NANS|0.000547885163269779__ 0 0 0 0 0 131884 16188953 174085 17189 9319 PPP4C PPX PPX- 7 0.3 TABLE 1 Plasma and brain levels of PPX- and SND-treated C57BL/6 C57BL 6 mice 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131885 16188953 174096 17189 9319 PPP4C PPX PPX 10 0.3 In contrast to acidification an increase to pH 8 doubles PPX influx in both cell types compared with pH 7.4 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131886 16188953 174097 17189 9319 PPP4C PPX PPX 3 0.3 Dilution of H PPX with unlabeled PPX results in a dose-dependent inhibition of H 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131887 16188953 174097 17189 9319 PPP4C PPX PPX 6 0.3 Dilution of H PPX with unlabeled PPX results in a dose-dependent inhibition of H PPX uptake ( 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131888 16188953 174097 17189 9319 PPP4C PPX PPX 14 0.3 with unlabeled PPX results in a dose-dependent inhibition of H PPX uptake ( Fig 1C which is caused by isotope dilution 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131889 16188953 174098 17189 9319 PPP4C PPX PPX 3 0.3 Multiplication of H PPX uptake ( Fig 1C by the molar excess of unlabeled 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131890 16188953 174098 17189 9319 PPP4C PPX PPX 15 0.3 uptake ( Fig 1C by the molar excess of unlabeled PPX yields the rate of total PPX uptake (labeled labeled plus 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131891 16188953 174098 17189 9319 PPP4C PPX PPX 21 0.3 molar excess of unlabeled PPX yields the rate of total PPX uptake (labeled labeled plus unlabeled Fig 1D which is proportional 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131892 16188953 174098 17189 9319 PPP4C PPX PPX 35 0.3 plus unlabeled Fig 1D which is proportional to the total PPX concentration (labeled labeled plus unlabeled over a range of seven 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131893 16188953 174099 17189 9319 PPP4C PPX PPX 8 0.3 In a second set of experiments entry of PPX into isolated mitochondria was measured and characterized 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131894 16188953 174100 17189 9319 PPP4C PPX PPX 8 0.3 As observed in cells the uptake of H PPX in mitochondria strongly depends on mitochondrial integrity ( Fig 2A 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131895 16188953 174102 17189 9319 PPP4C PPX PPX 6 0.3 By subtraction the amount of H PPX for unspecific binding (sonicated sonicated mitochondria from the amount obtained 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131896 16188953 174102 17189 9319 PPP4C PPX PPX 29 0.3 a specific uptake of 0.15 _amp_#177 0.01 pmol H]PPX/mg H PPX mg protein was obtained which corresponds to an intramitochondrial concentration 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131897 16188953 174103 17189 9319 PPP4C PPX PPX 2 0.3 Furthermore H PPX uptake is proportional to the mitochondria amount ( R = 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131898 16188953 174105 17189 9319 PPP4C PPX PPX 8 0.3 As observed in cells mitochondrial uptake of H PPX is significantly inhibited in the presence of unlabeled PPX (>1 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131899 16188953 174105 17189 9319 PPP4C PPX PPX 17 0.3 H PPX is significantly inhibited in the presence of unlabeled PPX (>1 >1 microM data not shown which after taking the 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131900 16188953 174105 17189 9319 PPP4C PPX PPX 51 0.3 of total uptake (labeled labeled plus unlabeled and the total PPX concentration ( R = 0.999 Fig 2D 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131901 16188953 174106 17189 9319 PPP4C PPX PPX 12 0.3 the membrane potential as a driving force for mitochondrial H PPX uptake we used different energy substrates to polarize the mitochondrial 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131902 16188953 174107 17189 9319 PPP4C PPX PPX 15 0.3 malate pyruvate succinate or ATP results in a comparable H PPX uptake 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131903 16188953 174109 24185 29175 WDTC1 ADP ADP 18 0.0 if mitochondrial membrane potential is reduced by the addition of ADP P i (57%), 57% valinomycin (47%), 47% calcium P i 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131904 16188953 174110 17189 9319 PPP4C PPX PPX 4 0.3 After demonstrating entry of PPX into brain cells and mitochondria we reevaluated the antioxidative properties 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131905 16188953 174110 17189 9319 PPP4C PPX PPX 16 0.3 brain cells and mitochondria we reevaluated the antioxidative properties of PPX and SND and compared the obtained efficacy with EUK-134 a 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131906 16188953 174110 20996 11179 SOD1 SOD SOD-catalase 28 2.2 SND and compared the obtained efficacy with EUK-134 a potent SOD-catalase mimetic (Melov Melov et al. 2001 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131907 16188953 174112 18723 10261 ROS1 ROS ROS 15 1.2 the dose response for the detoxification of in situ generated ROS by an antioxidant independent of its uptake properties 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131908 16188953 174114 18723 10261 ROS1 ROS ROS 20 1.2 a concentration of 300 microM was able to detoxify >95% ROS generated by xanthine oxidase 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131909 16188953 174115 17189 9319 PPP4C PPX PPX 1 0.3 Both PPX and SND were less potent at this concentration ( ~75% 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131910 16188953 174116 18723 10261 ROS1 ROS ROS 1 1.2 Comparable ROS detoxification was achieved at 3 microM EUK-134 and 1 mM 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131911 16188953 174116 17189 9319 PPP4C PPX PPX 14 0.3 achieved at 3 microM EUK-134 and 1 mM for either PPX or SND 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131912 16188953 174117 18723 10261 ROS1 ROS ROS 11 1.2 both enantiomers showed equipotent efficacy in detoxification of xanthine oxidase-generated ROS ( Fig 3A 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131913 16188953 174118 17189 9319 PPP4C PPX PPX 3 0.3 To show that PPX and EUK-134 are able to inhibit mitochondrial hydrogen peroxide release 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131914 16188953 174118 17189 9319 PPP4C PPX PPX 28 0.3 of hydrogen peroxide in succinate-energized mitochondria in the presence of PPX (300 300 microM or EUK-134 (30 30 microM 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131915 16188953 174119 5131 2524 CTRL CTRL Ctrl 25 0.0 the values obtained in the absence of an antioxidant (Ctrl, Ctrl Fig 3B 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131916 16188953 174120 17189 9319 PPP4C PPX PPX 7 0.3 To evaluate whether these antioxidative properties of PPX and SND are sufficient to confer neuroprotection in a cellular 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131917 16188953 174122 18723 10261 ROS1 ROS ROS 11 1.2 has been described to result in an early increase of ROS (5-10-fold) 5-10-fold followed by a later but massive increase in 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131918 16188953 174122 18723 10261 ROS1 ROS ROS 21 1.2 (5-10-fold) 5-10-fold followed by a later but massive increase in ROS (200-400-fold) 200-400-fold derived from mitochondria and paralleled by the time 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 131919 16188953 174125 17189 9319 PPP4C PPX PPX 7 0.3 In the absence of glutamate incubation with PPX or SND (both both at 1 mM does not significantly 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131920 16188953 174126 17189 9319 PPP4C PPX PPX 0 0.3 PPX SND and EUK were able to prevent glutamate-induced cell death 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131921 16188953 174127 17189 9319 PPP4C PPX PPX 11 0.3 up to 82% remaining viability occurred at 1 mM (PPX PPX and SND and 250 microM (EUK-134) EUK-134 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131922 16188953 174128 17189 9319 PPP4C PPX PPX 0 0.3 PPX SND and EUK-134 were able to protect cells in a 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131923 16188953 174130 17189 9319 PPP4C PPX PPX 22 0.3 Bonferroni's post hoc test resulted in no significant difference between PPX and EUK 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131924 16188953 174131 3897 2665 CD55 DAF DAF 32 1.2 the nitric oxide donor DETA which in the presence of DAF yields the fluorescent DAF-triazole 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131925 16188953 174131 3897 2665 CD55 DAF DAF-triazole 36 1.2 DETA which in the presence of DAF yields the fluorescent DAF-triazole 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131926 16188953 174132 17189 9319 PPP4C PPX PPX 1 0.3 Both PPX and SND ( Fig 4 equally inhibit the generation of 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131927 16188953 174132 3897 2665 CD55 DAF DAF-triazole 14 1.2 SND ( Fig 4 equally inhibit the generation of the DAF-triazole 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131928 16188953 174134 17189 9319 PPP4C PPX PPX 17 0.3 have relevance in vivo we tested whether micromolar concentrations of PPX and SND can be achieved in vivo 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131929 16188953 174135 17189 9319 PPP4C PPX PPX 8 0.3 We treated C57BL/6 C57BL 6 mice with high doses of PPX and SND (200 200 mg/kg mg kg p.o for 4 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131930 16188953 174138 17189 9319 PPP4C PPX PPX 11 0.3 was followed by an experiment where mitochondria were isolated after PPX treatment of mice to determine mitochondrial aconitase activity an indicator 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131931 16188953 174138 166 118 ACO2 aconitase aconitase 18 1.6 were isolated after PPX treatment of mice to determine mitochondrial aconitase activity an indicator for steady-state levels of superoxide (Tarpey Tarpey 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131932 16188953 174139 17189 9319 PPP4C PPX PPX 0 0.3 PPX treatment for 4 days (2 2 x 30 mg/kg) mg 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131933 16188953 174139 166 118 ACO2 aconitase aconitase 11 1.6 days (2 2 x 30 mg/kg) mg kg increased mitochondrial aconitase activity by 42% to 67 _amp_#177 16 mU/mg mU mg 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131934 16188953 174140 166 118 ACO2 aconitase aconitase 9 1.6 This was not due to altered expression of mitochondrial aconitase because protein levels were not affected by the PPX treatment 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131935 16188953 174140 17189 9319 PPP4C PPX PPX 18 0.3 mitochondrial aconitase because protein levels were not affected by the PPX treatment ( Fig 5B 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131936 16188953 174141 20996 11179 SOD1 SOD1 SOD1 10 2.2 Consequently we tested both compounds in mice expressing the G93A-mutant SOD1 a common and well described model of ALS where neuronal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131937 16188953 174141 20996 11179 SOD1 ALS ALS 18 2.2 the G93A-mutant SOD1 a common and well described model of ALS where neuronal cell death is associated with an increase in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131938 16188953 174145 17189 9319 PPP4C PPX PPX 7 0.3 Since we found equipotent antioxidative properties of PPX and SND and no evidence for a transporter which is 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131939 16188953 174145 17189 9319 PPP4C PPX PPX 23 0.3 for a transporter which is involved in the uptake of PPX we tested SND at a high dose of 100 mg/kg 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131940 16188953 174146 17189 9319 PPP4C PPX PPX 0 0.3 PPX was given at a lower dose of 3 mg/kg mg 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131941 16188953 174146 20996 11179 SOD1 ALS ALS 36 2.2 et al. 2001 to test for putative neuroprotection in the ALS model which might be mediated via activation of dopamine receptors 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131942 16188953 174148 17189 9319 PPP4C PPX PPX-treated 2 0.3 In contrast PPX-treated animals show a significant increase by 55% to 23 900 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131943 16188953 174150 17189 9319 PPP4C PPX PPX- 29 0.3 significantly delayed at day 106 105-106 or 109 108-110 in PPX- or SND-treated animals respectively 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131944 16188953 174151 20996 11179 SOD1 SOD1 SOD1 5 2.2 Additionally survival time in SND-treated SOD1 (G93A) G93A mice (132 132 _amp_#177 2 days mean _amp_#177 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 131945 16188953 174151 17189 9319 PPP4C PPX PPX-treated 47 0.3 _amp_#177 S.E.M. n = 11 and in comparison to the PPX-treated group (122 122 _amp_#177 2 days log rank test p 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131946 16188953 174152 17189 9319 PPP4C PPX PPX-treated 5 0.3 The survival times of the PPX-treated animals and the control group do not differ significantly (log 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131947 16188953 174155 17189 9319 PPP4C PPX PPX 1 0.3 ABBREVIATIONS PPX pramipexole ALS amyotrophic lateral sclerosis DETA ( Z -1- 2- 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131948 16188953 174155 20996 11179 SOD1 ALS ALS 3 2.2 ABBREVIATIONS PPX pramipexole ALS amyotrophic lateral sclerosis DETA ( Z -1- 2- 2-aminoethyl -N 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00113862687172083<>ScoreDetail__5468|IGFALS|0.000432549337658827__11179|SOD1|0.00113862687172083__ 0 0 0 0 0 131949 16188953 174155 3897 2665 CD55 DAF DAF 30 1.2 EUK-134 SND919CL2x 2-amino-4 5 6 7-tetrahydro-6-L -propylamino-benzathiazole dihydrochloride SND SND919CL2x DAF 4 5-diaminofluorescein HBSS Hanks' balanced salt solution AR Amplex Red 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 131950 16188953 174155 18723 10261 ROS1 ROS ROS 46 1.2 solution AR Amplex Red MS mass spectrometry HRP horseradish peroxidase ROS reactive oxygen species ANOVA analysis of variance FCCP carbonyl cyanide 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 132291 16194581 174693 18723 10261 ROS1 ROS ROS 25 0.3 defend against the cellular generation of reactive oxygen species (ROS) ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 132292 16194581 174694 18723 10261 ROS1 ROS ROS 1 0.3 These ROS cause oxidative damage to nucleic acid carbohydrate protein and lipids 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 132293 16194581 174698 9947 5468 IGFALS ALS ALS 11 1.2 are augmented by neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), ALS Alzheimer's disease (AD), AD and Parkinson's disease (PD) PD 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000574291995604416<>ScoreDetail__5468|IGFALS|0.000365916410969869__11179|SOD1|0.000574291995604416__ 0 0 0 0 0 132294 16194581 174705 9947 5468 IGFALS ALS ALS 13 1.2 in age-related neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), ALS Alzheimer's disease (AD), AD and Parkinson's disease (PD) PD 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000574291995604416<>ScoreDetail__5468|IGFALS|0.000365916410969869__11179|SOD1|0.000574291995604416__ 0 0 0 0 0 132295 16194581 174718 18723 10261 ROS1 ROS ROS 3 0.3 Reactive oxygen species (ROS) ROS collectively refer to oxygen radicals and non-radicals that are readily 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 132296 16194581 174719 18723 10261 ROS1 ROS ROS 0 0.3 ROS are the by-products of normal aerobic metabolism 3 and 14 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 132297 16194581 174721 18723 10261 ROS1 ROS ROS 3 0.3 The production of ROS is normally counterbalanced by cellular defense systems 24 and 32 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 132298 16194581 174722 18723 10261 ROS1 ROS ROS 5 0.3 However about 1% of the ROS escape daily elimination to give rise to oxidative cellular damage 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 132299 16194581 174723 18723 10261 ROS1 ROS ROS 7 0.3 The process by which the production of ROS is not effectively neutralized leading to cellular damage is known 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 132300 16194581 174730 18723 10261 ROS1 ROS ROS 8 0.3 Also many neurotransmitters themselves are autoxidized to generate ROS 26 53 64 and 71 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 132301 16194581 174733 9947 5468 IGFALS ALS ALS 22 1.2 the pathogenesis of neurodegenerative diseases such as AD PD and ALS 9 15 and 77 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000574291995604416<>ScoreDetail__5468|IGFALS|0.000365916410969869__11179|SOD1|0.000574291995604416__ 0 0 0 0 0 132302 16194581 174737 18723 10261 ROS1 ROS ROS 6 0.3 Inflammation is intimately linked to enhanced ROS production 17 29 52 and 56 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 132303 16194581 174738 18723 10261 ROS1 ROS ROS 4 0.3 Local unbridled over-production of ROS has been reported in several inflammatory diseases 11 31 and 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 132304 16194581 174740 14535 7873 NOS2A iNOS iNOS 20 2.2 activation genes such as the inducible nitric oxide synthase (iNOS), iNOS interleukin-1_amp_#x3b2 (IL-1_amp_#x3b2;), IL-1_amp_#x3b2 tumor necrosis factor-_amp_#x3b1 (TNF-_amp_#x3b1;), TNF-_amp_#x3b1 and nuclear 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132305 16194581 174740 22551 11892 TNF TNF TNF-A 26 1.2 synthase (iNOS), iNOS interleukin-1_amp_#x3b2 (IL-1_amp_#x3b2;), IL-1_amp_#x3b2 tumor necrosis factor-_amp_#x3b1 (TNF-_amp_#x3b1;), TNF-_amp_#x3b1 and nuclear factor-kappa B (NF-_amp_#x3ba;B) NF-_amp_#x3ba B 1 49 60 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132306 16194581 174741 18723 10261 ROS1 ROS ROS 17 0.3 to be activated by inflammation to produce high levels of ROS and cytokines 11 12 58 68 and 84 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 132307 16194581 174759 926 620 APP APP APP 3 0.3 Amyloid precursor protein/presenilin-1 protein presenilin-1 (APP/PSl) APP PSl transgenic mice have been used as a murine model 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132308 16194581 174759 926 620 APP amyloid amyloid 23 1.0 for AD since these mutations facilitate the production of beta amyloid and consequently Alzheimer-like plaques in several regions of the brain 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 132309 16194581 174763 926 620 APP APP APP 15 0.3 of plaques was observed between the BB-supplemented and non-supplemented APP/PSl APP PSl mice even though behavioral deficits were prevented in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132310 16194581 174766 926 620 APP APP APP 13 0.3 formation and improved Y-maze performance seen in the BB-supplemented APP/PSl APP PSl mice versus the non-supplemented APP/PSl APP PSl mice might 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132311 16194581 174766 926 620 APP APP APP 18 0.3 the BB-supplemented APP/PSl APP PSl mice versus the non-supplemented APP/PSl APP PSl mice might be due to alterations in signaling pathways 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132312 16194581 174767 12337 6871 MAPK1 ERK ERK 7 2.3 The levels of extracellular signal regulated kinase (ERK) ERK and protein kinase C (PKC) PKC were elevated in the 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.000534824703720569<>ScoreDetail__3393|EPHB2|0.000404600083710362__6871|MAPK1|0.000534824703720569__ 0 0 0 0 0 132313 16194581 174767 926 620 APP APP APP 18 0.3 kinase C (PKC) PKC were elevated in the BB-supplemented APP/PSl APP PSl mice as compared to those found in the non-supplemented 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132314 16194581 174768 12337 6871 MAPK1 ERK ERK 1 2.3 Both ERK and PKC kinases are important in mediating cognitive function especially 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.000534824703720569<>ScoreDetail__3393|EPHB2|0.000404600083710362__6871|MAPK1|0.000534824703720569__ 0 0 0 0 0 132315 16194581 174772 12339 6877 MAPK3 ERK1 ERK1 10 1.8 After these tests the hippocampal expression of signaling markers including ERK1 and ERK2 as well as PKC-_amp_#x3b1 and PKC-_amp_#x3b3 were analyzed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132316 16194581 174772 12337 6871 MAPK1 ERK2 ERK2 10 2.3 After these tests the hippocampal expression of signaling markers including ERK1 and ERK2 as well as PKC-_amp_#x3b1 and PKC-_amp_#x3b3 were analyzed 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132317 16194581 174772 12337 6871 MAPK1 ERK2 ERK2 12 2.3 tests the hippocampal expression of signaling markers including ERK1 and ERK2 as well as PKC-_amp_#x3b1 and PKC-_amp_#x3b3 were analyzed by immunoblotting 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132318 16194581 174774 12339 6877 MAPK3 ERK1 ERK1 3 1.8 The expression of ERK1 and ERK2 positively correlated with inclined screen latency (measurement measurement 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132319 16194581 174774 12337 6871 MAPK1 ERK2 ERK2 3 2.3 The expression of ERK1 and ERK2 positively correlated with inclined screen latency (measurement measurement 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132320 16194581 174774 12337 6871 MAPK1 ERK2 ERK2 5 2.3 The expression of ERK1 and ERK2 positively correlated with inclined screen latency (measurement measurement of muscle 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132321 16194581 174781 12337 6871 MAPK1 ERK ERK 4 2.3 The localized expression of ERK and insulin-like growth factor 1 (IGF-1) IGF-1 and its receptor 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.000534824703720569<>ScoreDetail__3393|EPHB2|0.000404600083710362__6871|MAPK1|0.000534824703720569__ 0 0 0 0 0 132322 16194581 174781 9939 5464 IGF1 IGF1 IGF-1 10 1.8 localized expression of ERK and insulin-like growth factor 1 (IGF-1) IGF-1 and its receptor (IGF-1R) IGF-1R was also assayed by immunohistochemistry 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132323 16194581 174781 9940 5465 IGF1R IGF1R IGF-1R 14 1.5 insulin-like growth factor 1 (IGF-1) IGF-1 and its receptor (IGF-1R) IGF-1R was also assayed by immunohistochemistry 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132324 16194581 174785 9939 5464 IGF1 IGF1 IGF-1 13 1.8 aged rats showed significant increases in the protein levels of IGF-1 IGF-1R and ERK and these increases were also inversely correlated 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132325 16194581 174785 9940 5465 IGF1R IGF1R IGF-1R 14 1.5 rats showed significant increases in the protein levels of IGF-1 IGF-1R and ERK and these increases were also inversely correlated with 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132326 16194581 174785 12337 6871 MAPK1 ERK ERK 16 2.3 significant increases in the protein levels of IGF-1 IGF-1R and ERK and these increases were also inversely correlated with the number 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.000534824703720569<>ScoreDetail__3393|EPHB2|0.000404600083710362__6871|MAPK1|0.000534824703720569__ 0 0 0 0 0 132327 16194581 174786 9939 5464 IGF1 IGF1 IGF-1 19 1.8 and cognitive performance via concerted mechanisms involving neurogenesis neurotrophic factor IGF-1 and its receptor and MAP kinase signal transduction cascades 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 132328 16194581 174786 12337 6871 MAPK1 MAP MAP 24 2.3 mechanisms involving neurogenesis neurotrophic factor IGF-1 and its receptor and MAP kinase signal transduction cascades 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133168 16227974 175706 18723 10261 ROS1 ROS ROS 11 0.6 growing body of evidence indicates that reactive oxygen species (ROS), ROS which are primarily generated by mitochondrial metabolism can fuel both 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133169 16227974 175709 18723 10261 ROS1 ROS ROS 6 0.6 Here I review the evidence that ROS contribute to neurodegenerative disease atherosclerosis and cancer and then discuss 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133170 16227974 175710 20996 11179 SOD1 ALS ALS 7 1.7 Oxidents and neurodegeneration Amyotrophic lateral sclerosis ( ALS is a devastating disease that is characterized by motor-neuron degeneration 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000589084383163048<>ScoreDetail__5468|IGFALS|0.000345076216439068__11179|SOD1|0.000589084383163048__ 0 0 0 0 0 133171 16227974 175711 20996 11179 SOD1 SOD1 SOD1 28 1.4 the cytosolic form of the antioxidant protein superoxide dismutase ( SOD1 1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133172 16227974 175712 18723 10261 ROS1 ROS ROS 19 0.6 the most tangible clues linking the inappropriate metabolism of cellular ROS to the development of a specific neurological disease 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133173 16227974 175713 20996 11179 SOD1 SOD1 SOD1 6 1.4 That said how disease-causing mutations in SOD1 lead to ALS remains controversial 2 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133174 16227974 175713 20996 11179 SOD1 ALS ALS 9 1.7 That said how disease-causing mutations in SOD1 lead to ALS remains controversial 2 3 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000589084383163048<>ScoreDetail__5468|IGFALS|0.000345076216439068__11179|SOD1|0.000589084383163048__ 0 0 0 0 0 133175 16227974 175715 20996 11179 SOD1 ALS ALS 2 1.7 Similar to ALS most cases are sporadic although a number of dominant and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000589084383163048<>ScoreDetail__5468|IGFALS|0.000345076216439068__11179|SOD1|0.000589084383163048__ 0 0 0 0 0 133176 16227974 175716 16063 16369 PARK7 DJ1 DJ1 24 0.6 been identified including those encoding alpha-synuclein parkin ubiquitin C-terminal hydrolase-1 DJ1 and PTEN-induced kinase-1 ( PINK1 (Refs Refs 2 4 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 133177 16227974 175716 16634 14581 PINK1 PINK1 PINK1 29 0.6 alpha-synuclein parkin ubiquitin C-terminal hydrolase-1 DJ1 and PTEN-induced kinase-1 ( PINK1 (Refs Refs 2 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133178 16227974 175716 17590 9588 PTEN PTEN PTEN-induced 26 0.1 including those encoding alpha-synuclein parkin ubiquitin C-terminal hydrolase-1 DJ1 and PTEN-induced kinase-1 ( PINK1 (Refs Refs 2 4 6 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133179 16227974 175717 18723 10261 ROS1 ROS ROS 21 0.6 unifying hypothesis is that they trigger an increase in neuronal ROS levels 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133180 16227974 175722 16063 16369 PARK7 DJ1 DJ1 5 0.6 In addition neurons that lack DJ1 were recently shown to have an increased sensitivity to oxidative 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 133181 16227974 175723 16634 14581 PINK1 PINK1 PINK1 1 0.6 Finally PINK1 has a mitochondrial-targeting sequence and in this subcellular location it 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133182 16227974 175727 926 620 APP amyloid amyloid 11 1.0 characteristic feature of Alzheimer's disease is the formation of extracellular amyloid plaques that contain cleavage products amyloid-beta (A A beta of 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 133183 16227974 175727 926 620 APP amyloid amyloid 22 1.0 plaques that contain cleavage products amyloid-beta (A A beta of amyloid precursor protein ( APP 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 133184 16227974 175727 926 620 APP APP APP 26 0.6 products amyloid-beta (A A beta of amyloid precursor protein ( APP 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133185 16227974 175728 926 620 APP APP APP 11 0.6 forms of Alzheimer's disease have been linked to mutations in APP or in gene products that are involved in APP processing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133186 16227974 175728 926 620 APP APP APP 20 0.6 in APP or in gene products that are involved in APP processing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133187 16227974 175734 18723 10261 ROS1 ROS ROS 17 0.6 inherited forms of these diseases therefore does not directly involve ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133188 16227974 175743 166 118 ACO2 aconitase aconitase 5 2.1 Studies with the mitochondrial protein aconitase have demonstrated that low levels of ROS caused mild oxidation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133189 16227974 175743 18723 10261 ROS1 ROS ROS 12 0.6 the mitochondrial protein aconitase have demonstrated that low levels of ROS caused mild oxidation and stimulated degradation whereas higher levels of 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133190 16227974 175743 18723 10261 ROS1 ROS ROS 23 0.6 caused mild oxidation and stimulated degradation whereas higher levels of ROS caused aconitase to aggregate and become more resistant to proteasomal 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133191 16227974 175743 166 118 ACO2 aconitase aconitase 25 2.1 oxidation and stimulated degradation whereas higher levels of ROS caused aconitase to aggregate and become more resistant to proteasomal degradation 20 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133192 16227974 175744 18723 10261 ROS1 ROS ROS 14 0.6 evidence indicates that certain intracellular protein aggregates can alter mitochondrial ROS production 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133193 16227974 175746 18723 10261 ROS1 ROS ROS 1 0.6 Alternatively ROS might contribute to the progression of these and other diseases 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133194 16227974 175747 18723 10261 ROS1 ROS ROS 8 0.6 Finally it is important to stress that cellular ROS can directly target nuclear DNA 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133195 16227974 175754 18723 10261 ROS1 ROS ROS 11 0.6 exist regarding how risk factors trigger an increase in vascular ROS levels and what oxidant source is responsible for the in 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133196 16227974 175760 20997 11180 SOD2 SOD2 Sod2 4 1.7 Superoxide dismutase-2 - Sod2 - mice which lack one copy of this mitochondrial antioxidant 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133197 16227974 175761 18723 10261 ROS1 ROS ROS 12 0.6 in mice with hypercholesterolaemia there is evidence of increased mitochondrial ROS production 27 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133198 16227974 175765 13744 7475 MT-TA TRNA tRNA 9 1.3 Further analysis indeed identified a mutation in a mitochondria-encoded tRNA that was the underlying basis for why members of this 14 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 133199 16227974 175770 18723 10261 ROS1 ROS ROS 14 0.6 is a considerable amount of literature on the role of ROS as DNA-damaging agents and as potential initiators of tumour formation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133200 16227974 175771 20997 11180 SOD2 SOD2 Sod2 17 1.7 protein peroxiredoxin-I (Ref Ref 32 or are heterozygous deleted for Sod2 (Ref Ref 33 have increased spontaneous tumour formation 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133201 16227974 175773 18723 10261 ROS1 ROS ROS 22 0.6 range of peptide growth factors trigger the rapid production of ROS in cells and that this ROS burst is required for 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133202 16227974 175773 18723 10261 ROS1 ROS ROS 28 0.6 the rapid production of ROS in cells and that this ROS burst is required for normal growth-factor signalling 35 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133203 16227974 175774 18723 10261 ROS1 ROS ROS 18 0.6 growth-factor and cytokine signalling has expanded the potential role of ROS in tumour formation and suggests that besides random damage to 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133204 16227974 175776 22671 11998 TP53 p53 p53 6 0.3 For example there is evidence that p53 Myc ataxia telangiectasia mutated ( ATM and Ras can all 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133205 16227974 175776 1271 795 ATM ATM ATM 12 2.2 there is evidence that p53 Myc ataxia telangiectasia mutated ( ATM and Ras can all alter intracellular ROS levels 31 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133206 16227974 175776 18723 10261 ROS1 ROS ROS 20 0.6 telangiectasia mutated ( ATM and Ras can all alter intracellular ROS levels 31 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133207 16227974 175776 13925 7553 MYC MYC Myc 7 0.2 For example there is evidence that p53 Myc ataxia telangiectasia mutated ( ATM and Ras can all alter 5 JUMiner_v2.2 1 0 0 2 7553 TotalCon:2<>7553|MYC|4609|Complete__7869|NOL3|8996|Complete__<>AvaiableGeneRif=2<>BEST:7553|MYC|0.000534467067351009<>ScoreDetail__7553|MYC|0.000534467067351009__7869|NOL3|0.000504227436234179__ 0 0 0 0 0 133208 16227974 175777 18723 10261 ROS1 ROS ROS 5 0.6 More importantly the alteration in ROS levels has been linked to the ability of gene products 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133209 16227974 175777 13925 7553 MYC MYC Myc 20 0.0 to the ability of gene products such as Ras and Myc to induce cellular transformation or genomic instability 36 37 2 JUMiner_v2.2 1 0 0 2 7553 TotalCon:2<>7553|MYC|4609|Complete__7869|NOL3|8996|Complete__<>AvaiableGeneRif=2<>BEST:7553|MYC|0.000534467067351009<>ScoreDetail__7553|MYC|0.000534467067351009__7869|NOL3|0.000504227436234179__ 0 0 0 0 0 133210 16227974 175779 18723 10261 ROS1 ROS ROS 4 0.6 In both phenotypes Ras-induced ROS production seems to have a crucial role 39 40 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133211 16227974 175784 5811 2859 DHCR24 seladin-1 seladin-1 5 1.3 Another group noted that inhibiting seladin-1 could also block Ras- or oxidant-induced senescence 42 (seladin-1 seladin-1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133212 16227974 175784 5811 2859 DHCR24 seladin-1 seladin-1 14 1.3 seladin-1 could also block Ras- or oxidant-induced senescence 42 (seladin-1 seladin-1 had been previously discovered in the context of Alzheimer's disease 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133213 16227974 175785 5811 2859 DHCR24 seladin-1 seladin-1 4 1.3 Notably following hydrogen-peroxide treatment seladin-1 translocates to the nucleus where it seems to bind to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133214 16227974 175785 22671 11998 TP53 p53 p53 17 0.3 the nucleus where it seems to bind to and stabilize p53 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133215 16227974 175786 18723 10261 ROS1 ROS ROS 10 0.6 Again these results indicate an intimate coupling between cellular metabolism ROS levels and tumour-causing genes ( Fig 3 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133216 16227974 175787 18723 10261 ROS1 ROS ROS 6 0.6 There is also considerable evidence that ROS can modulate the tumour phenotype 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133217 16227974 175788 10826 6206 JUND JUND JunD 4 0.3 Recently the transcription factor JunD was shown to regulate the levels of tumour-secreted angiogenic growth 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133218 16227974 175794 19982 10886 SIRT2 SIR2 SIR-2 19 1.3 melanogaster and Caenorhabditis elegans overexpression of the NAD-dependent histone deacetylase SIR-2 results in an increased lifespan 48 49 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133219 16227974 175795 19982 10886 SIRT2 SIR2 SIR-2 5 1.3 The closest mammalian orthologue of SIR-2 is SIRT1 and it is presently not known whether overexpression 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133220 16227974 175795 19981 14929 SIRT1 SIRT1 SIRT1 7 0.3 The closest mammalian orthologue of SIR-2 is SIRT1 and it is presently not known whether overexpression of SIRT1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133221 16227974 175795 19981 14929 SIRT1 SIRT1 SIRT1 17 0.3 SIRT1 and it is presently not known whether overexpression of SIRT1 will extend mammalian lifespan 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133222 16227974 175796 18723 10261 ROS1 ROS ROS 13 0.6 the family of SIR-2-related proteins (known known as sirtuins and ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133223 16227974 175797 19982 10886 SIRT2 SIR2 Sir2 3 1.3 For instance yeast Sir2 seems to be important in protecting cells from accumulation of 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133224 16227974 175797 19981 14929 SIRT1 SIRT1 SIRT1 20 0.3 cells from accumulation of oxidatively damaged proteins 50 and mammalian SIRT1 and SIRT3 might modulate mitochondrial activity 51 52 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133225 16227974 175797 19983 14931 SIRT3 SIRT3 SIRT3 20 0.3 cells from accumulation of oxidatively damaged proteins 50 and mammalian SIRT1 and SIRT3 might modulate mitochondrial activity 51 52 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133226 16227974 175797 19983 14931 SIRT3 SIRT3 SIRT3 22 0.3 accumulation of oxidatively damaged proteins 50 and mammalian SIRT1 and SIRT3 might modulate mitochondrial activity 51 52 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133227 16227974 175799 19981 14929 SIRT1 SIRT1 SIRT1 6 0.3 Recent studies have shown that overexpressing SIRT1 in mice seems to protect neurons from at least some 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133228 16227974 175800 19982 10886 SIRT2 SIR2 SIR-2 15 1.3 model of the neurodegenerative condition Huntington's disease upregulated expression of SIR-2 increased neuronal survival 54 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133229 16227974 175801 19982 10886 SIRT2 SIR2 SIR-2 32 1.3 has also been recently proposed to increase the activity of SIR-2 (Ref Ref 55 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133230 16227974 175803 19898 10840 SHC1 p66SHC p66SHC 6 3.2 Another known mammalian-longevity gene product is p66SHC the p66 isoform of the adaptor protein SHC (Src-homology-2-containing) Src-homology-2-containing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133231 16227974 175803 19898 10840 SHC1 p66 p66 8 2.9 Another known mammalian-longevity gene product is p66SHC the p66 isoform of the adaptor protein SHC (Src-homology-2-containing) Src-homology-2-containing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133232 16227974 175803 19898 10840 SHC1 SHC SHC 14 4.2 product is p66SHC the p66 isoform of the adaptor protein SHC (Src-homology-2-containing) Src-homology-2-containing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133233 16227974 175803 21242 11283 SRC SRC Src-homology-2-containing 15 0.2 p66SHC the p66 isoform of the adaptor protein SHC (Src-homology-2-containing) Src-homology-2-containing 5 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133234 16227974 175804 19898 10840 SHC1 SHC SHC 1 4.2 Normally SHC proteins serve as a molecular bridge linking various surface receptors 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133235 16227974 175805 19898 10840 SHC1 p66SHC p66SHC 2 3.2 Mice lacking p66SHC have a 30% increased lifespan 57 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133236 16227974 175806 18723 10261 ROS1 ROS ROS 15 0.6 to oxidative challenges and their cells contain lower levels of ROS 57 58 59 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133237 16227974 175807 19898 10840 SHC1 P66SHC p66Shc 2 3.2 Interestingly when p66Shc - -mice were bred with mice that had a predisposition 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133238 16227974 175808 19898 10840 SHC1 P66SHC p66Shc 16 3.2 vascular function that precede plaque formation were also absent in p66Shc - -animals 61 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133239 16227974 175811 18723 10261 ROS1 ROS ROS 29 0.6 evidence that this life extension might occur through reduced mitochondrial ROS generation 62 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133240 16227974 175817 18723 10261 ROS1 ROS ROS 9 0.6 For example why has the measurable release of mitochondrial ROS persisted throughout evolution when it is clear that simple increased 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133241 16227974 175817 18723 10261 ROS1 ROS ROS 26 0.6 clear that simple increased expression of antioxidant proteins can reduce ROS levels and apparently prolong lifespan 67 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133242 16227974 175818 18723 10261 ROS1 ROS ROS 6 0.6 Is it the sum of all ROS produced or only mitochondrial-derived oxidants that drive disease and ageing 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133243 16227974 175819 18723 10261 ROS1 ROS ROS 6 0.6 What are the relevant targets of ROS and are the targets the same or different for ageing 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133244 16227974 175820 18723 10261 ROS1 ROS ROS 22 0.6 once we have a more detailed understanding of how mitochondrial ROS are produced and what regulates their release 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133245 16227974 175821 18723 10261 ROS1 ROS ROS 6 0.6 My personal bias is that mitochondrial ROS are not incidentally produced or accidentally released but rather have 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133246 16227974 175822 166 118 ACO2 aconitase aconitase 45 2.1 the activity of a set of metabolic enzymes such as aconitase and components of mitochondrial complex I that contain Fe-S clusters 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133247 16227974 175822 7503 3657 FES FES Fe-S 54 0.0 as aconitase and components of mitochondrial complex I that contain Fe-S clusters 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133248 16227974 175823 12349 6881 MAPK8 JNK JNKs 17 0.3 cytosolic stress pathways (for for example Jun N-terminal kinases (JNKs) JNKs and p38 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133249 16227974 175823 12359 6876 MAPK14 p38 p38 19 0.3 pathways (for for example Jun N-terminal kinases (JNKs) JNKs and p38 1 JUMiner_v2.2 1 0 0 2 6878 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6878|MAPK4|0.000710908897024846<>ScoreDetail__1189|AHSA1|0.000464460479389566__6878|MAPK4|0.000710908897024846__6871|MAPK1|0.000556733255860255__6876|MAPK14|0.000545081115596972__ 0 0 0 0 0 133250 16227974 175823 18723 10261 ROS1 ROS ROS-mediated 1 0.0 Another ROS-mediated regulatory role might involve a number of cytosolic stress pathways 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133251 16227974 175824 18723 10261 ROS1 ROS ROS 9 0.6 Indeed I would suggest that the release of mitochondrial ROS is used as a common messenger to sustain stress-activated pathways 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133252 16227974 175824 18723 10261 ROS1 ROS ROS 38 0.6 able to actively regulate and titrate the amount of mitochondrial ROS released 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133253 16227974 175825 18723 10261 ROS1 ROS ROS 14 0.6 comfortable with the regulated release of large amounts of mitochondrial ROS during apoptosis I would suggest that in numerous other contexts 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133254 16227974 175827 18723 10261 ROS1 ROS ROS-regulatory 5 0.0 A potential hint to this ROS-regulatory role is already beginning to emerge 68 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133255 16227974 175828 18723 10261 ROS1 ROS ROS 6 0.6 It is this regulated release of ROS and this overall stress-signalling function of oxidants that I believe 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133256 16227974 175828 18723 10261 ROS1 ROS ROS 37 0.6 hypertension and protein misfolding and the sustained increase in measurable ROS levels 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133257 16227974 175830 18723 10261 ROS1 ROS ROS 15 0.6 intimate connection between cellular insult/stress, insult stress the production of ROS and the ultimate development of a disease or ageing phenotype 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133258 16227974 175834 19898 10840 SHC1 p66SHC p66SHC 14 3.2 out that drugs that augment sirtuins or those that inhibit p66SHC will only be effective in a discrete subset of age-related 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133259 16227974 175841 20997 11180 SOD2 SOD2 Sod2 0 1.7 Sod2 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133260 16227974 175843 20996 11179 SOD1 ALS ALS 0 1.7 ALS Alzheimer's disease Parkinson's disease 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000589084383163048<>ScoreDetail__5468|IGFALS|0.000345076216439068__11179|SOD1|0.000589084383163048__ 0 0 0 0 0 133261 16227974 175845 926 620 APP APP APP 1 0.6 alpha-synuclein APP ATM JunD parkin peroxiredoxin I PINK1 Ras seladin-1 SIRT1 SIRT3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133262 16227974 175845 1271 795 ATM ATM ATM 2 2.2 alpha-synuclein APP ATM JunD parkin peroxiredoxin I PINK1 Ras seladin-1 SIRT1 SIRT3 SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133263 16227974 175845 10826 6206 JUND JUND JunD 3 0.3 alpha-synuclein APP ATM JunD parkin peroxiredoxin I PINK1 Ras seladin-1 SIRT1 SIRT3 SOD1 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133264 16227974 175845 16634 14581 PINK1 PINK1 PINK1 7 0.6 alpha-synuclein APP ATM JunD parkin peroxiredoxin I PINK1 Ras seladin-1 SIRT1 SIRT3 SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133265 16227974 175845 5811 2859 DHCR24 seladin-1 seladin-1 9 1.3 alpha-synuclein APP ATM JunD parkin peroxiredoxin I PINK1 Ras seladin-1 SIRT1 SIRT3 SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133266 16227974 175845 19981 14929 SIRT1 SIRT1 SIRT1 10 0.3 alpha-synuclein APP ATM JunD parkin peroxiredoxin I PINK1 Ras seladin-1 SIRT1 SIRT3 SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133267 16227974 175845 19983 14931 SIRT3 SIRT3 SIRT3 11 0.3 APP ATM JunD parkin peroxiredoxin I PINK1 Ras seladin-1 SIRT1 SIRT3 SOD1 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133268 16227974 175845 20996 11179 SOD1 SOD1 SOD1 12 1.4 ATM JunD parkin peroxiredoxin I PINK1 Ras seladin-1 SIRT1 SIRT3 SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 133269 16227974 175859 18723 10261 ROS1 ROS ROS 16 0.6 proteins seems to be accelerated by reactive oxygen species (ROS) ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133270 16227974 175860 18723 10261 ROS1 ROS ROS 17 0.6 protein aggregates might affect mitochondria leading to higher levels of ROS production 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133271 16227974 175861 18723 10261 ROS1 ROS ROS 14 0.6 a positive-feedback loop that is fuelled by the levels of ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133272 16227974 175864 18723 10261 ROS1 ROS ROS 17 0.6 suppressors alter the levels of intracellular reactive oxygen species (ROS) ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133273 16227974 175866 18723 10261 ROS1 ROS ROS 2 0.6 Increased intracellular ROS levels can stimulate several cellular reactions/processes reactions processes that can 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133274 16227974 175870 18723 10261 ROS1 ROS ROS 15 0.6 the physiological and pathophysiological roles of reactive oxygen species (ROS) ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133275 16227974 175871 18723 10261 ROS1 ROS ROS 1 0.6 Mitochondrial ROS production and release is shown by the arrows with the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133276 16227974 175871 18723 10261 ROS1 ROS ROS 14 0.6 release is shown by the arrows with the intensity of ROS indicated by the width of the arrow 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133277 16227974 175873 18723 10261 ROS1 ROS ROS 11 0.6 cytosolic metabolic pathways might also be regulated by these mitochondrial-derived ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133278 16227974 175874 18723 10261 ROS1 ROS ROS 23 0.6 are postulated to in turn titrate the release of mitochondrial ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133279 16227974 175875 18723 10261 ROS1 ROS ROS 4 0.6 This regulated release of ROS has been suggested to be necessary to sustain these stress-activated 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133280 16227974 175876 18723 10261 ROS1 ROS ROS 13 0.6 loop provides a potential explanation for the concordance of increased ROS levels with a number of age-associated diseases 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 133281 16227974 175877 18723 10261 ROS1 ROS ROS 7 0.6 Finally continued cellular stress results in sustained ROS production and the resultant increase in cell death DNA mutations 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134145 16242643 176941 18723 10261 ROS1 ROS ROS 32 0.6 cardiolipin we observed that malonate induced reactive oxygen species (ROS) ROS production to an extent that surpasses the antioxidant defense capacity 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134146 16242643 176943 18723 10261 ROS1 ROS ROS 5 0.6 Moreover minocycline failed to block ROS production and to abrogate malonate-induced oxidation of GSH and cardiolipin 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134147 16242643 176945 14535 7873 NOS2A iNOS iNOS 9 2.5 Furthermore malonate did not induce the expression of the iNOS caspase-3 -8 and -9 genes which have been shown to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134148 16242643 176946 1576 990 BCL2 Bcl-2 Bcl-2 8 6.2 In addition malonate-induced down-regulation of the antiapoptotic gene Bcl-2 was not prevented by minocycline controversially the mechanism previously proposed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134149 16242643 176951 14535 7873 NOS2A iNOS iNOS 29 2.5 expression of interleukin 1 beta inducible nitric oxide synthase (iNOS), iNOS caspase-3 and -1 ( Chen et al. 2000 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134150 16242643 176952 17686 9683 PTPRU PTP PTP 37 0.3 opening of the mitochondrial high conductance permeability transition pore (PTP) PTP ( Zhu et al. 2002 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9683 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9683|PTPRU|0.000368527731711811<>ScoreDetail__9951|REG1A|0.000265498473383778__9683|PTPRU|0.000368527731711811__ 0 0 0 0 0 134151 16242643 176953 5854 21528 DIABLO SMAC SMAC 14 1.8 turn inhibits the release of the proapoptotic factors cytochrome c SMAC (DIABLO) DIABLO and apoptosis-inducing factor from the mitochondria ( Wang 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134152 16242643 176953 5854 21528 DIABLO DIABLO DIABLO 15 1.8 the release of the proapoptotic factors cytochrome c SMAC (DIABLO) DIABLO and apoptosis-inducing factor from the mitochondria ( Wang et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134153 16242643 176963 18723 10261 ROS1 ROS ROS 12 0.6 of this reversible succinate dehydrogenase inhibitor to cell cultures induced ROS production that resulted in the depletion of glutathione and cardiolipin 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134154 16242643 176965 14535 7873 NOS2A iNOS iNOS 12 2.5 no modifications in the expression of the mRNA's encoding for iNOS caspase-3 -8 and -9 after malonate additions were found we 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134155 16242643 176983 18723 10261 ROS1 ROS ROS 3 0.6 Intracellular generation of ROS 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134156 16242643 176991 18723 10261 ROS1 ROS ROS 4 0.6 The average relative percent ROS production from at least three separate cultures was determined 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134157 16242643 177013 6369 3186 EEC1 EEC EEC 21 0.0 Community Council Directive of 24 November 1986 (86/609/EEC) 86 609 EEC and were approved by the Ethical Committee of the University 1 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 134158 16242643 177024 17686 9683 PTPRU PTP PTP 15 0.3 540 nm ( A 540 indicating mitochondrial swelling due to PTP opening were determined after the addition of different compounds using 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9683 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9683|PTPRU|0.000368527731711811<>ScoreDetail__9951|REG1A|0.000265498473383778__9683|PTPRU|0.000368527731711811__ 0 0 0 0 0 134159 16242643 177037 8118 4141 GAPDH GAPDH GAPDH 18 0.3 (Cycle Cycle threshold method ( Livak and Schmittgen 2001 using GAPDH as internal control once demonstrated that the efficiency for the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134160 16242643 177038 19573 10691 SDS SDS SDS 23 0.0 computer Primer Express software program specially provided with the 7000 SDS (Applied Applied Biosystems 1 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000257402387039422<>ScoreDetail__10691|SDS|0.000228444618497487__19440|SBDS|0.000257402387039422__ 0 0 0 0 0 134161 16242643 177052 18723 10261 ROS1 ROS ROS 10 0.6 Tetracyclines have been reported to have the ability to inhibit ROS production in various cell types ( Gabler et al. 1992 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134162 16242643 177056 18723 10261 ROS1 ROS ROS 20 0.6 et al. 2005 and Maragos et al. 2004 malonate increased ROS production in cerebellar granular cell cultures ( Fig 2 B 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134163 16242643 177066 18723 10261 ROS1 ROS ROS 12 0.6 proteins and lipids commonly occurs as a consequence of increased ROS production and depletion of the antioxidant capacity 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134164 16242643 177073 17686 9683 PTPRU PTP PTP 11 0.3 some circumstances mitochondria respond to cellular stress by opening the PTP resulting in the swelling of the organelle 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9683 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9683|PTPRU|0.000368527731711811<>ScoreDetail__9951|REG1A|0.000265498473383778__9683|PTPRU|0.000368527731711811__ 0 0 0 0 0 134165 16242643 177078 14535 7873 NOS2A iNOS iNOS 0 2.5 iNOS caspase-3 -8 and -9 mRNA expression levels are not modulated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134166 16242643 177080 14535 7873 NOS2A iNOS iNOS 7 2.5 Among them the down-regulation of caspases and iNOS and the up-regulation of Bcl-2 have been documented recently ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134167 16242643 177080 1576 990 BCL2 Bcl-2 Bcl-2 12 6.2 the down-regulation of caspases and iNOS and the up-regulation of Bcl-2 have been documented recently ( Wang et al. 2004 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134168 16242643 177081 14535 7873 NOS2A iNOS iNOS 22 2.5 cell death we first analyzed the pattern of expression of iNOS caspase-3 -8 and -9 and the antiapoptotic gene Bcl-2 in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134169 16242643 177081 1576 990 BCL2 Bcl-2 Bcl-2 31 6.2 of iNOS caspase-3 -8 and -9 and the antiapoptotic gene Bcl-2 in malonate-treated cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134170 16242643 177082 14535 7873 NOS2A iNOS iNOS 28 2.5 in cell viability does not modify the expression of the iNOS caspase-3 -8 and -9 genes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134171 16242643 177083 1576 990 BCL2 Bcl-2 Bcl-2 12 6.2 mM malonate caused a significant down-regulation of the antiapoptotic gene Bcl-2 ( Fig 6 B 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134172 16242643 177085 1576 990 BCL2 Bcl-2 Bcl-2 10 6.2 Therefore we studied whether minocycline would prevent the down-regulation of Bcl-2 gene expression induced by malonate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134173 16242643 177086 1576 990 BCL2 Bcl-2 Bcl-2 20 6.2 lack of protective effect failed to block the down-regulation of Bcl-2 caused by malonate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134174 16242643 177089 18723 10261 ROS1 ROS ROS 17 0.6 abrogate any of the effects caused by malonate including increased ROS production and the subsequent depletion of GSH and cardiolipin 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134175 16242643 177091 14535 7873 NOS2A iNOS iNOS 18 2.5 mRNA expression of caspase-3 -8 and -9 as well as iNOS it decreases the mRNA of the antiapoptotic protein Bcl-2 an 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134176 16242643 177091 1576 990 BCL2 Bcl-2 Bcl-2 27 6.2 as iNOS it decreases the mRNA of the antiapoptotic protein Bcl-2 an effect that was not abrogated by minocycline 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134177 16242643 177093 18723 10261 ROS1 ROS ROS 6 0.6 For this reason we began measuring ROS levels in cerebellar granular cells treated with malonate minocycline or 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134178 16242643 177094 18723 10261 ROS1 ROS ROS 4 0.6 As expected malonate increased ROS production in a concentration-dependent manner 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134179 16242643 177097 18723 10261 ROS1 ROS ROS 13 0.6 to previous results showing that minocycline decreases the formation of ROS in various cell types ( Gabler et al. 1992 in 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134180 16242643 177097 18723 10261 ROS1 ROS ROS 35 0.6 our experimental model minocycline failed to prevent malonate-induced rise in ROS production 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134181 16242643 177098 18723 10261 ROS1 ROS ROS 21 0.6 capacity revealed that although this antibiotic decreased the abovementioned basal ROS production it did not modify reduced glutathione levels in cerebellar 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134182 16242643 177100 18723 10261 ROS1 ROS ROS 12 0.6 present data point to cardiolipin as a target of malonate-induced ROS 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134183 16242643 177104 17686 9683 PTPRU PTP PTP 0 0.3 PTP can be monitored by following mitochondrial swelling which interestingly has 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9683 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9683|PTPRU|0.000368527731711811<>ScoreDetail__9951|REG1A|0.000265498473383778__9683|PTPRU|0.000368527731711811__ 0 0 0 0 0 134184 16242643 177104 13412 7214 MPHOSPH6 MPP MPP 24 0.0 be involved in several death pathways including those induced by MPP staurosporine veratridine malonate or NMDA ( Boada et al. 2000 1 JUMiner_v2.2 1 0 0 2 7214 TotalCon:2<>7214|MPHOSPH6|10200|Complete__7225|MPZ|4359|Complete__<>AvaiableGeneRif=2<>BEST:7214|MPHOSPH6|0.000704914822792246<>ScoreDetail__7214|MPHOSPH6|0.000704914822792246__7225|MPZ|0.000384733731121043__ 0 0 0 0 0 134185 16242643 177105 17686 9683 PTPRU PTP PTP 8 0.3 On the other hand drugs able to block PTP formation afford complete or partial neuroprotection against a broad type 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9683 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9683|PTPRU|0.000368527731711811<>ScoreDetail__9951|REG1A|0.000265498473383778__9683|PTPRU|0.000368527731711811__ 0 0 0 0 0 134186 16242643 177110 17686 9683 PTPRU PTP PTP 5 0.3 Whether the main mechanism mediating PTP formation that is through an oxidative (e.g., e.g. tert -butyl 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9683 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9683|PTPRU|0.000368527731711811<>ScoreDetail__9951|REG1A|0.000265498473383778__9683|PTPRU|0.000368527731711811__ 0 0 0 0 0 134187 16242643 177110 22000 11730 TERT TERT tert 13 0.6 mediating PTP formation that is through an oxidative (e.g., e.g. tert -butyl hydroperoxide phenylarsine oxide or non-oxidative (Ca/Pi, Ca Pi t-Bid 14 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 134188 16242643 177110 7333 11920 FAS FAS Fas 23 0.3 hydroperoxide phenylarsine oxide or non-oxidative (Ca/Pi, Ca Pi t-Bid Bid Fas mechanism ( Chu et al. 2005 Wang et al. 2003 2 JUMiner_v2.2 1 0 0 2 3594 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:3594|FASN|0.000535752139405238<>ScoreDetail__11920|FAS|0.000520118217391753__3594|FASN|0.000535752139405238__ 0 0 0 0 0 134189 16242643 177110 17686 9683 PTPRU PTP PTP 48 0.3 et al. 2002 influences the ability of minocycline to block PTP formation needs to be studied further 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9683 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9683|PTPRU|0.000368527731711811<>ScoreDetail__9951|REG1A|0.000265498473383778__9683|PTPRU|0.000368527731711811__ 0 0 0 0 0 134190 16242643 177111 18723 10261 ROS1 ROS ROS-mediated 21 0.3 capable of blocking mitochondrial swelling when this process is mainly ROS-mediated as it is the case for malonate ( Fern_amp_#xe1 ndez-G_amp_#xf3 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 134191 16242643 177113 13412 7214 MPHOSPH6 MPP MPP 20 0.0 to block the effect of the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP MPP on mitochondrial swelling and also postulated a lack of direct 1 JUMiner_v2.2 1 0 0 2 7214 TotalCon:2<>7214|MPHOSPH6|10200|Complete__7225|MPZ|4359|Complete__<>AvaiableGeneRif=2<>BEST:7214|MPHOSPH6|0.000704914822792246<>ScoreDetail__7214|MPHOSPH6|0.000704914822792246__7225|MPZ|0.000384733731121043__ 0 0 0 0 0 134192 16242643 177114 14535 7873 NOS2A iNOS iNOS 39 2.5 be modulated by minocycline after different neurotoxic stimuli such as iNOS and several members of the caspase family ( Chen et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134193 16242643 177115 14535 7873 NOS2A iNOS iNOS 12 2.5 no changes in the expression of the genes coding for iNOS caspase-3 -8 and -9 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134194 16242643 177116 1576 990 BCL2 Bcl-2 Bcl-2 8 6.2 Conversely we did find a significant down-regulation of Bcl-2 expression after a 24-h malonate exposure 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134195 16242643 177117 1576 990 BCL2 Bcl-2 Bcl-2 8 6.2 It should be noted that the up-regulation of Bcl-2 gene expression has been recently proposed as a mechanism mediating 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134196 16242643 177118 1576 990 BCL2 Bcl-2 Bcl-2 22 6.2 present work this drug failed to reverse the down-regulation of Bcl-2 induced by malonate treatment nor induced Bcl-2 expression by itself 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134197 16242643 177118 1576 990 BCL2 Bcl-2 Bcl-2 29 6.2 the down-regulation of Bcl-2 induced by malonate treatment nor induced Bcl-2 expression by itself 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134198 16242643 177146 17686 9683 PTPRU PTP PTP 7 0.3 The effect of 50 _amp_#x3bc M minocycline on PTP was also measured 1 JUMiner_v2.2 1 2 permeability transition pore 0 2 9683 TotalCon:2<>9683|PTPRU|10076|Complete__9951|REG1A|5967|Complete__<>AvaiableGeneRif=2<>BEST:9683|PTPRU|0.000368527731711811<>ScoreDetail__9951|REG1A|0.000265498473383778__9683|PTPRU|0.000368527731711811__ 0 0 0 0 0 134199 16242643 177149 14535 7873 NOS2A iNOS iNOS 5 2.5 Fig 6._amp_#xa0 Malonate does not affect iNOS caspase-3 -8 and -9 but significantly reduces Bcl-2 mRNA expression 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134200 16242643 177149 1576 990 BCL2 Bcl-2 Bcl-2 13 6.2 not affect iNOS caspase-3 -8 and -9 but significantly reduces Bcl-2 mRNA expression levels mRNA expression in malonate-treated cerebellar granular cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134201 16242643 177150 14535 7873 NOS2A iNOS iNOS 8 2.5 (A) A Lack of effects of malonate on the iNOS caspase-3 -8 and -9 mRNA expression levels 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134202 16242643 177151 1576 990 BCL2 Bcl-2 Bcl-2 5 6.2 (B) B Effect of malonate on Bcl-2 mRNA expression levels 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 134203 16242643 177152 1576 990 BCL2 Bcl-2 Bcl-2 6 6.2 Minocycline pre-treatment fails to avoid the Bcl-2 down-regulation induced by malonate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 129625 16406002 170390 18723 10261 ROS1 ROS ROS 12 0.0 oxidative stress the production of highly reactive oxygen species (ROS) ROS overwhelms antioxidant defenses resulting in the modification of macromolecules and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 129626 16406002 170407 6554 3309 ELA2 HNE HNE 9 0.9 of such toxic compounds are 4-oxonon-2-enal (ONE), ONE 4-hydroxynon-2-enal (HNE), HNE and acrolein which contain an _amp_#x3b2 -unsaturated aldehyde capable of 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 129627 16406002 170413 7333 11920 FAS FAS FAS-independent 18 0.3 the activation of caspases and to DNA fragmentation through a FAS-independent and mitochondria-linked pro-apoptotic signal pathway 11 JUMiner_v2.2 1 0 0 2 3594 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:3594|FASN|0.000516190687117816<>ScoreDetail__11920|FAS|0.000483141590469407__3594|FASN|0.000516190687117816__ 0 0 0 0 0 129628 16406002 170415 10824 6204 JUN c-Jun c-Jun 10 1.3 In various cell lines reactive aldehyde-induced apoptosis was accompanied by c-Jun -N-terminal kinase and caspase-3 activation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 129629 16406002 170416 926 620 APP amyloid amyloid 12 1.0 lipid aldehyde-mediated _amp_#x3b2 PKC activation induced an increase in intracellular amyloid production 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 129630 16406002 170424 19572 10690 SDPR SDR SDR 42 0.3 aldo-keto reductases (AKR) AKR 12 and the short-chain dehydrogenases (SDR) SDR 13 (to to which Sniffer belongs 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 129631 16406002 170428 19572 10690 SDPR SDR SDR 8 0.3 Like CR the Sniffer protein belongs to the SDR superfamily 13 and both enzymes share all the essential motifs 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 129632 16406002 170439 6554 3309 ELA2 HNE HNE 16 0.9 to be both more neurotoxic and more protein reactive than HNE 8 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 129633 16406002 170440 6554 3309 ELA2 HNE HNE 9 0.9 NADPH-dependent ONE ketone reduction resulted in the production of HNE and ONE aldehyde reduction yielded 1-hydroxynon-2-en-4-one (HNO) HNO 17 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 129634 16406002 170443 523 381 AKR1B1 AKR1B1 AKR1B1 9 1.1 At a first glance compared to CR the enzyme AKR1B1 (previously previously named aldose reductase from the AKR superfamily exhibits 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 129635 16406002 170444 6554 3309 ELA2 HNE HNE 11 0.9 addition the fact that CR produces another reactive lipid aldehyde HNE from ONE may indicate that AKR1B1 is the more important 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 129636 16406002 170444 523 381 AKR1B1 AKR1B1 AKR1B1 17 1.1 another reactive lipid aldehyde HNE from ONE may indicate that AKR1B1 is the more important catalyst for ONE and GS-ONE reduction 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 129637 16406002 170446 6554 3309 ELA2 HNE HNE 4 0.9 First ONE but not HNE is the major product of breakdown of lipid hydroperoxides and 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 129638 16406002 170446 6554 3309 ELA2 HNE HNE 30 0.9 were detected as a result from ONE rather than from HNE 19 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 129639 16406002 170447 6554 3309 ELA2 HNE HNE 12 0.9 ONE is both more neurotoxic and more protein reactive than HNE 8 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 129640 16406002 170451 6554 3309 ELA2 HNE HNE 2 0.9 HNO and HNE are much less reactive toward thiols than ONE (i.e., i.e. 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 129641 16406002 170451 6554 3309 ELA2 HNE HNE 18 0.9 than ONE (i.e., i.e. 55-fold for HNO and 110-fold for HNE but are still electrophilic Michael acceptors 20 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 129642 16406002 170452 6554 3309 ELA2 HNE HNE 0 0.9 HNE in turn is a substrate for AKR1B1 (carbonyl carbonyl reduction 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 129643 16406002 170452 523 381 AKR1B1 AKR1B1 AKR1B1 7 1.1 HNE in turn is a substrate for AKR1B1 (carbonyl carbonyl reduction and/or and or ALDH (aldehyde aldehyde dehydrogenation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 129644 16406002 170458 6554 3309 ELA2 HNE HNE 7 0.9 Abbreviations DHN = 4-dihydroxynonene HNA = 4-hydroxynonan-acid HNE = 4-hydroxynon-2-enal HNO = 1-hydroxynon-2-en-4-one ONA = 4-oxononanal ONE = 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 129645 16406002 170458 523 381 AKR1B1 AKR1B1 AKR1B1 27 1.1 4-oxonon-2-enal GSH = reduced glutathione AR = aldose reductase (AKR1B1); AKR1B1 ALDH = aldehyde dehydrogenase CR = carbonyl reductase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 118661 16440303 154887 20996 11179 SOD1 ALS ALS 3 1.4 Amyotrophic lateral sclerosis (ALS) ALS is a progressive neurodegenerative disorder disease 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00135071453864046<>ScoreDetail__5468|IGFALS|0.000606167756926729__11179|SOD1|0.00135071453864046__ 0 0 0 0 0 118662 16440303 154888 20996 11179 SOD1 ALS ALS 4 1.4 Ten percent of the ALS patients are congenital (familial familial ALS and the other 90% 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00135071453864046<>ScoreDetail__5468|IGFALS|0.000606167756926729__11179|SOD1|0.00135071453864046__ 0 0 0 0 0 118663 16440303 154888 20996 11179 SOD1 ALS ALS 9 1.4 Ten percent of the ALS patients are congenital (familial familial ALS and the other 90% are sporadic ALS (SALS) SALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00135071453864046<>ScoreDetail__5468|IGFALS|0.000606167756926729__11179|SOD1|0.00135071453864046__ 0 0 0 0 0 118664 16440303 154888 20996 11179 SOD1 ALS ALS 16 1.4 congenital (familial familial ALS and the other 90% are sporadic ALS (SALS) SALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00135071453864046<>ScoreDetail__5468|IGFALS|0.000606167756926729__11179|SOD1|0.00135071453864046__ 0 0 0 0 0 118665 16440303 154889 20996 11179 SOD1 ALS ALS 15 1.4 found in the Cu Zn-SOD cause 20% of the familial ALS due to its low enzyme activity 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00135071453864046<>ScoreDetail__5468|IGFALS|0.000606167756926729__11179|SOD1|0.00135071453864046__ 0 0 0 0 0 118666 16440303 154896 18723 10261 ROS1 ROS ROS 17 0.0 and chaperone proteins proteins involved in reactive oxygen species (ROS), ROS enzyme proteins and proteins that mediated cell death and survival 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 109933 16546755 143260 9947 5468 IGFALS ALS ALS 3 0.3 Amyotrophic lateral sclerosis (ALS) ALS is a progressive lethal neurodegenerative disease that selectively affects motor 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000980643603940679<>ScoreDetail__5468|IGFALS|0.0009758382450525__11179|SOD1|0.000980643603940679__ 0 0 0 0 0 109934 16546755 143261 18723 10261 ROS1 ROS ROS 3 0.3 Reactive oxygen species (ROS) ROS are assumed to be involved in the pathogenesis of ALS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 109935 16546755 143261 9947 5468 IGFALS ALS ALS 13 0.3 ROS are assumed to be involved in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000980643603940679<>ScoreDetail__5468|IGFALS|0.0009758382450525__11179|SOD1|0.000980643603940679__ 0 0 0 0 0 109936 16546755 143262 18723 10261 ROS1 ROS ROS 8 0.3 Metallothioneins (MTs) MTs are self-protective multifunctional proteins that scavenge ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 109937 16546755 143264 9947 5468 IGFALS ALS ALS 12 0.3 been suggested to have important roles in the pathophysiology of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000980643603940679<>ScoreDetail__5468|IGFALS|0.0009758382450525__11179|SOD1|0.000980643603940679__ 0 0 0 0 0 113357 16624679 147569 20996 11179 SOD1 SOD1 SOD1 4 3.7 G93A Cu/Zn Cu Zn superoxide dismutase (SOD1), SOD1 a human mutant SOD1 associated with familial amyotrophic lateral sclerosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113358 16624679 147569 20996 11179 SOD1 SOD1 SOD1 8 3.7 Cu/Zn Cu Zn superoxide dismutase (SOD1), SOD1 a human mutant SOD1 associated with familial amyotrophic lateral sclerosis increased the toxicity of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113359 16624679 147570 20996 11179 SOD1 SOD1 SOD1 8 3.7 G93ASOD1 cells died more than untransfected and wild-type SOD1 cells after 6 and 24 h exposure to 12.5 _amp_#x3bc 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 113360 16624679 147575 20996 11179 SOD1 SOD1 SOD1 21 3.7 their basal level was higher than in untransfected and wild-type SOD1 cells 1 JUMiner_v2.2 1 2 32 0 0 0 0 0 0 0 0 113361 16624679 147580 20996 11179 SOD1 ALS ALS 16 2.7 and death of motor neurons in amyotrophic lateral sclerosis (ALS), ALS which occurs in clinically and pathologically similar sporadic (SALS) SALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00142357144152476<>ScoreDetail__5468|IGFALS|0.00040551500405515__11179|SOD1|0.00142357144152476__ 0 0 0 0 0 113362 16624679 147581 20996 11179 SOD1 ALS ALS 16 2.7 suggested by ultrastructural studies showing mitochondrial abnormalities in tissues of ALS patients including in the early stages of the disease the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00142357144152476<>ScoreDetail__5468|IGFALS|0.00040551500405515__11179|SOD1|0.00142357144152476__ 0 0 0 0 0 113363 16624679 147583 20221 10990 SLC25A4 ANT ANT 35 0.0 mitochondrial ETC the F0F1-ATPase and the adenine nucleotide translocator (ANT) ANT ( Fig 1 1 JUMiner_v2.2 1 1 adenine nucleotide translocator 0 0 0 0 0 0 0 0 113364 16624679 147585 18723 10261 ROS1 ROS ROS 12 0.0 also the major intracellular source of reactive oxygen species (ROS), ROS which are by-products of respiration 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113365 16624679 147586 18723 10261 ROS1 ROS ROS 11 0.0 mitochondrial dysfunction can lead to defective ATP production and increased ROS formation 1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113366 16624679 147587 20996 11179 SOD1 ALS ALS 27 2.7 to neuronal cell death including that of motor neurons in ALS 46 and 13 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00142357144152476<>ScoreDetail__5468|IGFALS|0.00040551500405515__11179|SOD1|0.00142357144152476__ 0 0 0 0 0 113367 16624679 147587 18723 10261 ROS1 ROS ROS 12 0.0 the result of an imbalance between production and degradation of ROS has long been linked to neuronal cell death including that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113368 16624679 147588 20996 11179 SOD1 ALS ALS 26 2.7 37 a function that has been thoroughly investigated to understand ALS pathogenesis 44 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00142357144152476<>ScoreDetail__5468|IGFALS|0.00040551500405515__11179|SOD1|0.00142357144152476__ 0 0 0 0 0 113369 16624679 147589 20996 11179 SOD1 SOD1 SOD1 11 3.7 have mutant forms of Cu/Zn Cu Zn superoxide dismutase (SOD1), SOD1 a free radical-scavenging enzyme that converts the superoxide anion radical 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113370 16624679 147590 20996 11179 SOD1 SOD1 SOD1 7 3.7 Apparently the motor neuron toxicity of mutant SOD1 is due to a _amp_#x201c gain of function(s)_amp_#x201d; function s 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113371 16624679 147591 20996 11179 SOD1 SOD1 SOD1 14 3.7 oxidative chemistry and/or and or misfolding and aggregation of mutant SOD1 11 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113372 16624679 147592 20996 11179 SOD1 SOD1 SOD1 3 3.7 The identification of SOD1 mutations as a cause of ALS has served for creating 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113373 16624679 147592 20996 11179 SOD1 ALS ALS 9 2.7 The identification of SOD1 mutations as a cause of ALS has served for creating experimental models of the disease expressing 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00142357144152476<>ScoreDetail__5468|IGFALS|0.00040551500405515__11179|SOD1|0.00142357144152476__ 0 0 0 0 0 113374 16624679 147592 20996 11179 SOD1 SOD1 SOD1 24 3.7 experimental models of the disease expressing mutant forms of human SOD1 in laboratory animals and cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113375 16624679 147593 20996 11179 SOD1 ALS ALS 19 2.7 also replicate alterations in the activities of ETC observed in ALS patients 7 33 32 42 and 9 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00142357144152476<>ScoreDetail__5468|IGFALS|0.00040551500405515__11179|SOD1|0.00142357144152476__ 0 0 0 0 0 113376 16624679 147596 20996 11179 SOD1 SOD1 SOD1 17 3.7 conversion more in NSC-34 motoneuronal cells expressing mutant (G93A) G93A SOD1 than in those expressing wild-type (wt) wt SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113377 16624679 147596 20996 11179 SOD1 SOD1 SOD1 24 3.7 (G93A) G93A SOD1 than in those expressing wild-type (wt) wt SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113378 16624679 147603 20996 11179 SOD1 SOD1 SOD1 12 3.7 stably expressing wild-type (wt) wt or mutant (G93A) G93A human SOD1 were generated and checked for SOD1 expression as previously described 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113379 16624679 147603 20996 11179 SOD1 SOD1 SOD1 18 3.7 mutant (G93A) G93A human SOD1 were generated and checked for SOD1 expression as previously described 43 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113380 16624679 147606 7361 20442 FBRS FBS FBS 19 0.0 high-glucose DMEM Biochrom Berlin Germany supplemented with 5% heat-inactivated defined FBS (defined defined FBS Hyclone Logan UT USA 1 mM glutamine 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 113381 16624679 147606 7361 20442 FBRS FBS FBS 21 0.0 Berlin Germany supplemented with 5% heat-inactivated defined FBS (defined defined FBS Hyclone Logan UT USA 1 mM glutamine 1 mM pyruvate 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 113382 16624679 147615 18723 10261 ROS1 ROS ROS 17 0.0 potential (_amp_#x394; _amp_#x394 _amp_#x3a8 m and reactive oxygen species (ROS) ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113383 16624679 147620 6603 3331 EMD EMD EMD 9 0.0 viability was determined with propidium iodide (PI) PI (Calbiochem, Calbiochem EMD Biosciences Inc. San Diego CA USA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113384 16624679 147627 18723 10261 ROS1 ROS ROS 1 0.0 Intracellular ROS were measured with 2_amp_#x2032 7_amp_#x2032 -dichlorodihydrofluorescein diacetate (Sigma_amp_#x2013;Aldrich Sigma_amp_#x2013 Aldrich 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113385 16624679 147644 20996 11179 SOD1 SOD1 SOD1 11 3.7 lines stably transfected with cDNAs of human wt/G93A wt G93A SOD1 were generated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113386 16624679 147645 20996 11179 SOD1 SOD1 SOD1 7 3.7 Western blotting indicated similar levels of murine SOD1 protein in all the lines wt or the G93A mutant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113387 16624679 147645 20996 11179 SOD1 SOD1 SOD1 22 3.7 lines wt or the G93A mutant form of the human SOD1 protein was expressed at comparable levels ( Fig 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113388 16624679 147663 20996 11179 SOD1 SOD1 SOD1 8 3.7 The greater susceptibility of cells transfected with G93A SOD1 to inhibition of complex I of the ETC persisted after 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113389 16624679 147678 18723 10261 ROS1 ROS ROS 4 0.0 Effect of rotenone on ROS generation in untransfected and transfected NSC-34 cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113390 16624679 147679 20996 11179 SOD1 SOD1 SOD1 7 3.7 To see why the presence of G93A SOD1 increased the motor neuron cells_amp_#x2019 susceptibility to rotenone we considered 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113391 16624679 147679 18723 10261 ROS1 ROS ROS 26 0.0 we considered the possibility of a toxicity pathway mediated by ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113392 16624679 147680 18723 10261 ROS1 ROS ROS 0 0.0 ROS formation was studied by biparametric DCF_amp_#x2013 PI flow cytometry 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113393 16624679 147684 18723 10261 ROS1 ROS ROS 12 0.0 h exposure to rotenone there was a significant increase of ROS formation in all three lines ( p _amp_#x3c 0.001 versus 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113394 16624679 147691 18723 10261 ROS1 ROS ROS 19 0.0 and irreversibly inhibits complex I of the ETC the main ROS generating site in mitochondria 27 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113395 16624679 147692 20996 11179 SOD1 SOD1 SOD1 28 3.7 toxin for motor neurons of humans with mutant forms of SOD1 and for unraveling the toxicity of these mutant forms 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113396 16624679 147694 18723 10261 ROS1 ROS ROS 18 0.0 by looking at changes in _amp_#x394 _amp_#x3a8 m ATP and ROS levels _amp_#x394 _amp_#x3a8 m (positive positive on the outside and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113397 16624679 147695 24185 29175 WDTC1 ADP ADP 20 0.3 out of the inner mitochondrial membrane to generate ATP from ADP and phosphate (by by F0F1-ATPase and to regulate mitochondrial protein 3 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 113398 16624679 147712 18723 10261 ROS1 ROS ROS 7 0.0 Mitochondrial membrane hyperpolarization has been linked to ROS formation 23 and 47 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113399 16624679 147713 18723 10261 ROS1 ROS ROS 1 0.0 Cellular ROS production increased after rotenone treatment 5 49 and 34 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113400 16624679 147713 18723 10261 ROS1 ROS ROS 16 0.0 rotenone treatment 5 49 and 34 and in HL-60 mitochondrial ROS were responsible for cell death 29 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113401 16624679 147714 18723 10261 ROS1 ROS ROS 2 0.0 Exposure to ROS favors opening of the mitochondrial permeability transition pore a channel 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113402 16624679 147715 18723 10261 ROS1 ROS ROS 8 0.0 This causes mitochondrial membrane depolarization so we studied ROS production to clarify how oxidative stress affected the selective susceptibility 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113403 16624679 147716 18723 10261 ROS1 ROS ROS 5 0.0 Rotenone caused comparable increases of ROS in untransfected and transfected cells however like before rotenone treatment 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113404 16624679 147716 18723 10261 ROS1 ROS ROS 21 0.0 however like before rotenone treatment G93ASOD1 cells had the highest ROS level indicating a persistent stronger oxidative environment in these motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113405 16624679 147717 20996 11179 SOD1 SOD1 SOD1 13 3.7 in the toxic _amp_#x201c gain of function_amp_#x201d of mutant SOD1(s) SOD1 s 11 free radical scavengers were protective in several models 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113406 16624679 147718 20996 11179 SOD1 SOD1 SOD1 17 3.7 might affect the mitochondria is reinforced by the finding that SOD1 also localizes in the mitochondrial intermembrane space and matrix 39 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113407 16624679 147718 20996 11179 SOD1 SOD1 SOD1 35 3.7 space and matrix 39 48 and 51 and that mutant SOD1 forms aggregates in the matrix 51 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113408 16624679 147718 18723 10261 ROS1 ROS ROS-derived 5 0.0 The idea that in FALS ROS-derived toxicity might affect the mitochondria is reinforced by the finding 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113409 16624679 147720 18723 10261 ROS1 ROS ROS 25 0.0 permeability transition pore components adding its effect to that of ROS formed in mitochondria after rotenone 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113410 16624679 147722 24185 29175 WDTC1 ADP ADP 21 0.3 of the mitochondrial permeability transition pore by affecting ATP/ADP ATP ADP binding sites 21 3 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 113411 16624679 147722 20221 10990 SLC25A4 ANT ANT 2 0.0 For example ANT changes its conformation after oxidative stress and this promotes opening 1 JUMiner_v2.2 1 1 adenine nucleotide translocator 0 0 0 0 0 0 0 0 113412 16624679 147724 1576 990 BCL2 Bcl-2 Bcl-2 1 1.3 Interestingly Bcl-2 which has protective activity against oxidative stress 24 and prevents 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113413 16624679 147724 20996 11179 SOD1 SOD1 SOD1 32 3.7 of mitochondrial membrane potential 45 and 49 was trapped by SOD1 aggregates in spinal cord mitochondria of transgenic SOD1 mice and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113414 16624679 147724 20996 11179 SOD1 SOD1 SOD1 40 3.7 trapped by SOD1 aggregates in spinal cord mitochondria of transgenic SOD1 mice and in spinal cord homogenates from human samples 40 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113415 16624679 147725 20996 11179 SOD1 SOD1 SOD1 26 3.7 factor for motor neurons of individuals carrying the mutant G93A SOD1 and might act in concert with other genetic defects associated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113416 16624679 147728 20996 11179 SOD1 ALS ALS 17 2.7 in the search for factors contributing to the etiology of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00142357144152476<>ScoreDetail__5468|IGFALS|0.00040551500405515__11179|SOD1|0.00142357144152476__ 0 0 0 0 0 113417 16624679 147733 20221 10990 SLC25A4 ANT ANT 12 0.0 released into the cytosol via the adenine nucleotide translocator (ANT) ANT and the _amp_#x201c voltage-dependent_amp_#x201d anion channel (VDAC), VDAC which are 1 JUMiner_v2.2 1 1 adenine nucleotide translocator 0 0 0 0 0 0 0 0 113418 16624679 147734 23264 1158 TSPO PBR PBR 11 0.3 components of this complex are the peripheral benzodiazepine receptor (PBR), PBR creatine kinase (CK), CK hexokinase II (HK), HK cyclophilin D 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113419 16624679 147734 17080 9257 PPID Cyp-D Cyp-D 20 1.0 kinase (CK), CK hexokinase II (HK), HK cyclophilin D (Cyp-D) Cyp-D and Bax/Bcl-2-like Bax Bcl-2-like proteins (Bax, Bax Bak Bcl-2 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 17082 9259 PPIF 0 113420 16624679 147734 1576 990 BCL2 Bcl-2 Bcl-2-like 22 1.5 II (HK), HK cyclophilin D (Cyp-D) Cyp-D and Bax/Bcl-2-like Bax Bcl-2-like proteins (Bax, Bax Bak Bcl-2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113421 16624679 147734 1514 949 BAK1 BAK Bak 25 0.3 D (Cyp-D) Cyp-D and Bax/Bcl-2-like Bax Bcl-2-like proteins (Bax, Bax Bak Bcl-2 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113422 16624679 147734 1576 990 BCL2 Bcl-2 Bcl-2 26 1.3 (Cyp-D) Cyp-D and Bax/Bcl-2-like Bax Bcl-2-like proteins (Bax, Bax Bak Bcl-2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113423 16624679 147735 24185 29175 WDTC1 ADP ADP 5 0.3 Cytosolic ATP is converted to ADP which re-enters the mitochondrial matrix 3 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 113424 16624679 147736 23632 12517 UCP1 UCP UCPs 2 0.3 Uncoupling proteins (UCPs) UCPs provide an alternative route for H to re-enter the matrix 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113425 16624679 147737 20996 11179 SOD1 SOD1 SOD1 0 3.7 SOD1 is present in the cytosol and in the mitochondrial intermembrane 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113426 16624679 147738 20996 11179 SOD1 SOD1 SOD1 4 3.7 Fig 2._amp_#xa0 Expression of human SOD1 in the NSC-34 cellular model of FALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113427 16624679 147739 20996 11179 SOD1 SOD1 SOD1 23 3.7 lane 2 human wild-type (lane lane 3 or G93A mutant SOD1 (lane lane 4 was done using a polyclonal anti-human SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113428 16624679 147739 20996 11179 SOD1 SOD1 SOD1 32 3.7 SOD1 (lane lane 4 was done using a polyclonal anti-human SOD1 antibody that crossreacts with murine SOD1(mSOD1) SOD1 mSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113429 16624679 147739 20996 11179 SOD1 SOD1 SOD1 38 3.7 a polyclonal anti-human SOD1 antibody that crossreacts with murine SOD1(mSOD1) SOD1 mSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113430 16624679 147739 20996 11179 SOD1 SOD1 mSOD1 38 2.7 polyclonal anti-human SOD1 antibody that crossreacts with murine SOD1(mSOD1) SOD1 mSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113431 16624679 147740 20996 11179 SOD1 SOD1 mSOD1 3 2.7 The positions of mSOD1 and human SOD1(hSOD1) SOD1 hSOD1 are indicated in SDS-PAGE they 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113432 16624679 147740 20996 11179 SOD1 SOD1 SOD1 6 3.7 The positions of mSOD1 and human SOD1(hSOD1) SOD1 hSOD1 are indicated in SDS-PAGE they can be resolved into 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113433 16624679 147740 20996 11179 SOD1 SOD1 hSOD1 6 2.7 The positions of mSOD1 and human SOD1(hSOD1) SOD1 hSOD1 are indicated in SDS-PAGE they can be resolved into two 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113434 16624679 147740 20996 11179 SOD1 SOD1 mSOD1 24 2.7 resolved into two bands due to the faster migration of mSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113435 16624679 147753 18723 10261 ROS1 ROS ROS 5 0.0 Fig 6._amp_#xa0 Effect of rotenone on ROS production 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 113436 16624679 147754 18723 10261 ROS1 ROS ROS 0 0.0 ROS were measured on the basis of the conversion of 2_amp_#x2032 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 103403 16681429 132318 20996 11179 SOD1 ALS ALS 15 1.9 erythrocytes from sporadic amyotrophic lateral sclerosis (SALS) SALS and familial ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00152035411554691<>ScoreDetail__5468|IGFALS|0.00098049896502887__11179|SOD1|0.00152035411554691__ 0 0 0 0 0 103404 16681429 132319 20996 11179 SOD1 ALS ALS 22 1.9 important factor in the pathogenesis of amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00152035411554691<>ScoreDetail__5468|IGFALS|0.00098049896502887__11179|SOD1|0.00152035411554691__ 0 0 0 0 0 103405 16681429 132323 20996 11179 SOD1 SOD SOD 12 1.9 activity of the following ADEs copper-zinc superoxide dismutase (CuZn CuZn SOD catalase (CAT), CAT glutathione peroxidase (GSH-Px) GSH-Px and glutathione reductase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 103406 16681429 132323 3544 1516 CAT CAT CAT 14 1.0 following ADEs copper-zinc superoxide dismutase (CuZn CuZn SOD catalase (CAT), CAT glutathione peroxidase (GSH-Px) GSH-Px and glutathione reductase (GR) GR in 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>1516|CAT|847|Complete__13734|GLYAT|10249|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 103407 16681429 132323 20996 11179 SOD1 ALS ALS 26 1.9 GSH-Px and glutathione reductase (GR) GR in erythrocytes from sporadic ALS patients SALS (-/+)], - familial ALS patients with the Leu144Phe 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00152035411554691<>ScoreDetail__5468|IGFALS|0.00098049896502887__11179|SOD1|0.00152035411554691__ 0 0 0 0 0 103408 16681429 132323 20996 11179 SOD1 ALS ALS 31 1.9 in erythrocytes from sporadic ALS patients SALS (-/+)], - familial ALS patients with the Leu144Phe mutation in the SOD1 gene FALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00152035411554691<>ScoreDetail__5468|IGFALS|0.00098049896502887__11179|SOD1|0.00152035411554691__ 0 0 0 0 0 103409 16681429 132323 20996 11179 SOD1 SOD1 SOD1 39 3.4 - familial ALS patients with the Leu144Phe mutation in the SOD1 gene FALS (+/+)], asymptomatic carriers with the Leu144Phe mutation in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 103410 16681429 132323 20996 11179 SOD1 SOD1 SOD1 51 3.4 FALS (+/+)], asymptomatic carriers with the Leu144Phe mutation in the SOD1 gene (+/-), - and control subjects (-/-) - - 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 103411 16681429 132324 20996 11179 SOD1 SOD SOD 12 1.9 the in vitro effect of diethyldithiocarbamate (DDC) DDC on CuZn SOD activity in erythrocytes from FALS patients SALS patients and control 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 103412 16681429 132324 5532 2719 DDC DDC DDC 9 0.0 We also examined the in vitro effect of diethyldithiocarbamate (DDC) DDC on CuZn SOD activity in erythrocytes from FALS patients SALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 103413 16681429 132326 20996 11179 SOD1 SOD1 SOD1 1 3.4 The SOD1 gene mutation decreased CuZn SOD and GSH-Px activity (two-way two-way 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 103414 16681429 132326 20996 11179 SOD1 SOD SOD 6 1.9 The SOD1 gene mutation decreased CuZn SOD and GSH-Px activity (two-way two-way ANOVA significant mutation effect 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 103415 16681429 132327 20996 11179 SOD1 SOD SOD 10 1.9 We noted that the disease also contributed to decreased CuZn SOD activity in SALS patients in comparison with the control group 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 103416 16681429 132328 3544 1516 CAT CAT CAT 4 1.0 The disease also influenced CAT and GR activity 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>1516|CAT|847|Complete__13734|GLYAT|10249|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 103417 16681429 132329 3544 1516 CAT CAT CAT 0 1.0 CAT activity was decreased in both SALS and FALS patients 1 JUMiner_v2.2 1 2 35 0 1 0 TotalCon:2<>1516|CAT|847|Complete__13734|GLYAT|10249|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 103418 16681429 132331 20996 11179 SOD1 SOD SOD 4 1.9 Finally DDC inhibited CuZn SOD activity in erythrocytes from control subjects FALS (Leu144Phe) Leu144Phe patients 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 103419 16681429 132331 5532 2719 DDC DDC DDC 1 0.0 Finally DDC inhibited CuZn SOD activity in erythrocytes from control subjects FALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 106246 16764863 137537 832 549 AOC2 RAO Rao 2 0.0 Shyam D Rao a Sandra Anne Banack b c Paul Alan Cox c 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 106247 16764863 137545 9947 5468 IGFALS ALS ALS 3 0.3 Amyotrophic lateral sclerosis (ALS) ALS is an adult onset neurodegenerative disease characterized by the selective 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106248 16764863 137548 9947 5468 IGFALS ALS ALS 25 0.3 the disease known as Guam ALS_amp_#x2013 Parkinsonism Dementia Complex (ALS/PDC) ALS PDC 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106249 16764863 137548 16271 8759 PDC PDC PDC 25 0.3 disease known as Guam ALS_amp_#x2013 Parkinsonism Dementia Complex (ALS/PDC) ALS PDC 4 JUMiner_v2.2 1 2 UserEdit 0 2 8759 TotalCon:2<>8759|PDC|5132|Complete__9153|PNKD|25953|Complete__<>AvaiableGeneRif=2<>BEST:8759|PDC|0.00141292829388909<>ScoreDetail__8759|PDC|0.00141292829388909__9153|PNKD|0.000468237864835336__ 1 1 0 0 0 106250 16764863 137549 9947 5468 IGFALS ALS ALS 4 0.3 In the 1950s the ALS incidence and death rate among the indigenous Chamorro people of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106251 16764863 137550 9947 5468 IGFALS ALS ALS 4 0.3 The Guam form of ALS shows the same pattern of selective MN death with the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106252 16764863 137551 9947 5468 IGFALS ALS ALS 19 0.3 but typically onset is 10_amp_#xa0 years later in life than ALS ( Mulder et al. 1954 and Kurland 1988 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106253 16764863 137551 16271 8759 PDC PDC PDC 9 0.0 Variant forms often exhibit Parkinsonism and an Alzheimer's-like dementia (PDC), PDC but typically onset is 10_amp_#xa0 years later in life than 1 JUMiner_v2.2 1 0 0 2 8759 TotalCon:2<>8759|PDC|5132|Complete__9153|PNKD|25953|Complete__<>AvaiableGeneRif=2<>BEST:8759|PDC|0.00141292829388909<>ScoreDetail__8759|PDC|0.00141292829388909__9153|PNKD|0.000468237864835336__ 0 0 0 0 0 106254 16764863 137556 9947 5468 IGFALS ALS ALS-like 26 0.3 doses of BMAA developed clinical electrophysiological and neuropathological evidence of ALS-like motor dysfunction ( Spencer et al. 1987 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106255 16764863 137558 9947 5468 IGFALS ALS ALS 7 0.3 However the relevance of BMAA to Guam ALS was called into question as the concentrations present in washed 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106256 16764863 137559 9947 5468 IGFALS ALS ALS 9 0.3 Further study of BMAA as a putative cause of ALS/PDC ALS PDC was largely discontinued 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106257 16764863 137559 16271 8759 PDC PDC PDC 9 0.3 study of BMAA as a putative cause of ALS/PDC ALS PDC was largely discontinued 4 JUMiner_v2.2 1 2 UserEdit 0 2 8759 TotalCon:2<>8759|PDC|5132|Complete__9153|PNKD|25953|Complete__<>AvaiableGeneRif=2<>BEST:8759|PDC|0.00141292829388909<>ScoreDetail__8759|PDC|0.00141292829388909__9153|PNKD|0.000468237864835336__ 1 1 0 0 0 106258 16764863 137562 9947 5468 IGFALS ALS ALS 46 0.3 in brain tissue from Chamorros who died of Guam ALS/PDC ALS PDC ( Cox et al. 2003 Murch et al. 2004a 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106259 16764863 137562 16271 8759 PDC PDC PDC 46 0.3 brain tissue from Chamorros who died of Guam ALS/PDC ALS PDC ( Cox et al. 2003 Murch et al. 2004a and 4 JUMiner_v2.2 1 2 UserEdit 0 2 8759 TotalCon:2<>8759|PDC|5132|Complete__9153|PNKD|25953|Complete__<>AvaiableGeneRif=2<>BEST:8759|PDC|0.00141292829388909<>ScoreDetail__8759|PDC|0.00141292829388909__9153|PNKD|0.000468237864835336__ 1 1 0 0 0 106260 16764863 137565 9947 5468 IGFALS ALS ALS 35 0.3 with which BMAA injures MNs the principal neurons affected in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106261 16764863 137566 9947 5468 IGFALS ALS ALS 10 0.3 than 50_amp_#xa0 years of study the cause of Guam ALS/PDC ALS PDC remains enigmatic 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106262 16764863 137566 16271 8759 PDC PDC PDC 10 0.3 50_amp_#xa0 years of study the cause of Guam ALS/PDC ALS PDC remains enigmatic 4 JUMiner_v2.2 1 2 UserEdit 0 2 8759 TotalCon:2<>8759|PDC|5132|Complete__9153|PNKD|25953|Complete__<>AvaiableGeneRif=2<>BEST:8759|PDC|0.00141292829388909<>ScoreDetail__8759|PDC|0.00141292829388909__9153|PNKD|0.000468237864835336__ 1 1 0 0 0 106263 16764863 137567 9947 5468 IGFALS ALS ALS 12 0.3 to identify mechanisms contributing to the loss of MNs in ALS and gleaning clues to disease processes which may be common 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106264 16764863 137567 9947 5468 IGFALS ALS ALS 24 0.3 gleaning clues to disease processes which may be common to ALS Parkinson's disease and Alzheimer's disease calls for further investigation of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106265 16764863 137583 1552 30000 BBS9 C18 C18 27 0.3 Injector Waters 1525 Binary Solvent Delivery System and Waters Nova-Pak C18 column 300_amp_#xa0 mm_amp_#xa0 _amp_#xd7 _amp_#xa0 3.9_amp_#xa0 mm at 37_amp_#xb0 C 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 106266 16764863 137591 832 549 AOC2 RAO Rao 16 0.0 primarily as described previously ( Carriedo et al. 1996 and Rao et al. 2003 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 106267 16764863 137593 6438 3229 EGF EGF EGF-treated 9 0.3 Cells were plated on a previously established layer of EGF-treated astrocytes grown on either 15_amp_#xa0 mm Primaria-coated culture plates (Falcon, 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 106268 16764863 137618 19254 10472 RUNX2 CCD CCD 39 0.0 emitted fluorescence signals were collected using a 12-bit cooled digital CCD camera (Orca-100; Orca-100 Hamamatsu Bridgewater NJ 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 106269 16764863 137621 8255 4236 GFER HSS HSS 24 0.3 2.5_amp_#xa0 _amp_#x3bc M Fura-2 AM in HEPES buffered solution (HSS) HSS containing 0.2% pluronic acid and 1.5% dimethylsulfoxide (DMSO) DMSO for 1 JUMiner_v2.2 1 2 UserEdit 0 2 4236 TotalCon:4<>4236|GFER|2671|Complete__15894|PANK2|80025|Complete__10818|SGSH|6448|Complete__14524|SPAG9|9043|Complete__<>AvaiableGeneRif=4<>BEST:4236|GFER|0.000388712105333359<>ScoreDetail__4236|GFER|0.000388712105333359__14524|SPAG9|0.000153540071796203__10818|SGSH|0.000190102021418161__15894|PANK2|0.000282834379169662__ 1 1 0 0 0 106270 16764863 137622 8255 4236 GFER HSS HSS 5 0.3 Cultures were then washed in HSS and kept in the dark for an additional 30_amp_#xa0 min 1 JUMiner_v2.2 1 2 UserEdit 0 2 4236 TotalCon:4<>4236|GFER|2671|Complete__15894|PANK2|80025|Complete__10818|SGSH|6448|Complete__14524|SPAG9|9043|Complete__<>AvaiableGeneRif=4<>BEST:4236|GFER|0.000388712105333359<>ScoreDetail__4236|GFER|0.000388712105333359__14524|SPAG9|0.000153540071796203__10818|SGSH|0.000190102021418161__15894|PANK2|0.000282834379169662__ 1 1 0 0 0 106271 16764863 137627 18723 10261 ROS1 ROS ROS 0 0.3 ROS generation was monitored by use of the oxidation-sensitive dye HEt 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106272 16764863 137628 8255 4236 GFER HSS HSS 7 0.3 Cultures were loaded with 5_amp_#xa0 _amp_#x3bc M HEt in HSS for 45_amp_#xa0 min at 25_amp_#xb0 C and then washed into 1 JUMiner_v2.2 1 2 UserEdit 0 2 4236 TotalCon:4<>4236|GFER|2671|Complete__15894|PANK2|80025|Complete__10818|SGSH|6448|Complete__14524|SPAG9|9043|Complete__<>AvaiableGeneRif=4<>BEST:4236|GFER|0.000388712105333359<>ScoreDetail__4236|GFER|0.000388712105333359__14524|SPAG9|0.000153540071796203__10818|SGSH|0.000190102021418161__15894|PANK2|0.000282834379169662__ 1 1 0 0 0 106273 16764863 137632 18723 10261 ROS1 ROS ROS 8 0.3 Because HEt fluorescence is cumulative the rate of ROS generation was assessed as the rate of increase (or or 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106274 16764863 137632 18723 10261 ROS1 ROS ROS 31 0.3 F x / F 0 curves over time and net ROS production was assessed as the increase in F x / 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106275 16764863 137651 18723 10261 ROS1 ROS ROS 9 0.3 BMAA induces high Ca 2 i rises and ROS generation in MNs 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106276 16764863 137653 17319 9413 PRKDC HYRC Hyrc 28 1.3 et al. 1993 Choi 1994 Lu et al. 1996 and Hyrc et al. 1997 2 JUMiner_v2.2 1 2 34 0 0 0 0 0 0 0 0 106277 16764863 137658 18723 10261 ROS1 ROS ROS 13 0.3 demonstrated that glutamate-receptor-mediated Ca 2 entry triggers the generation of ROS ( Lafon-Cazal et al. 1993 Dugan et al. 1995 Reynolds 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106278 16764863 137659 18723 10261 ROS1 ROS ROS 10 0.3 We therefore proceeded to examine the effects of BMAA on ROS production in MNs using the oxidant-sensitive fluorophore hydroethidine (HEt) HEt 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106279 16764863 137662 18723 10261 ROS1 ROS ROS 2 0.3 The BMAA-induced ROS generation was dose-dependent and paralleling the Ca 2 i rises 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106280 16764863 137675 832 549 AOC2 RAO Rao 18 0.0 previously established astrocytic monolayer ( Carriedo et al. 1996 and Rao et al. 2003 _amp_#x2013 is ideally suited for this type 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 106281 16764863 137680 18723 10261 ROS1 ROS ROS 12 0.3 toxic receptor activation caused high Ca 2 i rises and ROS generation in MNs suggesting a largely oxidative mechanism of injury 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106282 16764863 137683 9947 5468 IGFALS ALS ALS 8 0.3 Any plausible hypothesis regarding a proposed cause of ALS should be capable of explaining the selective loss of MNs 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106283 16764863 137686 9947 5468 IGFALS ALS ALS 24 0.3 populations of neurons that are largely resistant to injury in ALS ( Nunn et al. 1987 Ross et al. 1987 Weiss 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106284 16764863 137693 9947 5468 IGFALS ALS ALS 29 0.3 consistent with the pattern of selective neuronal loss seen in ALS and lends further support to its potential role as an 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106285 16764863 137699 9947 5468 IGFALS ALS ALS 9 0.3 Furthermore suggesting the possible relevance of this finding to ALS studies by ourselves and others have found MNs also to 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106286 16764863 137700 18723 10261 ROS1 ROS ROS 26 0.3 part from Ca 2 uptake into mitochondria with resultant mitochondrial ROS generation ( Lafon-Cazal et al. 1993 Dugan et al. 1995 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106287 16764863 137701 18723 10261 ROS1 ROS ROS 60 0.3 Ca 2 entry through this route can also cause mitochondrial ROS generation ( Carriedo et al. 1998 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106288 16764863 137703 18723 10261 ROS1 ROS ROS 44 0.3 with consequent disruption of function of these organelles and strong ROS generation ( Carriedo et al. 2000 and Bergmann and Keller 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106289 16764863 137705 18723 10261 ROS1 ROS ROS 31 0.3 2 entry through Ca-A/K Ca-A K channels and consequent mitochondrial ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106290 16764863 137706 9947 5468 IGFALS ALS ALS 9 0.3 Similar injury mechanisms may apply to sporadic forms of ALS where decreased glutamate uptake capacity in the spinal cord and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106291 16764863 137709 9947 5468 IGFALS ALS ALS 10 0.3 Consistent with its postulated role in the Guam form of ALS a low dilution of cycad extract caused virtually no injury 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106292 16764863 137716 9947 5468 IGFALS ALS ALS 6 0.3 Consistent with a role in Guam ALS BMAA acts through AMPA/kainate AMPA kainate receptors to induce preferential 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106293 16764863 137717 9947 5468 IGFALS ALS ALS 118 0.3 clues that this toxin may provide to the etiologies of ALS as well as of Parkinson's and Alzheimer's diseases 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000473617188114607<>ScoreDetail__5468|IGFALS|0.000309445364690464__11179|SOD1|0.000473617188114607__ 0 0 0 0 0 106294 16764863 137741 18723 10261 ROS1 ROS ROS 5 0.3 Fig 3._amp_#xa0 BMAA exposure causes preferential ROS generation in MNs 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106295 16764863 137749 18723 10261 ROS1 ROS ROS 0 0.3 ROS generation is assessed by normalizing HEt fluorescence to baseline levels 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 106296 16764863 137752 18723 10261 ROS1 ROS ROS 4 0.3 BMAA induced significantly greater ROS production in MNs than other spinal neurons after 30_amp_#xa0 min 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 100182 16877542 128957 20996 11179 SOD1 ALS ALS 1 2.2 Abstract ALS is a fatal paralytic disorder characterized by a progressive loss 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100183 16877542 128958 20996 11179 SOD1 ALS ALS 20 2.2 species-producing enzyme during inflammation is activated in spinal cords of ALS patients and in spinal cords in a genetic animal model 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100184 16877542 128959 20996 11179 SOD1 ALS ALS 8 2.2 We demonstrate that inactivation of NADPH oxidase in ALS mice delays neurodegeneration and extends survival 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100185 16877542 128960 9939 5464 IGF1 IGF1 IGF1 16 2.0 products damage proteins such as insulin-like growth factor 1 (IGF1) IGF1 receptors which are located on motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100186 16877542 128961 9939 5464 IGF1 IGF1 IGF1 15 2.0 data indicate that such an oxidative modification hinders the IGF1/Akt IGF1 Akt survival pathway in motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100187 16877542 128961 543 391 AKT1 AKT Akt 15 0.3 indicate that such an oxidative modification hinders the IGF1/Akt IGF1 Akt survival pathway in motor neurons 4 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100188 16877542 128962 20996 11179 SOD1 ALS ALS 23 2.2 death and contribute to the selective motor neuronal degeneration in ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100189 16877542 128963 20996 11179 SOD1 ALS ALS 2 2.2 Keywords Akt ALS microglia oxidation non-cell autonomous 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100190 16877542 128963 543 391 AKT1 AKT Akt 1 0.2 Keywords Akt ALS microglia oxidation non-cell autonomous 5 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100191 16877542 128966 20996 11179 SOD1 SOD1 SOD1 1 2.2 Transgenic SOD1 G93A mice [C57BL/6J-TgN(SOD1-G93A)1Gur C57BL 6J-TgN SOD1-G93A 1Gur dl were crossed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100192 16877542 128969 20996 11179 SOD1 SOD1 SOD1 26 2.2 for details about the timeline of behavioral abnormalities in transgenic SOD1 G93A mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100193 16877542 128972 8118 4141 GAPDH GAPDH GAPDH 15 0.0 phox glial fibrillary acidic protein macrophage antigen complex 1 and GAPDH and PCR conditions are presented in Supporting Text 1 JUMiner_v2.2 1 1 gapdh; 0 0 0 0 0 0 0 0 100194 16877542 128986 18723 10261 ROS1 ROS ROS 4 0.0 In Situ Visualization of ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100195 16877542 128991 6327 15531 EBNA1BP2 P40 P-40 9 0.3 Supernatants of mouse spinal cord tissue homogenized in Nonidet P-40 buffer containing 50 mM DTT were collected and incubated (at 11 JUMiner_v2.2 1 2 nonidet 0 2 6871 TotalCon:9<>682|ARHGEF2|9181|Complete__15531|EBNA1BP2|10969|Complete__9565|PSMD7|5713|Complete__6029|IL9|3578|Complete__6508|LANCL1|10314|No_GeneRif__6502|RPSA|3921|Complete__6871|MAPK1|5594|Complete__16896|RABEPK|10244|Complete__15979|TP63|8626|Complete__<>AvaiableGeneRif=8<>BEST:6871|MAPK1|0.000752624094504684<>ScoreDetail__15979|TP63|0.000496127774993406__16896|RABEPK|0.000101282916948008__6502|RPSA|0.000521222028738287__15531|EBNA1BP2|0.000738701616486897__682|ARHGEF2|0.000595108664553268__9565|PSMD7|0.000248157574288567__6029|IL9|0.000644004922037618__6871|MAPK1|0.000752624094504684__ 0 0 0 0 0 100196 16877542 128999 20996 11179 SOD1 ALS ALS 29 2.2 60.5 _amp_#x000b1 10.2 years and 8.0 _amp_#x000b1 2.6 h respectively ALS group ( n = 6 60.5 _amp_#x000b1 4.2 years and 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100197 16877542 129000 20996 11179 SOD1 ALS ALS 2 2.2 For the ALS patients the mean duration of disease was 19.3 _amp_#x000b1 2.6 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100198 16877542 129006 9939 5464 IGF1 IGF1 IGF1 9 2.0 Phosphorylation of Akt and cell viability in response to IGF1 recombinant and to H 2 O 2 or activated BV2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100199 16877542 129006 543 391 AKT1 AKT Akt 2 0.0 Phosphorylation of Akt and cell viability in response to IGF1 recombinant and to 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 100200 16877542 129014 20996 11179 SOD1 ALS ALS 9 2.2 NADPH Oxidase Is Up-Regulated in Inflamed Spinal Cords of ALS Mice 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100201 16877542 129015 20996 11179 SOD1 SOD1 SOD1 28 2.2 stages of the disease in transgenic mice expressing mutant human SOD1 with a substitution of glycine to alanine in position 93 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100202 16877542 129015 20996 11179 SOD1 SOD1 SOD1 39 2.2 a substitution of glycine to alanine in position 93 (SOD1 SOD1 G93A the most widely studied model of ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100203 16877542 129015 20996 11179 SOD1 ALS ALS 48 2.2 93 (SOD1 SOD1 G93A the most widely studied model of ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100204 16877542 129016 20996 11179 SOD1 ALS ALS 17 2.2 cord which carries the brunt of the pathology in this ALS model was determined by analyzing its catalytic subunit gp91 phox 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100205 16877542 129017 20996 11179 SOD1 SOD1 SOD1 18 2.2 whole-tissue extracts of spinal cord rose over time in transgenic SOD1 G93A mice ( Fig 1 A B D and E 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100206 16877542 129018 20996 11179 SOD1 SOD1 SOD1 32 2.2 in membrane fractions of spinal cord extracts from symptomatic transgenic SOD1 G93A mice ( Fig 1 C indicating that this cytosolic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100207 16877542 129018 3884 1659 CD33 p67 p67 4 0.0 The levels of the p67 phox subunit that contains the NADPH-binding site of the NADPH 1 JUMiner_v2.2 1 0 0 2 1659 TotalCon:2<>1659|CD33|945|Complete__16672|METAP2|10988|Complete__<>AvaiableGeneRif=2<>BEST:1659|CD33|0.000776415125613499<>ScoreDetail__1659|CD33|0.000776415125613499__16672|METAP2|0.000718318559914951__ 0 0 0 0 0 100208 16877542 129020 20996 11179 SOD1 SOD1 SOD1 9 2.2 Histological evaluation of the spinal cord of symptomatic transgenic SOD1 G93A mice showed numerous gp91 phox -positive cells primarily in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100209 16877542 129023 20996 11179 SOD1 SOD1 SOD1 7 2.2 NADPH Oxidase Causes Protein Oxidation in Transgenic SOD1 G93A Mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100210 16877542 129024 20996 11179 SOD1 SOD1 SOD1 12 2.2 characterized the status of spinal cord NADPH oxidase in transgenic SOD1 G93A mice by probing for formation of ROS and evidence 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100211 16877542 129024 18723 10261 ROS1 ROS ROS 20 0.0 in transgenic SOD1 G93A mice by probing for formation of ROS and evidence of protein oxidation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100212 16877542 129025 18723 10261 ROS1 ROS ROS 7 0.0 In nontransgenic mice spinal cord production of ROS evidenced by the fluorescence emitted by ethidium the oxidation product 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100213 16877542 129026 20996 11179 SOD1 SOD1 SOD1 5 2.2 In contrast in symptomatic transgenic SOD1 G93A mice carrying the wild-type gp91 phox allele (SOD SOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100214 16877542 129026 20996 11179 SOD1 SOD SOD 14 2.2 SOD1 G93A mice carrying the wild-type gp91 phox allele (SOD SOD G93A /gp91 gp91 phox spinal cord ethidium fluorescence was intense 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100215 16877542 129027 20996 11179 SOD1 SOD1 SOD1 3 2.2 In symptomatic transgenic SOD1 G93A mice carrying the nonfunctional mutant allele (SOD SOD G93A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100216 16877542 129027 20996 11179 SOD1 SOD SOD 11 2.2 transgenic SOD1 G93A mice carrying the nonfunctional mutant allele (SOD SOD G93A /gp91 gp91 phox_amp_#x02212 ( 12 spinal cord ethidium fluorescence 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100217 16877542 129029 20996 11179 SOD1 SOD1 SOD1 2 2.2 Symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice but not age-matched SOD1 G93A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100218 16877542 129029 20996 11179 SOD1 SOD1 SOD1 10 2.2 transgenic SOD1 G93A /gp91 gp91 phox mice but not age-matched SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice had increased levels of spinal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100219 16877542 129030 20996 11179 SOD1 SOD1 SOD1 15 2.2 for protein carbonyl adducts occurred in spinal cord sections from SOD1 G93A /gp91 gp91 phox mice at the level of cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100220 16877542 129031 20996 11179 SOD1 ALS ALS 9 2.2 NADPH Oxidase Induction and Neuronal Protein Carbonylation in Sporadic ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100221 16877542 129032 20996 11179 SOD1 SOD1 SOD1 13 2.2 to determine whether the NADPH oxidase alterations identified in transgenic SOD1 G93A mice were also present in human sporadic ALS the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100222 16877542 129032 20996 11179 SOD1 ALS ALS 22 2.2 transgenic SOD1 G93A mice were also present in human sporadic ALS the most common form of the disease ( 1 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100223 16877542 129033 20996 11179 SOD1 ALS ALS 45 2.2 was _amp_#x02248 3-fold higher and its immunoreactivity robust in sporadic ALS spinal cords ( Fig 2 E 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100224 16877542 129034 3901 1693 CD68 CD68 CD68 12 0.3 latter gp91 phox -positive cells colocalized with the microglial-associated antigen CD68 ( Fig 2 F and were identified in all of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100225 16877542 129034 20996 11179 SOD1 ALS ALS 26 2.2 2 F and were identified in all of the typical ALS loci of neurodegeneration including the anterior horn and the lateral 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100226 16877542 129035 20996 11179 SOD1 ALS ALS 22 2.2 protein carbonyl adducts in postmortem spinal cord sections from sporadic ALS cases which seemed to be mainly associated with large motor 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100227 16877542 129036 20996 11179 SOD1 ALS ALS 20 2.2 for protein carbonyl adducts per lumbar spinal cord section in ALS patients whereas no such immunoreactive motor neurons were seen in 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100228 16877542 129038 20996 11179 SOD1 SOD1 SOD1 10 2.2 Deletion of gp91 phox Mitigates the Disease Phenotype in Transgenic SOD1 G93A Mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100229 16877542 129039 20996 11179 SOD1 SOD1 SOD1 15 2.2 of NADPH oxidase activation on the disease phenotype in the SOD1 G93A mouse model of ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100230 16877542 129039 20996 11179 SOD1 ALS ALS 20 2.2 the disease phenotype in the SOD1 G93A mouse model of ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100231 16877542 129040 20996 11179 SOD1 SOD1 SOD1 1 2.2 Transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice reached end-stage paralysis (defined defined 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100232 16877542 129040 20996 11179 SOD1 SOD1 SOD1 21 2.2 a loss of the righting reflex later than their transgenic SOD1 G93A /gp91 gp91 phox counterparts ( Fig 3 A which 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100233 16877542 129040 20996 11179 SOD1 SOD1 SOD1 39 2.2 3 A which resulted in a longer lifespan of transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice (log-rank log-rank test = 15.3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100234 16877542 129042 20996 11179 SOD1 SOD1 SOD1 4 2.2 Compared with end-stage transgenic SOD1 G93A /gp91 gp91 phox mice age-matched transgenic SOD1 G93A /gp91 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100235 16877542 129042 20996 11179 SOD1 SOD1 SOD1 11 2.2 end-stage transgenic SOD1 G93A /gp91 gp91 phox mice age-matched transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice had _amp_#x02248 50% more anterior 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100236 16877542 129043 20996 11179 SOD1 SOD1 SOD1 23 2.2 the glial cytokine IL-1_amp_#x003b2 did not differ between age-matched transgenic SOD1 G93A /gp91 gp91 phox mice and SOD1 G93A /gp91 gp91 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100237 16877542 129043 20996 11179 SOD1 SOD1 SOD1 29 2.2 between age-matched transgenic SOD1 G93A /gp91 gp91 phox mice and SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice (Fig Fig 7 which is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100238 16877542 129044 20996 11179 SOD1 SOD1 SOD1 14 2.2 the deficit of gp91 phox were the levels of human SOD1 in transgenic SOD1 G93A mice (Fig Fig 7 or the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100239 16877542 129044 20996 11179 SOD1 SOD1 SOD1 17 2.2 gp91 phox were the levels of human SOD1 in transgenic SOD1 G93A mice (Fig Fig 7 or the size of muscle 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100240 16877542 129045 13956 23212 MYH14 myosin myosin 13 2.2 are mainly composed of fast-twitch fibers and by immunostaining for myosin heavy chain we did not observe any obvious alteration in 1 JUMiner_v2.2 1 0 0 2 7605 TotalCon:8<>23212|MYH14|79784|Complete__7599|MYO1E|4643|Complete__7600|MYO1F|4542|No_GeneRif__7603|MYO5B|4645|Complete__7604|MYO5C|55930|No_GeneRif__7605|MYO6|4646|Complete__7608|MYO9A|4649|No_GeneRif__7609|MYO9B|4650|Complete__<>AvaiableGeneRif=5<>BEST:7605|MYO6|0.000485207943838029<>ScoreDetail__7599|MYO1E|0.000437642233725961__7609|MYO9B|0.000474981955342383__7603|MYO5B|0.000320296404023615__23212|MYH14|0.000153049741165879__7605|MYO6|0.000485207943838029__ 0 0 0 0 0 100241 16877542 129047 9939 5464 IGF1 IGF1 IGF1 8 2.0 NADPH Oxidase Impairs the Insulin-Like Growth Factor 1 (IGF1)/Akt IGF1 Akt Pathway in Transgenic SOD1 G93A Mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100242 16877542 129047 20996 11179 SOD1 SOD1 SOD1 12 2.2 Insulin-Like Growth Factor 1 (IGF1)/Akt IGF1 Akt Pathway in Transgenic SOD1 G93A Mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100243 16877542 129047 543 391 AKT1 AKT Akt 8 0.3 NADPH Oxidase Impairs the Insulin-Like Growth Factor 1 (IGF1)/Akt IGF1 Akt Pathway in Transgenic SOD1 G93A Mice 4 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100244 16877542 129048 20996 11179 SOD1 ALS ALS 12 2.2 explored whether NADPH oxidase-mediated protein modifications might promote neurodegeneration in ALS by damaging essential surviving pathways for motor neurons such as 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100245 16877542 129048 9939 5464 IGF1 IGF1 IGF1 23 2.0 by damaging essential surviving pathways for motor neurons such as IGF1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100246 16877542 129049 9939 5464 IGF1 IGF1 IGF1 1 2.0 After IGF1 was immunoprecipitated from spinal cord extracts it was probed for 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100247 16877542 129050 9939 5464 IGF1 IGF1 IGF1 7 2.0 This approach failed to reveal evidence of IGF1 oxidation in any of the studied mouse genotypes (data data 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100248 16877542 129051 9939 5464 IGF1 IGF1 IGF1 11 2.0 carbonyl adducts were evident in the _amp_#x003b1 -chain of the IGF1 tyrosine kinase cognate receptor in the spinal cord of symptomatic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100249 16877542 129051 20996 11179 SOD1 SOD1 SOD1 23 2.2 kinase cognate receptor in the spinal cord of symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice ( Fig 4 A and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100250 16877542 129051 9939 5464 IGF1 IGF1 IGF1 43 2.0 B similar results were obtained for the _amp_#x003b2 -chain of IGF1 receptor (data data not shown 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100251 16877542 129052 9939 5464 IGF1 IGF1 IGF1 7 2.0 This finding might be quite significant because IGF1 receptors in mouse spinal cords were detected almost exclusively on 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100252 16877542 129053 9939 5464 IGF1 IGF1 IGF1 3 2.0 Contrasting with the IGF1 receptor findings oxidation indices in the intracellular serine/threonine serine threonine 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100253 16877542 129053 9939 5464 IGF1 IGF1 IGF1 16 2.0 in the intracellular serine/threonine serine threonine kinase Akt which transduces IGF1 receptor signaling ( 15 did not differ between symptomatic transgenic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100254 16877542 129053 20996 11179 SOD1 SOD1 SOD1 28 2.2 receptor signaling ( 15 did not differ between symptomatic transgenic SOD1 G93A mice and their nontransgenic littermates 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100255 16877542 129053 543 391 AKT1 AKT Akt 13 0.0 findings oxidation indices in the intracellular serine/threonine serine threonine kinase Akt which transduces IGF1 receptor signaling ( 15 did not differ 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 100256 16877542 129054 9939 5464 IGF1 IGF1 IGF1 6 2.0 These results suggest that the entire IGF1 molecular pathway is not oxidatively modified by inflammation in this 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100257 16877542 129054 20996 11179 SOD1 ALS ALS 17 2.2 molecular pathway is not oxidatively modified by inflammation in this ALS model 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100258 16877542 129056 9939 5464 IGF1 IGF1 IGF1 4 2.0 Next we compared selected IGF1 transduction events among the different mouse groups 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100259 16877542 129057 20996 11179 SOD1 SOD1 SOD1 2 2.2 Although mutant SOD1 is expressed in all cells markers of IGF1 transduction such 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100260 16877542 129057 9939 5464 IGF1 IGF1 IGF1 10 2.0 Although mutant SOD1 is expressed in all cells markers of IGF1 transduction such as phospho-IGF1 receptor phospho-Akt (data data not shown 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100261 16877542 129057 20996 11179 SOD1 SOD1 SOD1 52 2.2 smaller glia-like cells in spinal cord sections of symptomatic transgenic SOD1 G93A mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100262 16877542 129058 20996 11179 SOD1 SOD1 SOD1 14 2.2 phospho-IGF1 receptor-immunoreactive cells in spinal cord sections from symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice than from age-matched SOD1 G93A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100263 16877542 129058 20996 11179 SOD1 SOD1 SOD1 22 2.2 transgenic SOD1 G93A /gp91 gp91 phox mice than from age-matched SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice ( Fig 4 C _amp_#x02013 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100264 16877542 129059 1494 936 BAD BAD BAD 39 0.3 ( Fig 4 H _amp_#x02013 J and smaller phospho-BAD total BAD ratios ( Fig 4 K and L in symptomatic transgenic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100265 16877542 129059 20996 11179 SOD1 SOD1 SOD1 51 2.2 ratios ( Fig 4 K and L in symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice compared with their age-matched SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100266 16877542 129059 20996 11179 SOD1 SOD1 SOD1 60 2.2 SOD1 G93A /gp91 gp91 phox mice compared with their age-matched SOD1 G93A /gp91 gp91 phox_amp_#x02212 counterparts 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100267 16877542 129059 543 391 AKT1 AKT Akt 5 0.0 There were also smaller phospho-Akt total Akt ratios ( Fig 4 F and G as well as 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 100268 16877542 129059 543 391 AKT1 AKT Akt 27 0.0 fewer cells that were immunoreactive for a downstream target of Akt phospho-BAD ( Fig 4 H _amp_#x02013 J and smaller phospho-BAD 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 100269 16877542 129060 9939 5464 IGF1 IGF1 IGF1 10 2.0 These data further support the idea that oxidative modification of IGF1 receptor in symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100270 16877542 129060 20996 11179 SOD1 SOD1 SOD1 15 2.2 idea that oxidative modification of IGF1 receptor in symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice is associated with a range 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100271 16877542 129061 9939 5464 IGF1 IGF1 IGF1 4 2.0 Microglial-Derived ROS Recapitulate the IGF1/Akt IGF1 Akt Pathway Defect in Vitro 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100272 16877542 129061 18723 10261 ROS1 ROS ROS 1 0.0 Microglial-Derived ROS Recapitulate the IGF1/Akt IGF1 Akt Pathway Defect in Vitro 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100273 16877542 129061 543 391 AKT1 AKT Akt 4 0.3 Microglial-Derived ROS Recapitulate the IGF1/Akt IGF1 Akt Pathway Defect in Vitro 4 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100274 16877542 129062 9939 5464 IGF1 IGF1 IGF1 10 2.0 To test the idea that NADPH oxidase-derived ROS could impair IGF1 pathway function an in vitro cell system using the neuron-like 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100275 16877542 129062 18723 10261 ROS1 ROS ROS 7 0.0 To test the idea that NADPH oxidase-derived ROS could impair IGF1 pathway function an in vitro cell system 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100276 16877542 129063 9939 5464 IGF1 IGF1 IGF1 10 2.0 were briefly incubated with 0.1_amp_#x02013 100 _amp_#x003bc M human recombinant IGF1 in the presence of overnight-preconditioned serum-free medium supplemented with or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100277 16877542 129063 9939 5464 IGF1 IGF1 IGF1 37 2.0 to provide a constant flux of H 2 O 2 IGF1 pathway responsiveness was monitored by Akt phosphorylation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100278 16877542 129063 543 391 AKT1 AKT Akt 43 0.0 H 2 O 2 IGF1 pathway responsiveness was monitored by Akt phosphorylation 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 100279 16877542 129064 9939 5464 IGF1 IGF1 IGF1 2 2.0 Exposure to IGF1 caused a dose-dependent phosphorylation of Akt in SH-SY5Y cells ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100280 16877542 129064 543 391 AKT1 AKT Akt 8 0.0 Exposure to IGF1 caused a dose-dependent phosphorylation of Akt in SH-SY5Y cells ( Fig 5 A and B and 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 100281 16877542 129065 9939 5464 IGF1 IGF1 IGF1 1 2.0 Conversely IGF1 barely increased Akt phosphorylation in the neuroblastoma cell lines that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100282 16877542 129065 543 391 AKT1 AKT Akt 4 0.0 Conversely IGF1 barely increased Akt phosphorylation in the neuroblastoma cell lines that were exposed to 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 100283 16877542 129066 24053 12728 VWS LPS LPS-activated 11 0.0 SH-SY5Y cells were incubated with or without conditioned medium from LPS-activated BV2 microglial cells 11 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>12728|VWS||No_GeneRif__6121|IRF6|3664|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 100284 16877542 129067 9939 5464 IGF1 IGF1 IGF1-mediated 27 1.5 of H 2 O 2 ( Fig 5 E attenuated IGF1-mediated Akt phosphorylation in the neuroblastoma cell line ( Fig 5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100285 16877542 129067 24053 12728 VWS LPS LPS-activated 9 0.0 Akin to the glucose oxidase experiments brief exposure to LPS-activated microglial-conditioned medium which contained increased levels of H 2 O 11 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>12728|VWS||No_GeneRif__6121|IRF6|3664|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 100286 16877542 129067 543 391 AKT1 AKT Akt 28 0.2 H 2 O 2 ( Fig 5 E attenuated IGF1-mediated Akt phosphorylation in the neuroblastoma cell line ( Fig 5 C 5 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100287 16877542 129068 9939 5464 IGF1 IGF1 IGF1 13 2.0 to LPS-activated microglial-conditioned medium the Akt phosphorylation response to the IGF1 recombinant remained depressed and at 72 h a reduction of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100288 16877542 129068 9939 5464 IGF1 IGF1 IGF1 31 2.0 a reduction of cell viability indistinguishable from the condition without IGF1 was observed ( Fig 5 F 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100289 16877542 129068 24053 12728 VWS LPS LPS-activated 4 0.0 Upon longer exposure to LPS-activated microglial-conditioned medium the Akt phosphorylation response to the IGF1 recombinant 11 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>12728|VWS||No_GeneRif__6121|IRF6|3664|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 100290 16877542 129068 543 391 AKT1 AKT Akt 8 0.0 Upon longer exposure to LPS-activated microglial-conditioned medium the Akt phosphorylation response to the IGF1 recombinant remained depressed and at 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 100291 16877542 129069 9939 5464 IGF1 IGF1 IGF1-mediated 5 1.5 However both the alteration of IGF1-mediated Akt phosphorylation and the loss of cell viability mediated by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100292 16877542 129069 543 391 AKT1 AKT Akt 6 0.2 However both the alteration of IGF1-mediated Akt phosphorylation and the loss of cell viability mediated by LPS-activated 5 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100293 16877542 129069 24053 12728 VWS LPS LPS-activated 16 0.0 Akt phosphorylation and the loss of cell viability mediated by LPS-activated microglia were counteracted by the specific NADPH oxidase inhibitor apocynin 11 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>12728|VWS||No_GeneRif__6121|IRF6|3664|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 100294 16877542 129072 20996 11179 SOD1 ALS ALS 6 2.2 Experimental evidence supports a model for ALS neurodegeneration in which nonneuronal cells such as microglia contribute to 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100295 16877542 129074 18723 10261 ROS1 ROS ROS 40 0.0 morphology of resting microglia and did not seem to produce ROS ( Figs 1 and 6 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100296 16877542 129075 20996 11179 SOD1 SOD1 SOD1 3 2.2 Conversely in transgenic SOD1 G93A mice paralleling the worsening of the ALS phenotype there 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100297 16877542 129075 20996 11179 SOD1 ALS ALS 11 2.2 in transgenic SOD1 G93A mice paralleling the worsening of the ALS phenotype there was an intensification of spinal cord microgliosis accompanied 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100298 16877542 129076 20996 11179 SOD1 ALS ALS 30 2.2 of oxidatively damaging nearby macromolecules and cells homed within inflamed ALS tissues 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100299 16877542 129077 20996 11179 SOD1 SOD1 SOD1 20 2.2 were markedly elevated in spinal cord extracts of symptomatic transgenic SOD1 G93A mice for the most part in a NADPH oxidase-dependent 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100300 16877542 129078 20996 11179 SOD1 ALS ALS 19 2.2 was also found in postmortem spinal cords from human sporadic ALS cases ( Fig 2 supporting the conclusion that the occurrence 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100301 16877542 129078 20996 11179 SOD1 ALS ALS 40 2.2 occurrence of inflammation-mediated oxidative damage is not restricted to familial ALS caused by SOD1 mutations but is also a pathological hallmark 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100302 16877542 129078 20996 11179 SOD1 SOD1 SOD1 43 2.2 oxidative damage is not restricted to familial ALS caused by SOD1 mutations but is also a pathological hallmark of the prevalent 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100303 16877542 129078 20996 11179 SOD1 ALS ALS 58 2.2 a pathological hallmark of the prevalent nonfamilial sporadic form of ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100304 16877542 129079 20996 11179 SOD1 SOD1 SOD1 16 2.2 of the gp91 phox subunit of NADPH oxidase in transgenic SOD1 G93A mice eliminates the production of microglial-derived ROS ( Fig 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100305 16877542 129079 20996 11179 SOD1 ALS ALS 39 2.2 M and importantly prolongs survival and retards neurodegeneration in this ALS model ( Fig 3 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100306 16877542 129079 18723 10261 ROS1 ROS ROS 24 0.0 in transgenic SOD1 G93A mice eliminates the production of microglial-derived ROS ( Fig 1 M and importantly prolongs survival and retards 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100307 16877542 129080 20996 11179 SOD1 SOD1 SOD1 6 2.2 Deletion of gp91 phox in transgenic SOD1 G93A mice did not alter the spinal cord microglial response 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100308 16877542 129080 20996 11179 SOD1 SOD1 SOD1 22 2.2 the spinal cord microglial response or the expression of human SOD1 in transgenic SOD1 G93A mice (Fig Fig 7 which is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100309 16877542 129080 20996 11179 SOD1 SOD1 SOD1 25 2.2 microglial response or the expression of human SOD1 in transgenic SOD1 G93A mice (Fig Fig 7 which is a known determinant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100310 16877542 129080 20996 11179 SOD1 ALS ALS 40 2.2 which is a known determinant of disease severity in this ALS model ( 18 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100311 16877542 129081 20996 11179 SOD1 SOD1 SOD1 7 2.2 Consequently the attenuated phenotype seen in transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice is attributable to the lack 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100312 16877542 129081 20996 11179 SOD1 SOD1 SOD1 34 2.2 either an impaired microglial response or expression of the human SOD1 G93A transgene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100313 16877542 129082 20996 11179 SOD1 ALS ALS 16 2.2 NADPH oxidase contributes to the degeneration of motor neurons in ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100314 16877542 129083 20996 11179 SOD1 ALS ALS 19 2.2 in the pathogenesis of chronic noninfectious pathological conditions such as ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100315 16877542 129084 20996 11179 SOD1 SOD1 SOD1 12 2.2 magnitude of benefit afforded by gp91 phox deletion in transgenic SOD1 G93A mice argues that targeting neuroinflammation by inhibiting just one 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100316 16877542 129084 20996 11179 SOD1 ALS ALS 41 2.2 not be sufficient to produce robust and lasting neuroprotection in ALS patients 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100317 16877542 129085 18723 10261 ROS1 ROS ROS 28 0.0 their plasma membrane proteins and lipids damaged by NADPH oxidase-derived ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100318 16877542 129086 20996 11179 SOD1 ALS ALS 5 2.2 However the chronic nature of ALS suggests that neuroinflammation is likely protracted and not as strong 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100319 16877542 129087 20996 11179 SOD1 ALS ALS 29 2.2 oxidative stress with the selective demise of motor neurons in ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100320 16877542 129088 20996 11179 SOD1 ALS ALS 30 2.2 of those already compromised as motor neurons probably are in ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100321 16877542 129088 18723 10261 ROS1 ROS ROS 6 0.0 First at that lower level of ROS production oxidative stress may not kill cells but instead may 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100322 16877542 129090 9939 5464 IGF1 IGF1 IGF1 9 2.0 Relevant to the latter scenario are our results for IGF1 a trophic factor that is known to promote motor neuron 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100323 16877542 129091 9939 5464 IGF1 IGF1 IGF1 9 2.0 In this study we indeed found that receptors for IGF1 were primarily expressed on motor neurons in mouse spinal cords 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100324 16877542 129091 9939 5464 IGF1 IGF1 IGF1 25 2.0 in mouse spinal cords (Fig Fig 8 and that the IGF1 signaling pathway was impaired by a NADPH oxidase-dependent mechanism in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100325 16877542 129091 20996 11179 SOD1 SOD1 SOD1 38 2.2 was impaired by a NADPH oxidase-dependent mechanism in symptomatic transgenic SOD1 G93A mice ( Fig 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100326 16877542 129092 9939 5464 IGF1 IGF1 IGF1 1 2.0 Although IGF1 per se did not seem to be damaged by inflammation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100327 16877542 129092 9939 5464 IGF1 IGF1 IGF1 20 2.0 by inflammation NADPH oxidase did stimulate the oxidative modification of IGF1 receptors ( Fig 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100328 16877542 129093 9939 5464 IGF1 IGF1 IGF1 5 2.0 The ligand-dependent kinase activation of IGF1 receptor relies on its arrangement into a heterotetrameric 2_amp_#x003b1;/2_amp_#x003b2;-chain 2_amp_#x003b1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100329 16877542 129094 9939 5464 IGF1 IGF1 IGF1 9 2.0 It may thus be predicted that oxidation of the IGF1 receptor main extracellular domains (i.e., i.e. the _amp_#x003b1 -chains could 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100330 16877542 129095 9939 5464 IGF1 IGF1 IGF1 28 2.0 molecular events that are normally elicited by ligation of the IGF1 receptor including autophosphorylation and Akt phosphorylation were indeed abated by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100331 16877542 129095 543 391 AKT1 AKT Akt 33 0.0 elicited by ligation of the IGF1 receptor including autophosphorylation and Akt phosphorylation were indeed abated by ROS in a microglial NADPH 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 100332 16877542 129095 18723 10261 ROS1 ROS ROS 39 0.0 receptor including autophosphorylation and Akt phosphorylation were indeed abated by ROS in a microglial NADPH oxidase-dependent manner 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100333 16877542 129096 9939 5464 IGF1 IGF1 IGF1 11 2.0 data also show that microglial NADPH oxidase by impairing the IGF1 signaling pathway renders SH-SY5Y cells in our in vitro system 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100334 16877542 129096 24053 12728 VWS LPS LPS-activated 37 0.0 exposure to a hostile environment such as that emulated by LPS-activated microglial-conditioned medium ( Fig 5 11 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>12728|VWS||No_GeneRif__6121|IRF6|3664|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 100335 16877542 129097 20996 11179 SOD1 SOD1 SOD1 33 2.2 to withstand the toxicity of etiologic agents such as mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100336 16877542 129098 9939 5464 IGF1 IGF1 IGF1 3 2.0 Muscle-specific expression of IGF1 stabilizes neuromuscular junctions reduces inflammation in the spinal cord and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100337 16877542 129098 20996 11179 SOD1 SOD1 SOD1 20 2.2 the spinal cord and enhances motor neuronal survival in transgenic SOD1 G93A mice ( 23 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100338 16877542 129099 9939 5464 IGF1 IGF1 IGF1 15 2.0 did not find any evidence that the rescue of the IGF1 pathway by abrogating NADPH oxidase was associated with muscle hypertrophy 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100339 16877542 129100 20996 11179 SOD1 SOD1 SOD1 3 2.2 Nevertheless whether transgenic SOD1 G93A mice carrying the gp91 phox null mutation reach end-stage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100340 16877542 129101 20996 11179 SOD1 SOD1 SOD1 3 2.2 Injection of transgenic SOD1 G93A mice with an adeno-associated virus carrying an IGF1 gene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100341 16877542 129101 9939 5464 IGF1 IGF1 IGF1 12 2.0 transgenic SOD1 G93A mice with an adeno-associated virus carrying an IGF1 gene prolongs survival in these animals ( 20 24 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100342 16877542 129102 9939 5464 IGF1 IGF1 IGF1 23 2.0 but instead may blunt the motor neuron survival response to IGF1 in ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100343 16877542 129102 20996 11179 SOD1 ALS ALS 25 2.2 may blunt the motor neuron survival response to IGF1 in ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100344 16877542 129103 20996 11179 SOD1 ALS ALS 5 2.2 Perhaps the modest change in ALS progression that is seen in patients treated with human recombinant 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100345 16877542 129103 9939 5464 IGF1 IGF1 IGF1 16 2.0 progression that is seen in patients treated with human recombinant IGF1 ( 25 may be related to the issue raised above 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100346 16877542 129104 9939 5464 IGF1 IGF1 IGF1 10 2.0 It may thus be argued that optimal therapeutic response to IGF1 in diseases such as ALS may rely on a concomitant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100347 16877542 129104 20996 11179 SOD1 ALS ALS 15 2.2 that optimal therapeutic response to IGF1 in diseases such as ALS may rely on a concomitant administration of this trophic factor 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100348 16877542 129114 20996 11179 SOD1 SOD1 SOD1 12 2.2 oxidase stimulates carbonylation of spinal cord motor neurons in transgenic SOD1 G93A mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100349 16877542 129115 20996 11179 SOD1 SOD1 SOD1 29 2.2 E in 1-month-old (asymptomatic) asymptomatic to 4-month-old (end-stage) end-stage transgenic SOD1 (more more ... 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100350 16877542 129117 20996 11179 SOD1 ALS ALS 16 2.2 with motor neuron carbonylation in the spinal cord of sporadic ALS patients 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100351 16877542 129118 20996 11179 SOD1 ALS ALS 23 2.2 spinal cord extracts from six normal controls and six age-matched ALS patients 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100352 16877542 129121 20996 11179 SOD1 SOD1 SOD1 11 2.2 of gp91 phox increases lifespan and lessens neurodegeneration in transgenic SOD1 G93A mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100353 16877542 129122 20996 11179 SOD1 SOD1 SOD1 7 2.2 ( A Survival comparison of transgenic SOD1 G93A /gp91 gp91 phox mice (red) red (122.0 122.0 _amp_#x000b1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100354 16877542 129122 20996 11179 SOD1 SOD1 SOD1 22 2.2 (122.0 122.0 _amp_#x000b1 1.7 days n = 19 and transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 littermates (more more ... 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100355 16877542 129124 9939 5464 IGF1 IGF1 IGF1 3 2.0 Modulation of the IGF1/Akt IGF1 Akt pathway by NADPH oxidase-derived ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100356 16877542 129124 543 391 AKT1 AKT Akt 3 0.3 Modulation of the IGF1/Akt IGF1 Akt pathway by NADPH oxidase-derived ROS 4 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100357 16877542 129124 18723 10261 ROS1 ROS ROS 8 0.0 Modulation of the IGF1/Akt IGF1 Akt pathway by NADPH oxidase-derived ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100358 16877542 129125 9939 5464 IGF1 IGF1 IGF1 5 2.0 ( A Immunoprecipitation of IGF1 receptor _amp_#x003b1 -chain followed by OxyBlot (upper upper blot and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100359 16877542 129125 9939 5464 IGF1 IGF1 IGF1 18 2.0 by OxyBlot (upper upper blot and immunoblot for spinal cord IGF1 receptor _amp_#x003b1 -chain (lower lower blot 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100360 16877542 129128 9939 5464 IGF1 IGF1 IGF1 7 2.0 Glucose oxidase- and microglial-derived ROS impair the IGF1 Akt pathway in vitro 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100361 16877542 129128 18723 10261 ROS1 ROS ROS 4 0.0 Glucose oxidase- and microglial-derived ROS impair the IGF1 Akt pathway in vitro 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100362 16877542 129128 543 391 AKT1 AKT Akt 8 0.2 Glucose oxidase- and microglial-derived ROS impair the IGF1 Akt pathway in vitro 5 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100363 16877542 129129 9939 5464 IGF1 IGF1 IGF1-treated 13 1.5 upper blot and total Akt (lower lower blot immunoblots of IGF1-treated SH-SY5Y cells exposed or not exposed to 75 _amp_#x003bc M 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100364 16877542 129129 543 391 AKT1 AKT Akt 8 0.0 ( A Phospho-Akt (upper upper blot and total Akt (lower lower blot immunoblots of IGF1-treated SH-SY5Y cells exposed or 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 100365 16877542 129130 20996 11179 SOD1 SOD1 SOD1 4 2.2 ROS reactive oxygen species SOD1 superoxide dismutase 1 IGF1 insulin-like growth factor 1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100366 16877542 129130 9939 5464 IGF1 IGF1 IGF1 8 2.0 ROS reactive oxygen species SOD1 superoxide dismutase 1 IGF1 insulin-like growth factor 1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100367 16877542 129130 18723 10261 ROS1 ROS ROS 0 0.0 ROS reactive oxygen species SOD1 superoxide dismutase 1 IGF1 insulin-like growth 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100368 16877542 129131 20996 11179 SOD1 ALS ALS 0 2.2 ALS is the most common adult-onset paralytic disease and is characterized 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100369 16877542 129133 20996 11179 SOD1 SOD1 SOD1 18 2.2 dominant mutations in the gene for superoxide dismutase 1 (SOD1) SOD1 cause familial ALS ( 2 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100370 16877542 129133 20996 11179 SOD1 ALS ALS 21 2.2 the gene for superoxide dismutase 1 (SOD1) SOD1 cause familial ALS ( 2 3 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100371 16877542 129134 20996 11179 SOD1 SOD1 SOD1 2 2.2 Overexpression of SOD1 mutants in rodents emulate clinical and pathological hallmarks of ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100372 16877542 129134 20996 11179 SOD1 ALS ALS 12 2.2 SOD1 mutants in rodents emulate clinical and pathological hallmarks of ALS through a toxic gain of function ( 4 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100373 16877542 129135 20996 11179 SOD1 SOD1 SOD1 18 2.2 mixture of neuronal and nonneuronal cells expressing wild-type or mutant SOD1 ( 5 investigation of these animals suggested that nonneuronal cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100374 16877542 129136 20996 11179 SOD1 SOD1 SOD1 10 2.2 Corroborating this hypothesis is the demonstration that reduction of mutant SOD1 selectively in microglia extended survival in transgenic SOD1 G37R mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100375 16877542 129136 20996 11179 SOD1 SOD1 SOD1 18 2.2 of mutant SOD1 selectively in microglia extended survival in transgenic SOD1 G37R mice ( 6 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100376 16877542 129138 18723 10261 ROS1 ROS ROS 12 0.0 mediators that could promote neurodegeneration are reactive oxygen species (ROS) ROS produced by the enzyme NADPH oxidase complex ( 7 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100377 16877542 129139 18723 10261 ROS1 ROS ROS-generating 2 0.0 Although this ROS-generating multimeric oxidase is indispensable for protecting the host against invading 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 100378 16877542 129141 20996 11179 SOD1 ALS ALS 15 2.2 we undertook the study of NADPH oxidase in both human ALS and one of its genetic models 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100379 16877542 129142 20996 11179 SOD1 ALS ALS 15 2.2 and mouse postmortem tissues indicate that spinal cord microgliosis in ALS is accompanied with an up-regulation of NADPH oxidase 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00136196081569571<>ScoreDetail__5468|IGFALS|0.000485776832861226__11179|SOD1|0.00136196081569571__ 0 0 0 0 0 100380 16877542 129143 18723 10261 ROS1 ROS ROS-generating 29 0.0 provide compelling evidence that supports the concept that this microglial ROS-generating enzymatic complex promotes spinal cord motor neuron degeneration by a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 101473 16895581 130036 18723 10261 ROS1 ROS ROS 3 0.0 Reactive oxygen species (ROS) ROS play a major role in the pathogenesis of neurodegenerative diseases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 101474 16895581 130038 18723 10261 ROS1 ROS ROS 5 0.0 A major proportion of cellular ROS is generated at the inner mitochondrial membrane by the respiratory 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 101475 16895581 130039 20996 11179 SOD1 ALS ALS 36 2.7 in the G93A mouse model of amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0015288472966802<>ScoreDetail__5468|IGFALS|0.000391668150258145__11179|SOD1|0.0015288472966802__ 0 0 0 0 0 101476 16895581 130040 20996 11179 SOD1 SOD1 SOD1 24 2.7 either wild-type or mutant Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 101477 16895581 130043 20996 11179 SOD1 ALS ALS 19 2.7 oxidative stress is a therapeutic option for the treatment of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.0015288472966802<>ScoreDetail__5468|IGFALS|0.000391668150258145__11179|SOD1|0.0015288472966802__ 0 0 0 0 0 94441 17014688 122442 20996 11179 SOD1 ALS ALS 4 1.7 Reduced oxidative damage in ALS by high-dose enteral melatonin treatment 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00125167522188788<>ScoreDetail__5468|IGFALS|0.000719646345224633__11179|SOD1|0.00125167522188788__ 0 0 0 0 0 94442 17014688 122443 20996 11179 SOD1 ALS ALS 3 1.7 Amyotrophic lateral sclerosis (ALS) ALS is the collective term for a fatal motoneuron disease of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00125167522188788<>ScoreDetail__5468|IGFALS|0.000719646345224633__11179|SOD1|0.00125167522188788__ 0 0 0 0 0 94443 17014688 122445 20996 11179 SOD1 ALS ALS 31 1.7 cells (NSC-34), NSC-34 (2) 2 a genetic mouse model of ALS (SOD1(G93A)-transgenic SOD1 G93A -transgenic mice and (3) 3 a group 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00125167522188788<>ScoreDetail__5468|IGFALS|0.000719646345224633__11179|SOD1|0.00125167522188788__ 0 0 0 0 0 94444 17014688 122445 20996 11179 SOD1 SOD1 SOD1 32 1.7 NSC-34 (2) 2 a genetic mouse model of ALS (SOD1(G93A)-transgenic SOD1 G93A -transgenic mice and (3) 3 a group of 31 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 94445 17014688 122445 20996 11179 SOD1 ALS ALS 43 1.7 and (3) 3 a group of 31 patients with sporadic ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00125167522188788<>ScoreDetail__5468|IGFALS|0.000719646345224633__11179|SOD1|0.00125167522188788__ 0 0 0 0 0 94446 17014688 122447 20996 11179 SOD1 SOD1 SOD1 1 1.7 In SOD1(G93A)-transgenic SOD1 G93A -transgenic mice high-dose oral melatonin delayed disease progression and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 94447 17014688 122449 20996 11179 SOD1 ALS ALS 16 1.7 provide a surrogate marker for oxidative stress were elevated in ALS patients but were normalized to control values by melatonin treatment 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00125167522188788<>ScoreDetail__5468|IGFALS|0.000719646345224633__11179|SOD1|0.00125167522188788__ 0 0 0 0 0 94448 17014688 122450 20996 11179 SOD1 ALS ALS 25 1.7 suitable for clinical trials aimed at neuroprotection through antioxidation in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00125167522188788<>ScoreDetail__5468|IGFALS|0.000719646345224633__11179|SOD1|0.00125167522188788__ 0 0 0 0 0 83479 17025271 107541 18723 10261 ROS1 ROS ROS 10 0.0 are a major source of intracellular reactive oxygen species (ROS) ROS and are particularly vulnerable to oxidative stress 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 83480 17025271 107543 18723 10261 ROS1 ROS ROS 6 0.0 Because dysfunctional mitochondria will produce more ROS a feed-forward loop is set up whereby ROS-mediated oxidative damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 83481 17025271 107543 18723 10261 ROS1 ROS ROS-mediated 14 0.0 produce more ROS a feed-forward loop is set up whereby ROS-mediated oxidative damage to mitochondria favors more ROS generation resulting in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 83482 17025271 107543 18723 10261 ROS1 ROS ROS 21 0.0 set up whereby ROS-mediated oxidative damage to mitochondria favors more ROS generation resulting in a vicious cycle 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 83483 17025271 107545 18723 10261 ROS1 ROS ROS 9 0.0 However if mitochondria are the major source of intracellular ROS and mitochondria are most vulnerable to oxidative damage then it 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 87978 17099894 113909 20996 11179 SOD1 SOD1 mSOD1 7 1.4 The mechanisms of human mutant superoxide dismutase-1 (mSOD1) mSOD1 toxicity to motor neurons (MNs) MNs are unresolved 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 87979 17099894 113911 22671 11998 TP53 p53 p53 24 0.3 prior to double-strand breaks occurring in nuclear and mitochondrial DNA p53 and p73 are activated in degenerating MNs but without nuclear 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 87980 17099894 113911 1002 25361 ARHGAP24 p73 p73 26 0.1 double-strand breaks occurring in nuclear and mitochondrial DNA p53 and p73 are activated in degenerating MNs but without nuclear import 6 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 87981 17099894 113912 1432 13509 AVEN AVEN Aven 25 0.6 within MNs with a blockade of apoptosis possibly mediated by Aven up-regulation 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 87982 17099894 113913 20996 11179 SOD1 SOD1 mSOD1 10 1.4 swelling is associated with compromised Na K-ATPase activity and aggregation mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 87983 17099894 113914 20997 11180 SOD2 SOD2 SOD2 13 0.9 cytochrome c oxidase subunit-I and alpha-synuclein as well as nitrated SOD2 accumulate in mSOD1 mouse spinal cord 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 87984 17099894 113914 20996 11179 SOD1 SOD1 mSOD1 16 1.4 subunit-I and alpha-synuclein as well as nitrated SOD2 accumulate in mSOD1 mouse spinal cord 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 87985 17099894 113915 20996 11179 SOD1 SOD1 mSOD1 2 1.4 Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible nitric oxide synthase 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 87986 17099894 113915 14535 7873 NOS2A iNOS iNOS 13 3.2 MNs accumulate NADPH diaphorase and inducible nitric oxide synthase (iNOS)-like iNOS -like immunoreactivity and iNOS gene deletion extends significantly the life 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 87987 17099894 113915 14535 7873 NOS2A iNOS iNOS 16 3.2 and inducible nitric oxide synthase (iNOS)-like iNOS -like immunoreactivity and iNOS gene deletion extends significantly the life span of G93A-mSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 87988 17099894 113917 20996 11179 SOD1 ALS ALS 14 1.4 for mitochondriopathy and MN degeneration in amyotrophic lateral sclerosis (ALS) ALS mice involving blockade of apoptosis accumulation of MN mitochondria with 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00128416738679533<>ScoreDetail__5468|IGFALS|0.000381494951550141__11179|SOD1|0.00128416738679533__ 0 0 0 0 0 87989 17099894 113917 14535 7873 NOS2A NOS NOS 31 2.7 of MN mitochondria with enhanced toxic potential from distal terminals NOS localization in MN mitochondria and peroxynitrite damage and early degeneration 1 JUMiner_v2.2 1 0 0 2 7873 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7873|NOS2A|0.000755025876600122<>ScoreDetail__7873|NOS2A|0.000755025876600122__7872|NOS1|0.000525533963771572__ 0 0 0 0 0 87990 17099894 113918 20996 11179 SOD1 SOD1 mSOD1 23 1.4 as participants in the process of MN degeneration caused by mSOD1 10 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88106 17105868 114226 7333 11920 FAS FAS Fas 1 2.9 The Fas pathway and oxidative stress mediate neuronal death in stroke and 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88107 17105868 114227 20996 11179 SOD1 ALS ALS 18 1.9 produce spinal motor neuron degeneration in amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88108 17105868 114228 20996 11179 SOD1 ALS ALS 11 1.9 of reactive oxygen species were increased in motor neurons from ALS mice compared with wild-type mice at age 10 weeks before 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88109 17105868 114229 7333 11920 FAS FAS Fas 3 2.9 The proapoptotic proteins Fas Fas-associated death domain caspase 8 and caspase 3 were also 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88110 17105868 114229 7333 11920 FAS FAS Fas-associated 4 2.1 The proapoptotic proteins Fas Fas-associated death domain caspase 8 and caspase 3 were also elevated 1 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88111 17105868 114233 20996 11179 SOD1 ALS ALS 20 1.9 Fas-mediated apoptosis can prevent neuronal loss and motor dysfunction in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88112 17105868 114234 20996 11179 SOD1 ALS ALS 3 1.9 Amyotrophic lateral sclerosis (ALS) ALS is a neurodegenerative disorder characterized by degeneration of upper and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88113 17105868 114235 20996 11179 SOD1 ALS ALS 15 1.9 role for oxidative stress in the motor neuron loss in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88114 17105868 114236 20996 11179 SOD1 ALS ALS 22 1.9 in the motor cortex and spinal cord in patients with ALS (Bowling Bowling et al. 1993 Beal et al. 1997 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88115 17105868 114237 20996 11179 SOD1 ALS ALS 21 1.9 8-hydroxyl-2-deoxyguanosine in the cortex and spinal cord in patients with ALS (Fitzmaurice Fitzmaurice et al. 1996 Pedersen et al. 1998 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88116 17105868 114238 20996 11179 SOD1 ALS ALS 13 1.9 oxidative stress apoptosis probably contributes to motor neuron degeneration in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88117 17105868 114240 1576 990 BCL2 Bcl-2 Bcl-2 9 1.3 The ratio of apoptotic cell death genes Bax to Bcl-2 is increased at both the mRNA and protein level in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88118 17105868 114240 20996 11179 SOD1 ALS ALS 26 1.9 and protein level in spinal motor neurons from patients with ALS and from SOD1-G93A mice (Mu Mu et al. 1996 Vukosavic 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88119 17105868 114241 1576 990 BCL2 Bcl-2 Bcl-2 18 1.3 spinal cord mitochondria but not liver mitochondria and binds to Bcl-2 (Pasinelli Pasinelli et al. 2004 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88120 17105868 114242 1576 990 BCL2 Bcl-2 Bcl-2 5 1.3 Altered expression and dysfunction of Bcl-2 may contribute to the activation of mitochondrial apoptosis machinery such 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88121 17105868 114242 20996 11179 SOD1 ALS ALS 28 1.9 caspase 3 and cytochrome c in spinal motor neurons of ALS transgenic mice and humans with ALS (Guegan Guegan et al. 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88122 17105868 114242 20996 11179 SOD1 ALS ALS 34 1.9 spinal motor neurons of ALS transgenic mice and humans with ALS (Guegan Guegan et al. 2001 Inoue et al. 2003 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88123 17105868 114243 1576 990 BCL2 Bcl-2 Bcl-2 7 1.3 In support of this idea overexpression of Bcl-2 or the caspase inhibitory protein XIAP prolongs survival and improves 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88124 17105868 114243 24293 592 XIAP XIAP XIAP 13 1.1 this idea overexpression of Bcl-2 or the caspase inhibitory protein XIAP prolongs survival and improves motor performance in ALS mice expressing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88125 17105868 114243 20996 11179 SOD1 ALS ALS 21 1.9 inhibitory protein XIAP prolongs survival and improves motor performance in ALS mice expressing the SOD1-G93A mutation (Kostic Kostic et al. 1997 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88126 17105868 114244 20996 11179 SOD1 ALS ALS 16 1.9 caspase inhibitors prolongs survival and delays disease progression in transgenic ALS mice (Li Li et al. 2000 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88127 17105868 114247 20996 11179 SOD1 ALS ALS 15 1.9 prevents neuronal cell apoptosis and protects spinal motor neurons in ALS mice (Ryu Ryu et al. 1999 Kaspar et al. 2003 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88128 17105868 114248 20996 11179 SOD1 ALS ALS 29 1.9 and motor function than monotherapy in transgenic mouse models of ALS (Zhang Zhang et al. 2003 Petri et al. 2006 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88129 17105868 114249 20996 11179 SOD1 ALS ALS 24 1.9 and can contribute to neuronal death through distinctive routes in ALS we hypothesize that a therapeutic approach targeting both oxidative stress 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88130 17105868 114253 20996 11179 SOD1 SOD1 SOD1 7 2.4 G93A transgenic mice carrying the G93A human SOD1 mutation were obtained from the Jackson Laboratory (Bar Bar Harbor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88131 17105868 114257 7333 11920 FAS FAS Fas 9 2.9 In experiments investigating oxidative stress and activation of the Fas pathway mice received Neu2000 (30 30 mg/kg/day), mg kg day 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88132 17105868 114275 19976 9662 SIRPA MFR MFR 3 0.0 Mitochondrial free radicals (MFR) MFR generation was determined as described previously (Kim Kim et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88133 17105868 114279 19976 9662 SIRPA MFR MFRs 0 0.0 MFRs were determined by detection of the oxidized fluorescence product (excitation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88134 17105868 114280 19976 9662 SIRPA MFR MFR 0 0.0 MFR intensity was analyzed by Image Gauge 3.12 (Fuji Fuji Photo 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88135 17105868 114281 19976 9662 SIRPA MFR MFRs 2 0.0 To determine MFRs in spinal motor neurons sections were immunolabeled with mouse monoclonal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88136 17105868 114290 19573 10691 SDS SDS SDS 7 0.3 Protein samples were electrophoresed on a 12% SDS polyacrylamide gel and transferred to a nitrocellulose membrane 1 JUMiner_v2.2 1 2 sds 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000272650903678085<>ScoreDetail__10691|SDS|5.81327752586908e-05__19440|SBDS|0.000272650903678085__ 0 0 0 0 0 88137 17105868 114292 11823 16429 LIAS LAS LAS 20 0.0 Little Chalfont Buckinghamshire UK on X-ray film or with an LAS 1000 image analyzer (Fuji Fuji Photo Film Co. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88138 17105868 114294 7333 11920 FAS FAS Fas 6 2.9 The following primary antibodies were used Fas FADD (BD BD Bioscience Franklin Lakes NJ cleaved caspase 3 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88139 17105868 114294 6920 3573 FADD FADD FADD 7 1.4 The following primary antibodies were used Fas FADD (BD BD Bioscience Franklin Lakes NJ cleaved caspase 3 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88140 17105868 114321 19976 9662 SIRPA MFR MFRs 11 0.0 and G93A transgenic mice showed similar levels of nitrotyrosine and MFRs in dorsal horn neurons and white matter (data data not 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88141 17105868 114327 20996 11179 SOD1 ALS ALS 11 1.9 in both human patients and the transgenic mouse model of ALS have delineated multiple pathological mechanisms of neuronal death in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88142 17105868 114327 20996 11179 SOD1 ALS ALS 21 1.9 ALS have delineated multiple pathological mechanisms of neuronal death in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88143 17105868 114328 20996 11179 SOD1 SOD1 SOD1 5 2.4 These mechanisms include mitochondrial dysfunction SOD1 mutations and activation of Ca -permeable ionotropic glutamate receptors which 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88144 17105868 114329 20996 11179 SOD1 ALS ALS 7 1.9 Riluzole the only therapeutic drug approved for ALS extends survival by approximately 3 months and is thought to 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88145 17105868 114330 20996 11179 SOD1 ALS ALS 23 1.9 and probably constitutes an additional route toward neuronal death in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88146 17105868 114331 20996 11179 SOD1 ALS ALS 30 1.9 and progression of motor function deficit and extend survival in ALS transgenic mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88147 17105868 114332 20996 11179 SOD1 ALS ALS 3 1.9 Oxidative stress in ALS seems to be attributable to multiple factors including mitochondrial dysfunction 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88148 17105868 114332 20996 11179 SOD1 SOD1 SOD1 29 2.4 and point mutations in the Cu Zn superoxide dismutase ( SOD1 gene the last of which are present in approximately 20% 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88149 17105868 114332 20996 11179 SOD1 ALS ALS 43 1.9 last of which are present in approximately 20% of familial ALS cases (Rosen Rosen et al. 1993 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88150 17105868 114333 20996 11179 SOD1 SOD1 SOD1 10 2.4 Two findings in particular suggest a strong link between the SOD1 gene mutation and oxidative stress 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88151 17105868 114335 20996 11179 SOD1 ALS ALS 9 1.9 Second in transgenic mice expressing the SOD1-G93A mutation (transgenic transgenic ALS mice administration of antioxidants such as coenzyme Q10 a component 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88152 17105868 114335 4772 26515 COQ10A Q10 Q10 17 0.9 (transgenic transgenic ALS mice administration of antioxidants such as coenzyme Q10 a component of the mitochondrial respiratory chain and creatine an 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88153 17105868 114336 20996 11179 SOD1 ALS ALS 23 1.9 that such stress causes degeneration of spinal motor neurons in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88154 17105868 114337 19976 9662 SIRPA MFR MFRs 4 0.0 Levels of nitrotyrosine and MFRs were increased before neuronal death in the lumbar spinal cord 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88155 17105868 114341 20996 11179 SOD1 SOD1 SOD1 6 2.4 This raises the possibility that the SOD1 mutation not only enhances oxidative stress in lumbar motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88156 17105868 114342 20996 11179 SOD1 SOD1 SOD1 10 2.4 The latter effect may be attributable to interaction of mutant SOD1 and Bcl-2 causing mitochondrial dysfunction and subsequently increased sensitivity to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88157 17105868 114342 1576 990 BCL2 Bcl-2 Bcl-2 12 1.3 effect may be attributable to interaction of mutant SOD1 and Bcl-2 causing mitochondrial dysfunction and subsequently increased sensitivity to oxidative stress 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88158 17105868 114345 20996 11179 SOD1 ALS ALS 21 1.9 to Neu2000 contributing to degeneration of spinal motor neurons in ALS mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88159 17105868 114346 20996 11179 SOD1 ALS ALS 11 1.9 lines of evidence support a potential role of apoptosis in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88160 17105868 114348 7333 11920 FAS FAS Fas 5 2.9 We found that expression of Fas and FADD were increased selectively in the ventral motor neurons 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88161 17105868 114348 6920 3573 FADD FADD FADD 7 1.4 We found that expression of Fas and FADD were increased selectively in the ventral motor neurons of G93A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88162 17105868 114349 20996 11179 SOD1 ALS ALS 4 1.9 In motor neurons of ALS mice the Fas-signaling pathway remained activated after complete blockade of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88163 17105868 114349 7333 11920 FAS FAS Fas-signaling 7 1.8 In motor neurons of ALS mice the Fas-signaling pathway remained activated after complete blockade of oxidative stress by 1 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88164 17105868 114351 7333 11920 FAS FAS Fas 9 2.9 In support of this Li blocked activation of the Fas pathway during serum deprivation-induced apoptosis and attenuated motor neuron degeneration 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88165 17105868 114351 7333 11920 FAS FAS Fas 25 2.9 and attenuated motor neuron degeneration as well as activation of Fas caspase 8 and caspase 3 in the spinal cords of 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88166 17105868 114351 20996 11179 SOD1 ALS ALS 36 1.9 caspase 8 and caspase 3 in the spinal cords of ALS mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88167 17105868 114354 543 391 AKT1 AKT1 Akt-1 44 0.0 that result in activation of the serine/threonine serine threonine kinase Akt-1 and phospholipase C gamma (Chalecka-Franaszek Chalecka-Franaszek and Chuang 1999 ~0.425 11 JUMiner_v2.2 1 1 akt1; 0 0 0 0 0 0 0 0 88168 17105868 114357 14727 8023 NTF3 NT3 NT-3 10 1.3 neurotrophins nerve growth factor brain-derived neurotrophic factor neurotrophin 3 (NT-3), NT-3 and NT-4/5 NT-4 5 promote neuronal survival by preventing programmed 11 JUMiner_v2.2 1 0 0 2 8023 TotalCon:3<>8020|NT3|4877|Complete__11186|SORT1|6272|Complete__8023|NTF3|4908|Complete__<>AvaiableGeneRif=3<>BEST:8023|NTF3|0.000520781159670417<>ScoreDetail__8023|NTF3|0.000520781159670417__11186|SORT1|0.000261597488664109__8020|NT3|3.17087865047405e-05__ 0 0 0 0 0 88169 17105868 114357 14728 8024 NTF4 NT-4/5 NT-4/5 12 1.3 growth factor brain-derived neurotrophic factor neurotrophin 3 (NT-3), NT-3 and NT-4/5 NT-4 5 promote neuronal survival by preventing programmed cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88170 17105868 114357 14728 8024 NTF4 NT4 NT-4 12 1.3 factor brain-derived neurotrophic factor neurotrophin 3 (NT-3), NT-3 and NT-4/5 NT-4 5 promote neuronal survival by preventing programmed cell death or 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88171 17105868 114361 7333 11920 FAS FAS Fas 11 2.9 conclusion the present study suggests that oxidative stress and the Fas death pathway constitute two separate routes of the motor neuron 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88172 17105868 114363 7333 11920 FAS FAS Fas 1 2.9 The Fas pathway is slowly activated even in the blockade of oxidative 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88173 17105868 114365 7333 11920 FAS FAS Fas 7 2.9 Thus targeting both oxidative stress and the Fas apoptosis pathway with concurrent treatment with Neu2000 and Li may 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88174 17105868 114365 20996 11179 SOD1 ALS ALS 26 1.9 Li may additively improve neurological function and neuronal survival in ALS and possibly other neurological diseases including stroke Alzheimer's disease and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88175 17105868 114368 20996 11179 SOD1 ALS ALS 15 1.9 sections from the control (a a and c and G93A ALS transgenic mice (b b and d at 8 weeks of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88176 17105868 114376 7333 11920 FAS FAS Fas 7 2.9 A Western blot analysis showing expression of Fas FADD and actin in lumbar segments from control or G93A 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88177 17105868 114376 6920 3573 FADD FADD FADD 8 1.4 A Western blot analysis showing expression of Fas FADD and actin in lumbar segments from control or G93A transgenic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88178 17105868 114377 7333 11920 FAS FAS Fas 2 2.9 Levels of Fas (b) b and FADD (c) c were measured and scaled 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88179 17105868 114377 6920 3573 FADD FADD FADD 5 1.4 Levels of Fas (b) b and FADD (c) c were measured and scaled to actin mean _amp_#177 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88180 17105868 114379 6920 3573 FADD FADD FADD 4 1.4 Western blot analysis of FADD and Fas after immunoprecipitation with Fas antibody in the same 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88181 17105868 114379 7333 11920 FAS FAS Fas 6 2.9 Western blot analysis of FADD and Fas after immunoprecipitation with Fas antibody in the same samples shown 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88182 17105868 114379 7333 11920 FAS FAS Fas 10 2.9 Western blot analysis of FADD and Fas after immunoprecipitation with Fas antibody in the same samples shown above (d) d 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88183 17105868 114380 7333 11920 FAS FAS Fas 22 2.9 (b) b at 12 weeks of age after immuno-labeling with Fas antibody 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88184 17105868 114381 7333 11920 FAS FAS Fas 4 2.9 Note increased levels of Fas in the motor neurons (arrows) arrows from G93A mice 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88185 17105868 114383 3532 1509 CASP8 caspase-8 caspase-8 8 3.0 C Western blot analysis showing expression of cleaved caspase-8 cleaved caspase-3 and actin in lumbar segments from control or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88186 17105868 114395 6920 3573 FADD FADD FADD 5 1.4 C Western blot analysis of FADD after immunoprecipitation (IP) IP with Fas antibody cleaved caspase 8 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88187 17105868 114395 7333 11920 FAS FAS Fas 10 2.9 Western blot analysis of FADD after immunoprecipitation (IP) IP with Fas antibody cleaved caspase 8 cleaved caspase 3 and actin in 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88188 17105868 114403 7333 11920 FAS FAS Fas 5 2.9 F Western blot analysis of Fas FADD cleaved caspase 8 cleaved caspase 3 and actin in 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88189 17105868 114403 6920 3573 FADD FADD FADD 6 1.4 F Western blot analysis of Fas FADD cleaved caspase 8 cleaved caspase 3 and actin in lumbar 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88190 17105868 114423 7333 11920 FAS FAS Fas 2 2.9 Fas- and Fas ligand-mediated apoptosis plays a role in neuronal loss in animal 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88191 17105868 114424 7333 11920 FAS FAS Fas 4 2.9 We examined whether the Fas pathway would mediate apoptosis in ALS mice 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88192 17105868 114424 20996 11179 SOD1 ALS ALS 10 1.9 We examined whether the Fas pathway would mediate apoptosis in ALS mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88193 17105868 114425 7333 11920 FAS FAS Fas 2 2.9 Expression of Fas and its cytoplasmic adaptor protein FADD and Fas-FADD interaction were 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88194 17105868 114425 6920 3573 FADD FADD FADD 8 1.4 Expression of Fas and its cytoplasmic adaptor protein FADD and Fas-FADD interaction were also increased in the lumbar spinal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88195 17105868 114426 7333 11920 FAS FAS Fas 3 2.9 Immunohistochemistry revealed that Fas expression was increased selectively in large spinal motor neurons of 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88196 17105868 114429 7333 11920 FAS FAS Fas 4 2.9 These findings suggest that Fas FADD caspase 8 and caspase 3 are activated in spinal 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88197 17105868 114429 6920 3573 FADD FADD FADD 5 1.4 These findings suggest that Fas FADD caspase 8 and caspase 3 are activated in spinal motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88198 17105868 114429 20996 11179 SOD1 ALS ALS 23 1.9 in spinal motor neurons and mediate subsequent neuronal apoptosis in ALS mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88199 17105868 114430 7333 11920 FAS FAS Fas-signaling 4 1.8 No activation of the Fas-signaling molecules in G93A mice was detectable at 16 weeks of 1 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88200 17105868 114440 7333 11920 FAS FAS Fas 9 2.9 We also investigated whether serum deprivation would activate the Fas apoptosis pathway and whether this activation was sensitive to Li 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88201 17105868 114441 6920 3573 FADD FADD FADD 2 1.4 Interaction of FADD with Fas cleaved caspase 8 and cleaved caspase 3 were 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88202 17105868 114441 7333 11920 FAS FAS Fas 4 2.9 Interaction of FADD with Fas cleaved caspase 8 and cleaved caspase 3 were all increased 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88203 17105868 114443 19976 9662 SIRPA MFR MFR 24 0.0 from 8 weeks of age the increase in nitrotyrosine and MFR in lumbar spinal motor neurons at 10 weeks of age 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88204 17105868 114445 7333 11920 FAS FAS Fas 15 2.9 the diet slightly but statistically insignificantly attenuated the increase in Fas FADD and cleaved caspase 8 and caspase 3 in the 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88205 17105868 114445 6920 3573 FADD FADD FADD 16 1.4 diet slightly but statistically insignificantly attenuated the increase in Fas FADD and cleaved caspase 8 and caspase 3 in the lumbar 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88206 17105868 114446 7333 11920 FAS FAS Fas 12 2.9 noteworthy that daily administration of Li completely blocked activation of Fas and its downstream mediators in G93A mice 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88207 17105868 114447 7333 11920 FAS FAS Fas 18 2.9 Neu2000 can block both oxidative stress and activation of the Fas apoptosis pathway induced in the spinal cords of G93A mice 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88208 17105868 114454 20996 11179 SOD1 ALS ALS 17 1.9 oxidative stress and Fas-mediated apoptosis additively improves motor performance in ALS mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88209 17105868 114469 20996 11179 SOD1 ALS ALS 1 1.9 ABBREVIATIONS ALS amyotrophic lateral sclerosis PaGE paw grip endurance MFR mitochondrial free 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00121630583376416<>ScoreDetail__5468|IGFALS|0.000614029028222309__11179|SOD1|0.00121630583376416__ 0 0 0 0 0 88210 17105868 114469 20996 11179 SOD1 SOD SOD 24 1.9 DIV days in vitro BSO DL -buthionine- S R -sulfoximine SOD superoxide dismutase LDH lactate dehydrogenase FADD Fas-associated death domain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88211 17105868 114469 6920 3573 FADD FADD FADD 30 1.4 -buthionine- S R -sulfoximine SOD superoxide dismutase LDH lactate dehydrogenase FADD Fas-associated death domain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 88212 17105868 114469 7333 11920 FAS FAS Fas-associated 31 2.1 S R -sulfoximine SOD superoxide dismutase LDH lactate dehydrogenase FADD Fas-associated death domain 1 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000846066197386271<>ScoreDetail__11920|FAS|0.000846066197386271__3594|FASN|0.00060731585747676__ 0 0 0 0 0 88213 17105868 114469 19976 9662 SIRPA MFR MFR 9 0.0 ABBREVIATIONS ALS amyotrophic lateral sclerosis PaGE paw grip endurance MFR mitochondrial free radicals DIV days in vitro BSO DL -buthionine- 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 79986 17127561 103313 7643 3769 FMO1 FMO1 FMO1 3 3.4 Increased incidence of FMO1 gene single nucleotide polymorphisms in sporadic amyotrophic lateral sclerosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 79987 17127561 103316 20996 11179 SOD1 ALS ALS 19 0.3 reactive oxygen species and its involvement has been documented in ALS and other neurodegenerative disorders 3 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000921332310364603<>ScoreDetail__5468|IGFALS|0.000877165502333887__11179|SOD1|0.000921332310364603__ 0 0 0 0 0 79988 17127561 103318 7643 3769 FMO1 FMO1 FMO1 2 3.4 The human FMO1 gene presents 20 single nucleotide polymorphisms (SNPs) SNPs located in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 79989 17127561 103319 7643 3769 FMO1 FMO1 FMO1 1 3.4 The FMO1 gene has also recently been found underexpressed in spinal cord 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 79990 17127561 103319 20996 11179 SOD1 ALS ALS 13 0.3 has also recently been found underexpressed in spinal cord of ALS patients 3 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000921332310364603<>ScoreDetail__5468|IGFALS|0.000877165502333887__11179|SOD1|0.000921332310364603__ 0 0 0 0 0 79991 17127561 103320 7643 3769 FMO1 FMO1 FMO1 18 3.4 allelic and genotypic frequency of two 3'UTR SNPs of the FMO1 gene in sporadic ALS patients compared to a healthy control 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 79992 17127561 103320 20996 11179 SOD1 ALS ALS 22 0.3 of two 3'UTR SNPs of the FMO1 gene in sporadic ALS patients compared to a healthy control population 3 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000921332310364603<>ScoreDetail__5468|IGFALS|0.000877165502333887__11179|SOD1|0.000921332310364603__ 0 0 0 0 0 79993 17127561 103321 7643 3769 FMO1 FMO1 FMO1 29 3.4 controls (p_lt_0.01), p_lt_0.01 suggesting that specific allelic variants of the FMO1 gene might be associated to susceptibility to develop ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 79994 17127561 103321 20996 11179 SOD1 ALS ALS 38 0.3 the FMO1 gene might be associated to susceptibility to develop ALS 3 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000921332310364603<>ScoreDetail__5468|IGFALS|0.000877165502333887__11179|SOD1|0.000921332310364603__ 0 0 0 0 0 72470 17150307 92624 20996 11179 SOD1 ALS ALS 15 2.2 age-dependent motor neuron degeneration in human amyotrophic lateral sclerosis (ALS) ALS has not been defined and the role of glutathione (GSH) 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72471 17150307 92626 18723 10261 ROS1 ROS ROS 30 0.0 was accompanied by increased production of reactive oxygen species (ROS) ROS measured by the DCF fluorescent oxidation assay 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72472 17150307 92627 10824 6204 JUN AP-1 AP-1 8 2.8 In addition GSH depletion enhanced oxidative stress markers AP-1 transcriptional activation c-Jun c-Fos and HO-1 expression in NSC34 cells 1 JUMiner_v2.2 1 0 0 2 6204 TotalCon:5<>3796|FOS|2353|Complete__3797|FOSB|2354|Complete__6204|JUN|3725|Complete__6205|JUNB|3726|Complete__6206|JUND|3727|Complete__<>AvaiableGeneRif=5<>BEST:6204|JUN|0.000645032050978163<>ScoreDetail__3796|FOS|0.000618551383058785__3797|FOSB|0.000580266731819423__6205|JUNB|0.000545089770551059__6204|JUN|0.000645032050978163__6206|JUND|0.000507183782798545__ 0 0 0 0 0 72473 17150307 92627 10824 6204 JUN c-Jun c-Jun 11 2.8 addition GSH depletion enhanced oxidative stress markers AP-1 transcriptional activation c-Jun c-Fos and HO-1 expression in NSC34 cells analyzed by a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72474 17150307 92627 9462 5013 HMOX1 HO-1 HO-1 14 1.0 enhanced oxidative stress markers AP-1 transcriptional activation c-Jun c-Fos and HO-1 expression in NSC34 cells analyzed by a luciferase reporter western 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72475 17150307 92628 480 8768 AIFM1 AIF AIF 11 0.6 of GSH decreased mitochondrial function facilitated apoptosis inducing factor (AIF) AIF translocation cytochrome c release and caspase 3 activation and consequently 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72476 17150307 92629 20996 11179 SOD1 ALS ALS-like 2 2.2 In an ALS-like transgenic mouse model overexpressing mutant G93A-SOD1 gene we showed that 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72477 17150307 92629 480 8768 AIFM1 AIF AIF 28 0.6 the spinal cord and motor neuron cells is correlated with AIF translocation caspase 3 activation and motor neuron degeneration during ALS-like 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72478 17150307 92629 20996 11179 SOD1 ALS ALS-like 38 2.2 AIF translocation caspase 3 activation and motor neuron degeneration during ALS-like disease onset and progression 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72479 17150307 92630 20996 11179 SOD1 ALS ALS 31 2.2 pathways contributing at least partially to motor neuron degeneration in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72480 17150307 92632 20996 11179 SOD1 ALS ALS 3 2.2 Amyotrophic lateral sclerosis (ALS) ALS is a fatal neurodegenerative disease that primarily affects motor neurons 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72481 17150307 92633 20996 11179 SOD1 ALS ALS 17 2.2 motor neuron degeneration remain largely unidentified and effective therapy for ALS is not yet available 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72482 17150307 92634 20996 11179 SOD1 SOD1 SOD1 4 3.2 Mutations of Cu Zn-superoxide dismutase (SOD1) SOD1 gene cause motor neuron degeneration and have linked to 2_amp_#x02013 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72483 17150307 92634 20996 11179 SOD1 ALS ALS 16 2.2 motor neuron degeneration and have linked to 2_amp_#x02013 5% of ALS cases ( Rosen et al. 1994 Rosen et al. 1993 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72484 17150307 92635 20996 11179 SOD1 ALS ALS 8 2.2 Several potential mechanisms of motor neuron degeneration in ALS have been proposed based on clinical studies animal model and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72485 17150307 92637 20996 11179 SOD1 ALS ALS 20 2.2 and sustained event in association with motor neuron death in ALS ( Bogdanov et al. 1998 Liu et al. 1998 although 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72486 17150307 92638 18723 10261 ROS1 ROS ROS 13 0.0 potentially increased by enhanced production of reactive oxygen species (ROS), ROS decreased antioxidants/antioxidant antioxidants antioxidant enzyme systems or a combination of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72487 17150307 92640 18723 10261 ROS1 ROS ROS 4 0.0 Reduction of GSH enhances ROS production and promotes oxidative damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72488 17150307 92641 20996 11179 SOD1 ALS ALS 15 2.2 GSH binding in the spinal cords of patients with sporadic ALS ( Lanius et al. 1993 suggesting that GSH may play 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72489 17150307 92641 20996 11179 SOD1 ALS ALS 33 2.2 that GSH may play a role in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72490 17150307 92642 20996 11179 SOD1 SOD1 SOD1 13 3.2 culture model it has been shown that expression of mutant SOD1 gene decreased cellular levels of GSH suggesting the reduction in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72491 17150307 92642 20996 11179 SOD1 SOD1 SOD1-mediated 31 2.2 the reduction in GSH bioavailability may participate in the mutant SOD1-mediated motor neuron degeneration ( Lee et al. 2001 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72492 17150307 92643 18723 10261 ROS1 ROS ROS 9 0.0 GSH is the most abundant and effective scavenger against ROS directly in mammalian cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72493 17150307 92646 8204 4311 GCLC GCS GCS 12 0.0 sequential enzymatic reactions catalyzed by _amp_#x003b3 -glutamylcysteine synthetase (_amp_#x003b3;-GCS) _amp_#x003b3 -GCS and GSH synthetase 11 JUMiner_v2.2 1 0 0 2 12524 TotalCon:2<>4311|GCLC|2729|Complete__12524|UGCG|7357|Complete__<>AvaiableGeneRif=2<>BEST:12524|UGCG|0.000797573098998761<>ScoreDetail__12524|UGCG|0.000797573098998761__4311|GCLC|0.000637308880421754__ 0 0 0 0 0 72494 17150307 92647 8204 4311 GCLC GCS GCS 8 0.0 L-Buthionine Sulfoximine (BSO) BSO is a selective inhibitor of _amp_#x003b3 -GCS 11 JUMiner_v2.2 1 0 0 2 12524 TotalCon:2<>4311|GCLC|2729|Complete__12524|UGCG|7357|Complete__<>AvaiableGeneRif=2<>BEST:12524|UGCG|0.000797573098998761<>ScoreDetail__12524|UGCG|0.000797573098998761__4311|GCLC|0.000637308880421754__ 0 0 0 0 0 72495 17150307 92652 20996 11179 SOD1 ALS ALS 13 2.2 of GSH in the pathogenesis of motor neuron degeneration in ALS remained largely undefined 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72496 17150307 92653 20996 11179 SOD1 ALS ALS-like 13 2.2 we have focused on a cell culture system and an ALS-like transgenic mouse model to study the effect of GSH on 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72497 17150307 92666 7361 20442 FBRS FBS FBS 54 0.0 DMEM supplemented with 10% heat inactivated fetal bovine serum (FBS), FBS 100 units/ml units ml penicillin and 100 _amp_#x003bc;g/ml _amp_#x003bc g 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 72498 17150307 92679 12519 6983 ME1 MES MES 16 0.0 control EA or BSO treated experiments were homogenized completely in MES buffer 200 mM 2-(N-morpholino)ethanesulphonic 2- N-morpholino ethanesulphonic acid 50 mM 1 JUMiner_v2.2 1 0 0 2 7121 TotalCon:2<>6983|ME1|4199|Complete__7121|MKS1|54903|Complete__<>AvaiableGeneRif=2<>BEST:7121|MKS1|0.000227616700271272<>ScoreDetail__7121|MKS1|0.000227616700271272__6983|ME1|0.000213635651517525__ 0 0 0 0 0 72499 17150307 92682 18723 10261 ROS1 ROS ROS 11 0.0 Methods Assay of cellular production of reactive oxygen species (ROS) ROS A dichlorofluorescin (DCF) DCF assay was used to determine cellular 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72500 17150307 92682 18723 10261 ROS1 ROS ROS 24 0.0 assay was used to determine cellular reactive oxygen species (ROS) ROS generation in NSC34 cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72501 17150307 92686 18723 10261 ROS1 ROS ROS 9 0.0 The fluorescent intensity measuring the oxidation of DCFH-DA by ROS represents the relative steady state of ROS generation in cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72502 17150307 92686 18723 10261 ROS1 ROS ROS 16 0.0 of DCFH-DA by ROS represents the relative steady state of ROS generation in cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72503 17150307 92690 4682 2197 COL1A1 collagen collagen 12 0.3 Methods Adhesion assay Twenty four-well plates were coated with fibronectin collagen or laminin overnight in 1_amp_#x000d7 phosphate buffer solution (PBS) PBS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72504 17150307 92699 9462 5013 HMOX1 HO-1 HO-1 10 1.0 The forward and reverse real-time PCR primers for amplification of HO-1 transcripts were 5_amp_#x02019 -CTCACTGGCAGGAAATCATCCC -3_amp_#x02019 and 5_amp_#x02019 -GAGAGGTCACCCAGGTAGCG respectively 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72505 17150307 92712 480 8768 AIFM1 AIF AIF 10 0.6 Western analysis was performed to analyze cytochrome c release and AIF translocation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72506 17150307 92714 480 8768 AIFM1 AIF AIF 24 0.6 incubated with specific antibodies overnight at 4 _amp_#x000b0 C (AIF, AIF cytochrome c and active caspase 3 antibodies were all at 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72507 17150307 92720 8255 4236 GFER HPO HPO 21 0.0 l of ice cold lysis buffer (10mM 10mM K 2 HPO 4 pH 7.2/1mM 7.2 1mM EDTA/5mM EDTA 5mM EGTA/10mM EGTA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72508 17150307 92722 19573 10691 SDS SDS SDS 10 0.0 samples (20 20 _amp_#x003bc g were separated in a 12.5% SDS PAGE gel and transferred onto nitrocellulose membrane 1 JUMiner_v2.2 1 0 0 2 10691 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:10691|SDS|0.000401160278960686<>ScoreDetail__10691|SDS|0.000401160278960686__19440|SBDS|0.000357263000331185__ 0 0 0 0 0 72509 17150307 92725 3778 10620 CCL21 ECL ECL 15 0.0 times with TBST for 5 min each and visualized in ECL reagents (Amersham Amersham Bioscience Piscataway NJ 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72510 17150307 92736 20996 11179 SOD1 ALS ALS-like 36 2.2 Cashman et al. 1992 Bishop et al. 1999 and an ALS-like transgenic mouse model ( Gurney et al. 1994 were employed 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72511 17150307 92736 20996 11179 SOD1 ALS ALS 60 2.2 the role of GSH in motor neuron death associated with ALS disease onset and progression 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72512 17150307 92740 18723 10261 ROS1 ROS ROS 5 0.0 Results GSH depletion elevated cellular ROS production in NSC34 cells The DCF assay was applied to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72513 17150307 92740 18723 10261 ROS1 ROS ROS 20 0.0 The DCF assay was applied to measure the kinetics of ROS production in GSH depleted cells ( Wang and Joseph 1999 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72514 17150307 92742 18723 10261 ROS1 ROS ROS 14 0.0 intracellular GSH more effectively ( Figure 1 and promoted more ROS production ( Figure 2A than BSO ( Figure 2B 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72515 17150307 92746 10824 6204 JUN AP-1 AP-1 3 2.8 EA treatment enhanced AP-1 transcriptional activation as detected by a luciferase reporter gene assay 1 JUMiner_v2.2 1 0 0 2 6204 TotalCon:5<>3796|FOS|2353|Complete__3797|FOSB|2354|Complete__6204|JUN|3725|Complete__6205|JUNB|3726|Complete__6206|JUND|3727|Complete__<>AvaiableGeneRif=5<>BEST:6204|JUN|0.000645032050978163<>ScoreDetail__3796|FOS|0.000618551383058785__3797|FOSB|0.000580266731819423__6205|JUNB|0.000545089770551059__6204|JUN|0.000645032050978163__6206|JUND|0.000507183782798545__ 0 0 0 0 0 72516 17150307 92746 10824 6204 JUN c-Jun c-Jun 18 2.8 detected by a luciferase reporter gene assay ( Figure 3A c-Jun ( Figure 3B and c-Fos expression (data data not shown 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72517 17150307 92747 9462 5013 HMOX1 HO-1 HO-1 5 1.0 Similarly GSH depletion also increased HO-1 expression as detected by quantitative real-time PCR reaction and western 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72518 17150307 92755 480 8768 AIFM1 AIF AIF 4 0.6 Results GSH depletion promoted AIF redistribution cytochrome c release caspase 3 activation and apoptotic cell 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72519 17150307 92756 480 8768 AIFM1 AIF AIF 12 0.6 nuclear fractionations coupled with western analysis showed an increase of AIF translocation to nucleus following GSH depletion in NSC34 cells ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72520 17150307 92757 480 8768 AIFM1 AIF AIF 6 0.6 Immunohistochemical staining confirmed the increase of AIF translocation to the nucleus from the mitochondria upon GSH depletion 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72521 17150307 92764 20996 11179 SOD1 ALS ALS-like 22 2.2 mouse spinal cords was associated with motor neuron death and ALS-like disease onset and progression The well-established mutant G93A-SOD1 transgenic mouse 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72522 17150307 92764 20996 11179 SOD1 ALS ALS-like 35 2.2 and progression The well-established mutant G93A-SOD1 transgenic mouse model of ALS-like disease was used to analyze the levels of GSH in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72523 17150307 92764 20996 11179 SOD1 ALS ALS 49 2.2 to analyze the levels of GSH in the course of ALS disease onset and progression 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72524 17150307 92766 20996 11179 SOD1 ALS ALS-like 13 2.2 oxidized GSH (GSSG) GSSG levels were significantly increased during both ALS-like disease onset and progression ( Figure 8B and 8D 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72525 17150307 92768 20996 11179 SOD1 ALS ALS-like 19 2.2 G93A-SOD1 transgenic mouse motor neuron cells were decreased at both ALS-like disease onset and progression ( Figure 8E 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72526 17150307 92769 480 8768 AIFM1 AIF AIF 5 0.6 Decreased GSH was associated with AIF nuclear translocation caspase 3 activation and motor neuron cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72527 17150307 92769 20996 11179 SOD1 ALS ALS-like 21 2.2 activation and motor neuron cell death ( Figure 9 in ALS-like transgenic mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72528 17150307 92772 20996 11179 SOD1 ALS ALS 19 2.2 plays an important role in motor neuron degeneration leading to ALS disease onset and progression ( Hall et al. 1998 Tu 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72529 17150307 92775 20996 11179 SOD1 ALS ALS 34 2.2 a cell culture model and a mouse model recapitulating human ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72530 17150307 92778 480 8768 AIFM1 AIF AIF 8 0.6 Reduction in GSH was associated with redistribution of AIF from mitochondria to nuclei 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72531 17150307 92780 20996 11179 SOD1 ALS ALS 15 2.2 as an important factor associated with motor neuron degeneration in ALS by activation of multiple apoptotic pathways 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72532 17150307 92782 8204 4311 GCLC GCS GCS 7 0.0 BSO is an inhibitor of _amp_#x003b3 -glutamylcysteine synthetase (_amp_#x003b3;-GCS) _amp_#x003b3 -GCS which blocks GSH synthesis 11 JUMiner_v2.2 1 0 0 2 12524 TotalCon:2<>4311|GCLC|2729|Complete__12524|UGCG|7357|Complete__<>AvaiableGeneRif=2<>BEST:12524|UGCG|0.000797573098998761<>ScoreDetail__12524|UGCG|0.000797573098998761__4311|GCLC|0.000637308880421754__ 0 0 0 0 0 72533 17150307 92787 20996 11179 SOD1 ALS ALS-like 4 2.2 The lifespan of the ALS-like mice have been characterized into three stages namely disease free 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72534 17150307 92790 20996 11179 SOD1 ALS ALS 34 2.2 of intracellular GSH to motor neuron death (apoptosis) apoptosis in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72535 17150307 92793 8204 4311 GCLC GCS GCS 7 0.0 GSH is biosynthesized from L-glutamate catalyzed by _amp_#x003b3 -GCS and glutathione synthetase (GS) GS in the cytosol 11 JUMiner_v2.2 1 0 0 2 12524 TotalCon:2<>4311|GCLC|2729|Complete__12524|UGCG|7357|Complete__<>AvaiableGeneRif=2<>BEST:12524|UGCG|0.000797573098998761<>ScoreDetail__12524|UGCG|0.000797573098998761__4311|GCLC|0.000637308880421754__ 0 0 0 0 0 72536 17150307 92797 18723 10261 ROS1 ROS ROS 10 0.0 As shown in Figure 2 GSH reduction dramatically increased ROS generation as measured by the DCF assay 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72537 17150307 92798 10824 6204 JUN c-Jun c-Jun 13 2.8 depletion increased the expression of the early oxidative stress markers c-Jun c-Fos (data data not shown and AP-1 activation ( Figure 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72538 17150307 92798 10824 6204 JUN AP-1 AP-1 19 2.8 oxidative stress markers c-Jun c-Fos (data data not shown and AP-1 activation ( Figure 3 and secondary oxidative stress markers such 1 JUMiner_v2.2 1 0 0 2 6204 TotalCon:5<>3796|FOS|2353|Complete__3797|FOSB|2354|Complete__6204|JUN|3725|Complete__6205|JUNB|3726|Complete__6206|JUND|3727|Complete__<>AvaiableGeneRif=5<>BEST:6204|JUN|0.000645032050978163<>ScoreDetail__3796|FOS|0.000618551383058785__3797|FOSB|0.000580266731819423__6205|JUNB|0.000545089770551059__6204|JUN|0.000645032050978163__6206|JUND|0.000507183782798545__ 0 0 0 0 0 72539 17150307 92798 9462 5013 HMOX1 HO-1 HO-1 32 1.0 ( Figure 3 and secondary oxidative stress markers such as HO-1 expression ( Figure 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72540 17150307 92803 480 8768 AIFM1 AIF AIF 13 0.6 cell death mechanisms potentially induced by GSH depletion we assessed AIF redistribution and found that there was an increase in AIF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72541 17150307 92803 480 8768 AIFM1 AIF AIF 23 0.6 AIF redistribution and found that there was an increase in AIF translocation from mitochondria to nuclei upon GSH depletion ( Figure 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72542 17150307 92804 480 8768 AIFM1 AIF AIF 0 0.6 AIF is a flavoprotein residing in mitochondrial intermembrane ( Cande et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72543 17150307 92805 480 8768 AIFM1 AIF AIF 2 0.6 Translocation of AIF initiates cell apoptosis by cleavage internucleosomal DNA to relative large 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72544 17150307 92806 480 8768 AIFM1 AIF AIF 0 0.6 AIF nuclear translocation has been observed in a variety of cell 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72545 17150307 92807 480 8768 AIFM1 AIF AIF 1 0.6 The AIF redistribution detected in EA treated cells and also observed in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72546 17150307 92808 480 8768 AIFM1 AIF AIF 13 0.6 coupled with increased oxidative stress by mutant G93A-SOD1 that facilitates AIF nuclear translocation may underlie some of the events linked to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72547 17150307 92808 20996 11179 SOD1 ALS ALS 24 2.2 nuclear translocation may underlie some of the events linked to ALS disease onset and progression 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72548 17150307 92810 20996 11179 SOD1 ALS ALS-like 14 2.2 has also been shown to lead motor neuron degeneration in ALS-like mouse and human ALS patients ( Guegan et al. 2001 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72549 17150307 92810 20996 11179 SOD1 ALS ALS 18 2.2 to lead motor neuron degeneration in ALS-like mouse and human ALS patients ( Guegan et al. 2001 Li et al. 2000 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72550 17150307 92811 20996 11179 SOD1 ALS ALS-like 10 2.2 Discussion Decreased GSH is associated with motor neuron degeneration and ALS-like disease onset and progression in the G93A-SOD1 transgenic mouse model 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72551 17150307 92811 20996 11179 SOD1 ALS ALS 33 2.2 alterations of glutathione S-transferase pi activity have been reported in ALS patients ( Kuzma et al. 2006 Usarek et al. 2005 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72552 17150307 92812 20996 11179 SOD1 ALS ALS 10 2.2 Nevertheless the effects of GSH to motor neuron degeneration in ALS remains largely unknown even though abnormalities in GSH are associated 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72553 17150307 92814 20996 11179 SOD1 ALS ALS-like 13 2.2 of GSH and reciprocal increase of GSSG occurred in the ALS-like mice during the stages of disease progression 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72554 17150307 92817 20996 11179 SOD1 ALS ALS-like 4 2.2 More significantly treatment of ALS-like transgenic mice with antioxidants such as SOD and catalase mimetics 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72555 17150307 92817 20996 11179 SOD1 SOD SOD 11 2.2 significantly treatment of ALS-like transgenic mice with antioxidants such as SOD and catalase mimetics ( Jung et al. 2001 DMPO ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72556 17150307 92818 20996 11179 SOD1 ALS ALS 33 2.2 damage incurred by motor neurons and may therefore lead to ALS disease onset and progression 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72557 17150307 92824 20996 11179 SOD1 ALS ALS-like 19 2.2 a frequent phenomenon occurring in the spinal cord of G93A-SOD1 ALS-like mice that is temporally associated with disease onset and progression 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72558 17150307 92826 20996 11179 SOD1 ALS ALS 21 2.2 therapeutic approaches targeting to mitochondria at early stage for delay ALS disease onset and progression 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72559 17150307 92832 16315 30012 PDF PDF PDF 6 0.3 Footnotes Publisher's Disclaimer This is a PDF file of an unedited manuscript that has been accepted for 1 JUMiner_v2.2 1 2 pdf file 0 2 30012 TotalCon:3<>30012|PDF|64146|Complete__30142|GDF15|9518|Complete__8866|PFDN1|5201|Complete__<>AvaiableGeneRif=3<>BEST:30012|PDF|0.00113735551617425<>ScoreDetail__8866|PFDN1|0.000283898043572178__30142|GDF15|0.000578194553623238__30012|PDF|0.00113735551617425__ 0 0 0 0 0 72560 17150307 92837 18723 10261 ROS1 ROS ROS 8 0.0 Figure 2 GSH depletion enhances reactive oxygen species (ROS) ROS production in NSC34 cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72561 17150307 92844 480 8768 AIFM1 AIF AIF 4 0.6 Figure 9 Redistribution of AIF and active caspase 3 in motor neuron cells of ALS-like 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72562 17150307 92844 20996 11179 SOD1 ALS ALS-like 14 2.2 AIF and active caspase 3 in motor neuron cells of ALS-like mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72563 17150307 92846 480 8768 AIFM1 AIF AIF 0 0.6 AIF Apoptosis Inducing Factor ALS Amyotrophic Lateral Sclerosis BSO L-Buthionine Sulfoximine 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72564 17150307 92846 20996 11179 SOD1 ALS ALS 4 2.2 AIF Apoptosis Inducing Factor ALS Amyotrophic Lateral Sclerosis BSO L-Buthionine Sulfoximine DCF Dichlorofluorescin DMEM Dulbecco_amp_#x02019 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00127347925873815<>ScoreDetail__5468|IGFALS|0.000806860188017188__11179|SOD1|0.00127347925873815__ 0 0 0 0 0 72565 17150307 92846 20996 11179 SOD1 SOD1 SOD1 41 3.2 Oxidized Glutathione MBM Monobromobimane PFA Paraformaldehyde ROS Reactive Oxygen Species SOD1 Cu Zn-Superoxide Dismutase TUNEL Terminal Deoxynucleotidyl Transferase-Mediated Nick End Labeling 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 72566 17150307 92846 7361 20442 FBRS FBS FBS 21 0.0 DMEM Dulbecco_amp_#x02019 s Modified Eagle_amp_#x02019 s Medium EA Ethacrynic Acid FBS Fetal Bovine Serum _amp_#x003b3 -GCS _amp_#x003b3 -Glutamylcysteine Synthetase GSH Glutathione 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 72567 17150307 92846 8204 4311 GCLC GCS GCS 25 0.0 s Medium EA Ethacrynic Acid FBS Fetal Bovine Serum _amp_#x003b3 -GCS _amp_#x003b3 -Glutamylcysteine Synthetase GSH Glutathione GSSG Oxidized Glutathione MBM Monobromobimane 11 JUMiner_v2.2 1 0 0 2 12524 TotalCon:2<>4311|GCLC|2729|Complete__12524|UGCG|7357|Complete__<>AvaiableGeneRif=2<>BEST:12524|UGCG|0.000797573098998761<>ScoreDetail__12524|UGCG|0.000797573098998761__4311|GCLC|0.000637308880421754__ 0 0 0 0 0 72568 17150307 92846 18723 10261 ROS1 ROS ROS 37 0.0 Synthetase GSH Glutathione GSSG Oxidized Glutathione MBM Monobromobimane PFA Paraformaldehyde ROS Reactive Oxygen Species SOD1 Cu Zn-Superoxide Dismutase TUNEL Terminal Deoxynucleotidyl 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74189 17174478 95142 18723 10261 ROS1 ROS ROS 9 0.0 Proteins that control cellular levels of reactive oxygen species (ROS) ROS or DNA damage responses are essential to the nervous system 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74190 17174478 95143 18723 10261 ROS1 ROS ROS 6 0.0 This is because an imbalance of ROS may cause significant damage to the cell which often produces 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74191 17174478 95148 18723 10261 ROS1 ROS ROS 2 0.0 Responses to ROS and DNA damage have many critical links to neuroscience 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74192 17174478 95149 18723 10261 ROS1 ROS ROS 8 0.0 The damage from stroke is likely linked to ROS with resulting damage to membrane components proteins and DNA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74193 17174478 95154 18723 10261 ROS1 ROS ROS 3 0.0 Defects in either ROS controlling enzymes or DNA double-strand break (DSB) DSB repair genes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74194 17174478 95157 18723 10261 ROS1 ROS ROS 11 0.0 the emerging knowledge of mutations and polymorphisms in key human ROS and DNA repair genes may provide an informed basis for 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74195 17174478 95159 18723 10261 ROS1 ROS ROS 15 0.0 important gains in our knowledge of the cellular mechanisms controlling ROS and DNA repair events through insights provided by structural biochemistry 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74196 17174478 95160 18723 10261 ROS1 ROS ROS 12 0.0 the known roles disease phenotypes and molecular mechanisms of key ROS and DNA repair proteins within the nervous system 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74197 17174478 95162 18723 10261 ROS1 ROS ROS 17 0.0 provide a more unified understanding of molecular survival mechanisms from ROS and DNA damaging insults 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74198 17174478 95166 16315 30012 PDF PDF PDF 6 0.6 Footnotes Publisher's Disclaimer This is a PDF file of an unedited manuscript that has been accepted for 1 JUMiner_v2.2 1 2 pdf file 0 2 30012 TotalCon:3<>30012|PDF|64146|Complete__30142|GDF15|9518|Complete__8866|PFDN1|5201|Complete__<>AvaiableGeneRif=3<>BEST:30012|PDF|0.000818341494571003<>ScoreDetail__8866|PFDN1|0.000403626428216592__30142|GDF15|0.000355705901713305__30012|PDF|0.000818341494571003__ 0 0 0 0 0 74199 17174478 95170 20997 11180 SOD2 MnSOD MnSOD 4 1.9 Fig 1 The Human MnSOD active site 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74200 17174478 95171 20997 11180 SOD2 MnSOD MnSOD 4 1.9 In the wild type MnSOD structure (PDB PDB code 1N0J the His26 His74 His163 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74201 17174478 95171 16266 8757 PDB1 PDB PDB 6 0.3 In the wild type MnSOD structure (PDB PDB code 1N0J the His26 His74 His163 and Asp159 side chains 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74202 17174478 95173 14533 7872 NOS1 NOS NOS 4 2.7 Fig 2 Proposed holo -NOS 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74203 17174478 95174 14533 7872 NOS1 nNOS nNOS 5 2.7 a The modular structure of nNOS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74204 17174478 95175 14533 7872 NOS1 nNOS nNOS 8 2.7 This schematic representation shows the domain organization of nNOS indicated above the regions binding the substrate and cofactors below 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74205 17174478 95176 14533 7872 NOS1 NOS NOS 4 2.7 Fig 3 Proposed holo -NOS assembly and domain movements 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74206 17174478 95177 14533 7872 NOS1 NOS NOS 7 2.7 a Three possible models for dimeric holo -NOS dimeric NOSox and NOSred modules are represented by pairs of 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74207 17174478 95178 7638 3768 FMN1 FMN FMN 1 0.0 The FMN domain is shown as a yellow box 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74208 17174478 95184 17886 9816 RAD50 RAD50 Rad50 5 0.6 b DNA binding straightens the Rad50 coiled coils which favors inter-complex tethering via Rad50 Zn-hooks with 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74209 17174478 95184 17886 9816 RAD50 RAD50 Rad50 13 0.6 straightens the Rad50 coiled coils which favors inter-complex tethering via Rad50 Zn-hooks with extended and parallel (more more ... 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74210 17174478 95185 24250 12791 WRN WRN WRN 2 3.5 Fig 6 WRN exonuclease structure and hexameric ring model 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74211 17174478 95186 24250 12791 WRN WRN WRN 1 3.5 a WRN protein is modular composed of an N-terminal exnuclease domain (blue), 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74212 17174478 95187 24250 12791 WRN WRN WRN 2 3.5 b The WRN exonuclease (more more ... 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74213 17174478 95188 6736 3435 ERCC3 XPB XPB 2 2.4 Fig 7 XPB conserved motifs and structural architecture 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74214 17174478 95189 6736 3435 ERCC3 XPB XPB 5 2.4 a Schematic alignment between Af XPB Af and human XPB Hs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74215 17174478 95189 6736 3435 ERCC3 XPB XPB 9 2.4 a Schematic alignment between Af XPB Af and human XPB Hs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74216 17174478 95190 6277 3094 DYRK3 RED RED 6 0.0 The conserved helicase motifs I-VI and RED are colored by bars the N-terminal DRD and ThM domains 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>3094|DYRK3|8444|Complete__5958|IK|3550|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 74217 17174478 95190 22116 11792 THM THM ThM 15 0.0 and RED are colored by bars the N-terminal DRD and ThM domains are colored by boxes 14 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 74218 17174478 95192 6736 3435 ERCC3 XPB XPB 9 2.4 Fig 8 Proposed structure-based mechanism whereby damage verification by XPB promotes unwinding of damaged dsDNA for NER 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74219 17174478 95192 14635 7965 NR1H2 NER NER 16 1.3 damage verification by XPB promotes unwinding of damaged dsDNA for NER 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74220 17174478 95193 6736 3435 ERCC3 XPB XPB 5 2.4 a Schematic model shows how XPB DRD depicted in blue HD1 cyan RED motif red HD2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74221 17174478 95193 9122 4852 HDAC1 HD1 HD1 10 0.3 a Schematic model shows how XPB DRD depicted in blue HD1 cyan RED motif red HD2 green and ThM purple may 1 JUMiner_v2.2 1 2 UserEdit 0 2 9069 TotalCon:2<>4852|HDAC1|3065|Complete__9069|PLEC1|5339|Complete__<>AvaiableGeneRif=2<>BEST:9069|PLEC1|0.000743006237796555<>ScoreDetail__9069|PLEC1|0.000743006237796555__4852|HDAC1|0.000271388197420876__ 1 1 0 0 0 74222 17174478 95193 6277 3094 DYRK3 RED RED 12 0.1 model shows how XPB DRD depicted in blue HD1 cyan RED motif red HD2 green and ThM purple may be activated 6 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>3094|DYRK3|8444|Complete__5958|IK|3550|No_GeneRif__<>AvaiableGeneRif=1<> 1 1 0 0 0 74223 17174478 95193 22116 11792 THM THM ThM 18 0.0 in blue HD1 cyan RED motif red HD2 green and ThM purple may be activated by dsDNA (more more ... 14 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 74224 17174478 95194 6736 3435 ERCC3 XPB XPB 1 2.4 Af XPB Archaeoglobus fulgidus XPB AH auto-inhibitory helix ATLD ataxiatelangiectasia-like disorder BER 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74225 17174478 95194 6736 3435 ERCC3 XPB XPB 4 2.4 Af XPB Archaeoglobus fulgidus XPB AH auto-inhibitory helix ATLD ataxiatelangiectasia-like disorder BER base excision repair 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74226 17174478 95194 13444 7230 MRE11A ATLD ATLD 8 2.3 Af XPB Archaeoglobus fulgidus XPB AH auto-inhibitory helix ATLD ataxiatelangiectasia-like disorder BER base excision repair CS Cockayne syndrome CD 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74227 17174478 95194 1755 1101 BRCA2 FAD FAD 31 0.8 CT C-terminal tail DRD damage recognition domain DSBs double-strand breaks FAD flavin adenine dinucleotide (F)ALS F ALS (Familial) Familial amyotrophic lateral 1 JUMiner_v2.2 1 2 nadph 0 2 3585 TotalCon:3<>1101|BRCA2|675|Complete__3585|FANCD2|2177|Complete__9508|PSEN1|5663|Complete__<>AvaiableGeneRif=3<>BEST:3585|FANCD2|0.000968810183662925<>ScoreDetail__1101|BRCA2|0.000307126255127774__9508|PSEN1|0.000428328502098994__3585|FANCD2|0.000968810183662925__ 0 0 0 0 0 74228 17174478 95194 20996 11179 SOD1 ALS ALS 35 2.9 domain DSBs double-strand breaks FAD flavin adenine dinucleotide (F)ALS F ALS (Familial) Familial amyotrophic lateral sclerosis FMN flavin mononucleotide GG-NER global 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000921146267190215<>ScoreDetail__5468|IGFALS|0.000205613241492752__11179|SOD1|0.000921146267190215__ 0 0 0 0 0 74229 17174478 95194 9122 4852 HDAC1 HD1 HD1 49 0.3 sclerosis FMN flavin mononucleotide GG-NER global genome nucleotide excision repair HD1 and HD2 helicase domains 1 and 2 HR homologous recombination 1 JUMiner_v2.2 1 2 UserEdit 0 2 9069 TotalCon:2<>4852|HDAC1|3065|Complete__9069|PLEC1|5339|Complete__<>AvaiableGeneRif=2<>BEST:9069|PLEC1|0.000743006237796555<>ScoreDetail__9069|PLEC1|0.000743006237796555__4852|HDAC1|0.000271388197420876__ 1 1 0 0 0 74230 17174478 95194 13444 7230 MRE11A MRE11 Mre11 74 2.3 helicase RNase D conserved domain MMR mismatch repair MRN Mre11/Rad50/Nbs1 Mre11 Rad50 Nbs1 mtDNA mitochondrial DNA NER nucleotide excision repair NO 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74231 17174478 95194 17886 9816 RAD50 RAD50 Rad50 74 0.6 RNase D conserved domain MMR mismatch repair MRN Mre11/Rad50/Nbs1 Mre11 Rad50 Nbs1 mtDNA mitochondrial DNA NER nucleotide excision repair NO nitric 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74232 17174478 95194 14453 22948 NLRP2 NBS1 Nbs1 74 1.3 D conserved domain MMR mismatch repair MRN Mre11/Rad50/Nbs1 Mre11 Rad50 Nbs1 mtDNA mitochondrial DNA NER nucleotide excision repair NO nitric oxide 2 JUMiner_v2.2 1 0 0 2 7652 TotalCon:2<>7652|NBN|4683|Complete__22948|NLRP2|55655|Complete__<>AvaiableGeneRif=2<>BEST:7652|NBN|0.00139471313639611<>ScoreDetail__22948|NLRP2|0.000579150579150579__7652|NBN|0.00139471313639611__ 0 0 0 0 0 74233 17174478 95194 14635 7965 NR1H2 NER NER 78 1.3 mismatch repair MRN Mre11/Rad50/Nbs1 Mre11 Rad50 Nbs1 mtDNA mitochondrial DNA NER nucleotide excision repair NO nitric oxide e i or nNOS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74234 17174478 95194 14533 7872 NOS1 nNOS nNOS 88 2.7 NER nucleotide excision repair NO nitric oxide e i or nNOS endothelial inducible or neuronal nitric oxide synthase NOSox NOS catalytic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74235 17174478 95194 14533 7872 NOS1 NOS NOS 97 2.7 or nNOS endothelial inducible or neuronal nitric oxide synthase NOSox NOS catalytic oxygenase module NOSred NOS reductase module NHEJ nonhomologous end 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74236 17174478 95194 14533 7872 NOS1 NOS NOS 102 2.7 neuronal nitric oxide synthase NOSox NOS catalytic oxygenase module NOSred NOS reductase module NHEJ nonhomologous end joining ROS reactive oxygen species 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74237 17174478 95194 20996 11179 SOD1 SOD SOD 113 3.4 reductase module NHEJ nonhomologous end joining ROS reactive oxygen species SOD superoxide dismutase SSBs single-strand breaks TC-NER transcription-coupled nucleotide excision repair 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74238 17174478 95194 21298 11316 SSB SSB SSBs 116 0.3 nonhomologous end joining ROS reactive oxygen species SOD superoxide dismutase SSBs single-strand breaks TC-NER transcription-coupled nucleotide excision repair ThM thumb domain 13 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74239 17174478 95194 8901 21157 GTF2H5 TTD TTD 127 1.2 single-strand breaks TC-NER transcription-coupled nucleotide excision repair ThM thumb domain TTD trichothiodystropy WS Werner syndrome XP xeroderma pigmentosum 1 JUMiner_v2.2 1 2 UserEdit 0 2 21157 TotalCon:2<>21157|GTF2H5|404672|Complete__3434|ERCC2|2068|Complete__<>AvaiableGeneRif=2<>BEST:21157|GTF2H5|0.00104353482027836<>ScoreDetail__21157|GTF2H5|0.00104353482027836__3434|ERCC2|0.000283645881010553__ 1 1 0 0 0 74240 17174478 95194 7638 3768 FMN1 FMN FMN 40 0.0 adenine dinucleotide (F)ALS F ALS (Familial) Familial amyotrophic lateral sclerosis FMN flavin mononucleotide GG-NER global genome nucleotide excision repair HD1 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74241 17174478 95194 18723 10261 ROS1 ROS ROS 109 0.0 oxygenase module NOSred NOS reductase module NHEJ nonhomologous end joining ROS reactive oxygen species SOD superoxide dismutase SSBs single-strand breaks TC-NER 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74242 17174478 95194 22116 11792 THM THM ThM 124 0.0 superoxide dismutase SSBs single-strand breaks TC-NER transcription-coupled nucleotide excision repair ThM thumb domain TTD trichothiodystropy WS Werner syndrome XP xeroderma pigmentosum 14 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 74243 17174478 95195 18723 10261 ROS1 ROS ROS 0 0.0 ROS Removal by Manganese Superoxide Dismutase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74244 17174478 95196 18723 10261 ROS1 ROS ROS 13 0.0 activity of post-mitotic neuronal cells typically produces significant quantities of ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74245 17174478 95197 18723 10261 ROS1 ROS ROS 7 0.0 However neurons are also relatively sensitive to ROS and neurodegenerative disorders including amyotrophic lateral sclerosis Alzheimer disease and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74246 17174478 95197 18723 10261 ROS1 ROS ROS 27 0.0 and Parkinson disease have been linked to damage caused by ROS ( Andersen 2004 90 % of the ROS in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74247 17174478 95197 18723 10261 ROS1 ROS ROS 36 0.0 caused by ROS ( Andersen 2004 90 % of the ROS in the cell are generated by mitochondria as the toxic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74248 17174478 95198 20996 11179 SOD1 SOD SOD 15 3.4 rapidly scavenged in the cell by the superoxide dismutase (SOD) SOD enzymes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74249 17174478 95199 20996 11179 SOD1 SOD SOD 0 3.4 SOD enzymes catalyze the disproportionation of superoxide anion radicals to molecular 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74250 17174478 95199 18723 10261 ROS1 ROS ROS 25 0.0 and are the enzymes that provide the master controls for ROS levels in the cell ( Silverman and Nick 2002 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74251 17174478 95200 20996 11179 SOD1 SOD SOD 4 3.4 The important role of SOD in the brain was highlighted by genetic inactivation of the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74252 17174478 95200 20996 11179 SOD1 SOD SOD 18 3.4 was highlighted by genetic inactivation of the mitochondrial form of SOD manganese SOD (MnSOD), MnSOD in mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74253 17174478 95200 20996 11179 SOD1 SOD SOD 20 3.4 by genetic inactivation of the mitochondrial form of SOD manganese SOD (MnSOD), MnSOD in mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74254 17174478 95200 20997 11180 SOD2 MnSOD MnSOD 21 1.9 inactivation of the mitochondrial form of SOD manganese SOD (MnSOD), MnSOD in mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74255 17174478 95202 20996 11179 SOD1 SOD SOD 3 3.4 Treatment with an SOD mimetic MnTBAP rescued the MnSOD _amp_#x02212;/_amp_#x02212; _amp_#x02212 _amp_#x02212 mutant mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74256 17174478 95202 20997 11180 SOD2 MnSOD MnSOD 8 1.9 Treatment with an SOD mimetic MnTBAP rescued the MnSOD _amp_#x02212;/_amp_#x02212; _amp_#x02212 _amp_#x02212 mutant mice from this systemic pathology and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74257 17174478 95206 20997 11180 SOD2 MnSOD MnSOD 34 1.9 of ROS ( Melov et al. 1998 normally removed by MnSOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74258 17174478 95206 18723 10261 ROS1 ROS ROS 24 0.0 barrier progressive neuropathology is caused by excessive mitochondrial production of ROS ( Melov et al. 1998 normally removed by MnSOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74259 17174478 95207 20997 11180 SOD2 MnSOD MnSOD 3 1.9 To define how MnSOD controls ROS levels in the cell the molecular mechanism of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74260 17174478 95207 20997 11180 SOD2 MnSOD MnSOD 14 1.9 controls ROS levels in the cell the molecular mechanism of MnSOD has been extensively characterized through combined structural and biochemical studies 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74261 17174478 95207 18723 10261 ROS1 ROS ROS 5 0.1 To define how MnSOD controls ROS levels in the cell the molecular mechanism of MnSOD has 6 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 74262 17174478 95208 20997 11180 SOD2 MnSOD MnSOD 5 1.9 The crystal structure of human MnSOD revealed that the enzyme forms a homotetramer ( Borgstahl et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74263 17174478 95216 18723 10261 ROS1 ROS ROS 0 0.0 ROS Removal by Manganese Superoxide Dismutase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74264 17174478 95220 10965 21302 KCTD11 REN Ren 48 0.3 al. 2003 Hearn et al. 2004 Ayala et al. 2005a Ren et al. 2006 2 JUMiner_v2.2 1 2 34 0 2 9958 TotalCon:2<>9958|REN|5972|Complete__21302|KCTD11|147040|Complete__<>AvaiableGeneRif=2<>BEST:9958|REN|0.000348036476140382<>ScoreDetail__21302|KCTD11|0.000290391864644516__9958|REN|0.000348036476140382__ 0 0 0 0 0 74265 17174478 95226 20997 11180 SOD2 MnSOD MnSOD 18 1.9 suggests that maintenance of the correct hydrogen bond partners in MnSOD is essential for the highly tuned reactivity of the active 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74266 17174478 95226 18723 10261 ROS1 ROS ROS 33 0.0 highly tuned reactivity of the active site functioning to minimize ROS damage to the brain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74267 17174478 95227 18723 10261 ROS1 ROS ROS 0 0.0 ROS and Copper Zinc Superoxide Dismutase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74268 17174478 95228 20996 11179 SOD1 ALS ALS 13 2.9 common neurological disorders in humans is amyotrophic lateral sclerosis (ALS ALS or Lou Gehrig's disease which affects approximately 1 in 200 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000921146267190215<>ScoreDetail__5468|IGFALS|0.000205613241492752__11179|SOD1|0.000921146267190215__ 0 0 0 0 0 74269 17174478 95230 20996 11179 SOD1 ALS ALS 19 2.9 5_amp_#x02013 10% of cases which is referred to as familial ALS (FALS)( FALS Cleveland and Rothstein 2001 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000921146267190215<>ScoreDetail__5468|IGFALS|0.000205613241492752__11179|SOD1|0.000921146267190215__ 0 0 0 0 0 74270 17174478 95232 20996 11179 SOD1 SOD1 SOD1 6 2.9 However mutations in the superoxide dismutase1 (SOD1) SOD1 gene give rise to approximately 20% of FALS cases ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74271 17174478 95232 622 443 ALS2 ALS2 ALS2 39 1.8 et al. 2002 while mutations in several other genes including ALS2 SETX or VAPB cause much rarer forms of FALS ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74272 17174478 95232 19760 445 SETX SETX SETX 40 0.3 al. 2002 while mutations in several other genes including ALS2 SETX or VAPB cause much rarer forms of FALS ( Kunst 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74273 17174478 95232 23868 12649 VAPB VAPB VAPB 42 0.3 while mutations in several other genes including ALS2 SETX or VAPB cause much rarer forms of FALS ( Kunst 2004 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74274 17174478 95233 20996 11179 SOD1 SOD1 SOD1 0 2.9 SOD1 encodes a cytosolic copper zinc superoxide dismutase (Cu,Zn Cu Zn 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74275 17174478 95233 20996 11179 SOD1 SOD SOD 8 3.4 encodes a cytosolic copper zinc superoxide dismutase (Cu,Zn Cu Zn SOD which similar to the mitochondrial MnSOD is responsible for the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74276 17174478 95233 20997 11180 SOD2 MnSOD MnSOD 14 1.9 dismutase (Cu,Zn Cu Zn SOD which similar to the mitochondrial MnSOD is responsible for the disproportionation of harmful superoxide radicals to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74277 17174478 95234 20996 11179 SOD1 SOD SOD 5 3.4 Structural studies on human Cu Zn SOD have revealed that the enzyme is composed of two identical 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74278 17174478 95236 20996 11179 SOD1 SOD1 SOD1 3 2.9 A multitude of SOD1 mutations have been identified in FALS patients ( Gaudette et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74279 17174478 95237 20996 11179 SOD1 SOD SOD 10 3.4 The mutations are dispersed throughout the 153 amino acid residue SOD polypeptide ( Deng et al. 1993 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74280 17174478 95239 20996 11179 SOD1 SOD SOD 13 3.4 data support the idea that toxicity of intracellular Cu Zn SOD aggregates may result from protein misfolding or impaired protein degradation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74281 17174478 95241 20996 11179 SOD1 ALS ALS 12 2.9 been observed in both mouse and cell culture models of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000921146267190215<>ScoreDetail__5468|IGFALS|0.000205613241492752__11179|SOD1|0.000921146267190215__ 0 0 0 0 0 74282 17174478 95242 20996 11179 SOD1 SOD SOD 12 3.4 found in the cytoplasm are strongly immunoreactive to Cu Zn SOD antibodies and cannot be dissociated with strong detergents or reducing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74283 17174478 95243 20996 11179 SOD1 ALS ALS 5 2.9 Furthermore in transgenic mice the ALS aggregates can be detected biochemically months before the onset of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000921146267190215<>ScoreDetail__5468|IGFALS|0.000205613241492752__11179|SOD1|0.000921146267190215__ 0 0 0 0 0 74284 17174478 95244 20996 11179 SOD1 SOD SOD-mediated 6 2.9 One proposed mechanism of FALS mutant SOD-mediated toxicity is the coprecipitation of mutant Cu Zn SOD with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74285 17174478 95244 20996 11179 SOD1 SOD SOD 14 3.4 mutant SOD-mediated toxicity is the coprecipitation of mutant Cu Zn SOD with essential cellular components ( Bruijn et al. 1998 Johnston 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74286 17174478 95244 20996 11179 SOD1 SOD SOD 45 3.4 and this has been demonstrated with the copper chaperone for SOD (CCS)( CCS Kato et al. 2001 nitric oxide synthase (NOS) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74287 17174478 95244 3838 1613 CCS CCS CCS 46 1.2 has been demonstrated with the copper chaperone for SOD (CCS)( CCS Kato et al. 2001 nitric oxide synthase (NOS) NOS and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74288 17174478 95244 14533 7872 NOS1 NOS NOS 55 2.7 (CCS)( CCS Kato et al. 2001 nitric oxide synthase (NOS) NOS and phosphorylated neurofilaments ( Chou et al. 1996 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74289 17174478 95245 20996 11179 SOD1 SOD SOD 11 3.4 is not entirely clear how the many different Cu Zn SOD single-site mutations which are widely dispersed throughout the protein sequence 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74290 17174478 95246 20996 11179 SOD1 SOD SOD 15 3.4 combined structural biochemical and biophysical characterizations of two FALS mutant SOD proteins ( DiDonato et al. 2003 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74291 17174478 95247 20996 11179 SOD1 SOD SOD 11 3.4 two FALS proteins represent the two major structural classes of SOD mutations 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74292 17174478 95253 926 620 APP amyloid amyloid-like 28 1.0 post-mortem studies of FALS patients and bind dyes that detect amyloid-like structure 11 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 74293 17174478 95256 18723 10261 ROS1 ROS ROS 8 0.0 The catalase protein completes the process of eliminating ROS by converting hydrogen peroxide into water and oxygen 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74294 17174478 95271 18723 10261 ROS1 ROS ROS 0 0.0 ROS and Nitric Oxide Synthase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74295 17174478 95277 14533 7872 NOS1 NOS NOS 23 2.7 at the synthesis level by the nitric oxide synthase (NOS) NOS enzymes 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74296 17174478 95278 14533 7872 NOS1 NOS NOS 1 2.7 The NOS enzymes produce NO through the conversion of arginine to citrulline 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74297 17174478 95279 14533 7872 NOS1 NOS NOS 5 2.7 In mammals there are three NOS isoforms which have been named after the activity or tissue 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74298 17174478 95280 14533 7872 NOS1 NOS NOS 1 2.7 These NOS isoforms are neuronal NOS (nNOS), nNOS endothelial NOS (eNOS) eNOS 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74299 17174478 95280 14533 7872 NOS1 NOS NOS 5 2.7 These NOS isoforms are neuronal NOS (nNOS), nNOS endothelial NOS (eNOS) eNOS and inducible NOS (iNOS) 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74300 17174478 95280 14533 7872 NOS1 nNOS nNOS 6 2.7 These NOS isoforms are neuronal NOS (nNOS), nNOS endothelial NOS (eNOS) eNOS and inducible NOS (iNOS) iNOS nNOS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74301 17174478 95280 14533 7872 NOS1 NOS NOS 8 2.7 These NOS isoforms are neuronal NOS (nNOS), nNOS endothelial NOS (eNOS) eNOS and inducible NOS (iNOS) iNOS nNOS and eNOS 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74302 17174478 95280 14538 7876 NOS3 eNOS eNOS 9 2.2 NOS isoforms are neuronal NOS (nNOS), nNOS endothelial NOS (eNOS) eNOS and inducible NOS (iNOS) iNOS nNOS and eNOS are constitutively 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74303 17174478 95280 14533 7872 NOS1 NOS NOS 12 2.7 neuronal NOS (nNOS), nNOS endothelial NOS (eNOS) eNOS and inducible NOS (iNOS) iNOS nNOS and eNOS are constitutively expressed isozymes controlling 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74304 17174478 95280 14535 7873 NOS2A iNOS iNOS 13 2.7 (nNOS), nNOS endothelial NOS (eNOS) eNOS and inducible NOS (iNOS) iNOS nNOS and eNOS are constitutively expressed isozymes controlling basal NO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74305 17174478 95280 14533 7872 NOS1 nNOS nNOS 14 2.7 nNOS endothelial NOS (eNOS) eNOS and inducible NOS (iNOS) iNOS nNOS and eNOS are constitutively expressed isozymes controlling basal NO levels 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74306 17174478 95280 14538 7876 NOS3 eNOS eNOS 16 2.2 NOS (eNOS) eNOS and inducible NOS (iNOS) iNOS nNOS and eNOS are constitutively expressed isozymes controlling basal NO levels and synthesizing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74307 17174478 95280 14535 7873 NOS2A iNOS iNOS 36 2.7 synthesizing NO in response to increases in intracellular calcium levels iNOS is expressed in response to specific cytokines growth factors or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74308 17174478 95281 14533 7872 NOS1 NOS NOS 1 2.7 Functional NOS isozymes are homodimers and each isozyme subunit contains an N-terminal 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74309 17174478 95284 14533 7872 NOS1 NOS NOS 16 2.7 two tetrahydrobiopterin cofactors and a zinc ion that stabilize the NOS dimer interface ( Crane et al. 1998 Raman et al. 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74310 17174478 95286 1755 1101 BRCA2 FAD FAD 21 0.8 domain with the aid of one flavin adenine dinucleotide (FAD) FAD and one flavin mononucleotide (FMN) FMN moiety 1 JUMiner_v2.2 1 2 nadph 0 2 3585 TotalCon:3<>1101|BRCA2|675|Complete__3585|FANCD2|2177|Complete__9508|PSEN1|5663|Complete__<>AvaiableGeneRif=3<>BEST:3585|FANCD2|0.000968810183662925<>ScoreDetail__1101|BRCA2|0.000307126255127774__9508|PSEN1|0.000428328502098994__3585|FANCD2|0.000968810183662925__ 0 0 0 0 0 74311 17174478 95286 7638 3768 FMN1 FMN FMN 26 0.0 flavin adenine dinucleotide (FAD) FAD and one flavin mononucleotide (FMN) FMN moiety 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74312 17174478 95288 5353 2615 CYP2B6 P450 P450 10 1.9 NOSred belongs to a large protein family including NADPH-dependent cytochrome P450 reductase and sulfite reductase flavoprotein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74313 17174478 95289 1755 1101 BRCA2 FAD FAD-binding 9 0.8 _amp_#x003b1 -helical connecting domain (CD) CD orients flanking FMN- and FAD-binding domains to align the two flavins ( Wang et al. 1 JUMiner_v2.2 1 2 nadph 0 2 3585 TotalCon:3<>1101|BRCA2|675|Complete__3585|FANCD2|2177|Complete__9508|PSEN1|5663|Complete__<>AvaiableGeneRif=3<>BEST:3585|FANCD2|0.000968810183662925<>ScoreDetail__1101|BRCA2|0.000307126255127774__9508|PSEN1|0.000428328502098994__3585|FANCD2|0.000968810183662925__ 0 0 0 0 0 74314 17174478 95289 7638 3768 FMN1 FMN FMN- 7 0.1 An _amp_#x003b1 -helical connecting domain (CD) CD orients flanking FMN- and FAD-binding domains to align the two flavins ( Wang 6 JUMiner_v2.2 1 2 flavin mononucleotide 0 0 0 0 0 0 0 0 74315 17174478 95290 1755 1101 BRCA2 FAD FAD 7 0.8 Electron transfer proceeds from NADPH to the FAD to FMN and then to the oxygenase heme ( Adak 1 JUMiner_v2.2 1 2 nadph 0 2 3585 TotalCon:3<>1101|BRCA2|675|Complete__3585|FANCD2|2177|Complete__9508|PSEN1|5663|Complete__<>AvaiableGeneRif=3<>BEST:3585|FANCD2|0.000968810183662925<>ScoreDetail__1101|BRCA2|0.000307126255127774__9508|PSEN1|0.000428328502098994__3585|FANCD2|0.000968810183662925__ 0 0 0 0 0 74316 17174478 95290 7638 3768 FMN1 FMN FMN 9 0.1 Electron transfer proceeds from NADPH to the FAD to FMN and then to the oxygenase heme ( Adak et al. 6 JUMiner_v2.2 1 2 flavin mononucleotide 0 0 0 0 0 0 0 0 74317 17174478 95293 18723 10261 ROS1 ROS ROS 0 0.0 ROS and Nitric Oxide Synthase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74318 17174478 95294 14533 7872 NOS1 nNOS nNOS 11 2.7 biochemistry data elucidated from a fully assembled reductase dimer of nNOS ( Fig 2b c provided critical insights into this domain's 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74319 17174478 95295 14533 7872 NOS1 NOS NOS 16 2.7 regulatory element the C-terminal tail and phosphorylation function to regulate NOS activity which is exquisitely tuned to control NO production ( 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74320 17174478 95296 7638 3768 FMN1 FMN FMN-binding 14 0.0 C-terminal tail (CT) CT represses electron transfer by locking the FMN-binding domain in the electron-accepting position 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74321 17174478 95297 14538 7876 NOS3 eNOS eNOS 2 2.2 In addition eNOS and nNOS contain the 42_amp_#x02013 45-residue auto-inhibitory helix (AH) AH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74322 17174478 95297 14533 7872 NOS1 nNOS nNOS 4 2.7 In addition eNOS and nNOS contain the 42_amp_#x02013 45-residue auto-inhibitory helix (AH) AH within the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74323 17174478 95297 7638 3768 FMN1 FMN FMN-binding 13 0.0 contain the 42_amp_#x02013 45-residue auto-inhibitory helix (AH) AH within the FMN-binding domain which interferes with Ca 2 /CaM CaM binding and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74324 17174478 95298 14538 7876 NOS3 eNOS eNOS 16 2.2 of a protruding _amp_#x003b2 -finger present in the CD of eNOS and nNOS plays an autoinhibitory role in the control of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74325 17174478 95298 14533 7872 NOS1 nNOS nNOS 18 2.7 protruding _amp_#x003b2 -finger present in the CD of eNOS and nNOS plays an autoinhibitory role in the control of NO by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74326 17174478 95299 14538 7876 NOS3 eNOS eNOS 3 2.2 The upregulation of eNOS and nNOS activity is controlled by phosphorylation of both the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74327 17174478 95299 14533 7872 NOS1 nNOS nNOS 5 2.7 The upregulation of eNOS and nNOS activity is controlled by phosphorylation of both the CT and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74328 17174478 95300 14533 7872 NOS1 NOS NOS 6 2.7 An experimentally determined structure of full-length NOS remains elusive perhaps due to the required flexibility of its 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74329 17174478 95301 14533 7872 NOS1 nNOS nNOS 19 2.7 dimer provided a template for a model of the holo -nNOS enzyme assembly ( Garcin et al. 2004 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74330 17174478 95302 14533 7872 NOS1 NOS NOS 1 2.7 The NOS model was built by connecting the dimeric NOSox modules and 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74331 17174478 95302 14533 7872 NOS1 NOS NOS-peptide 14 2.7 built by connecting the dimeric NOSox modules and a CaM NOS-peptide complex ( Aoyagi et al. 2003 to the NOSred structure 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74332 17174478 95306 7638 3768 FMN1 FMN FMN 5 0.0 The shortest distance between the FMN and heme cofactors is 70 _amp_#x0212b in this model which 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74333 17174478 95307 7638 3768 FMN1 FMN FMN 11 0.0 the structural biochemical and modeling results indicate that the entire FMN domain serves as a one-electron shuttle by swinging back and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74334 17174478 95308 14533 7872 NOS1 NOS NOS 5 2.7 The flexible hinge region in NOS would serve as the pivot point for this motion ( 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74335 17174478 95310 14533 7872 NOS1 NOS NOS 17 2.7 account for the slow rate of inter-module electron transfer in NOS 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74336 17174478 95310 7638 3768 FMN1 FMN FMN 3 0.0 Additionally this swinging FMN domain mechanism would account for the slow rate of inter-module 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74337 17174478 95311 14533 7872 NOS1 NOS NOS 2 2.7 The dimerization NOS would provide a means for fine-tuning this electron transfer mechanism 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74338 17174478 95311 7638 3768 FMN1 FMN FMN 20 0.0 electron transfer mechanism where the two redox partners of the FMN shuttles are located on adjacent polypeptides 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74339 17174478 95312 7638 3768 FMN1 FMN FMN-binding 29 0.0 would displace the repressive C-terminal tail and thereby unlock the FMN-binding domain for shuttling 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74340 17174478 95313 18723 10261 ROS1 ROS ROS 0 0.0 ROS and Nitric Oxide Synthase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74341 17174478 95314 18723 10261 ROS1 ROS ROS 0 0.0 ROS and Pathogens 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74342 17174478 95315 18723 10261 ROS1 ROS ROS 5 0.0 Pathogens are likely to amplify ROS damage in the CNS during pathogenesis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74343 17174478 95320 23898 12669 VDAC1 PORIN porin 19 1.6 substantial sequence conservation with N meningitides acts cooperatively with a porin to induce calcium ion transients in infected epithelial cells ( 14 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74344 17174478 95321 14533 7872 NOS1 NOS NOS 28 2.7 Koedel and Pfister 1999 through the calcium-mediated activation of neuronal NOS ( Aoyagi et al. 2003 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74345 17174478 95321 18723 10261 ROS1 ROS ROS 14 0.0 by pathogen invasion in neuronal cells is expected to increase ROS stress ( Koedel and Pfister 1999 through the calcium-mediated activation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74346 17174478 95322 18723 10261 ROS1 ROS ROS 7 0.0 Therefore a combination of factors may exacerbate ROS production and provide increased risk of damage to the brain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74347 17174478 95324 14533 7872 NOS1 NOS NOS 17 2.7 accentuated by NO used in signaling and by stimulation of NOS by calcium burst during invasion 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74348 17174478 95324 18723 10261 ROS1 ROS ROS 3 0.0 Their high metabolic ROS generation is further accentuated by NO used in signaling and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74349 17174478 95325 18723 10261 ROS1 ROS ROS 6 0.0 Besides directly increasing cellular apoptosis these ROS events increase DNA damage with implications for degenerative diseases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74350 17174478 95327 18723 10261 ROS1 ROS ROS 11 0.0 of mitochondrial and nuclear DNA damage which can occur by ROS and a large variety of other genotoxic agents in post-mitotic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74351 17174478 95331 14635 7965 NR1H2 NER NER 3 1.3 Nucleotide excision repair (NER) NER differs from BER by responding to DNA helix distorting damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74352 17174478 95332 14635 7965 NR1H2 NER NER 2 1.3 Evidence for NER in the brain also includes studies on cerebellar extracts ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74353 17174478 95332 14635 7965 NR1H2 NER NER 25 1.3 1998 and also a few rare hereditary diseases in known NER genes that cause marked neurological pathology which are discussed later 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74354 17174478 95335 21298 11316 SSB SSB SSBs 15 0.3 in the backbone can occur either as single-strand breaks (SSBs) SSBs or as DSBs 13 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74355 17174478 95336 21298 11316 SSB SSB SSBs 0 0.3 SSBs are efficiently repaired by a mechanism that shares many common 13 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74356 17174478 95350 18723 10261 ROS1 ROS ROS 12 0.0 mechanisms to avoid mutations in mtDNA are the control of ROS and the repair of DNA damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74357 17174478 95351 18723 10261 ROS1 ROS ROS 5 0.0 Reduced DNA repair or increased ROS are correlated with the induction of apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74358 17174478 95369 13444 7230 MRE11A MRE11 Mre11 3 2.3 Double-Strand Breaks and Mre11/Rad50/Nbs1 Mre11 Rad50 Nbs1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74359 17174478 95369 17886 9816 RAD50 RAD50 Rad50 3 0.6 Double-Strand Breaks and Mre11/Rad50/Nbs1 Mre11 Rad50 Nbs1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74360 17174478 95369 14453 22948 NLRP2 NBS1 Nbs1 3 1.3 Double-Strand Breaks and Mre11/Rad50/Nbs1 Mre11 Rad50 Nbs1 2 JUMiner_v2.2 1 0 0 2 7652 TotalCon:2<>7652|NBN|4683|Complete__22948|NLRP2|55655|Complete__<>AvaiableGeneRif=2<>BEST:7652|NBN|0.00139471313639611<>ScoreDetail__22948|NLRP2|0.000579150579150579__7652|NBN|0.00139471313639611__ 0 0 0 0 0 74361 17174478 95370 13444 7230 MRE11A MRE11 Mre11 1 2.3 The Mre11/Rad50/Nbs1 Mre11 Rad50 Nbs1 (MRN) MRN protein complex plays a central role 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74362 17174478 95370 17886 9816 RAD50 RAD50 Rad50 1 0.6 The Mre11/Rad50/Nbs1 Mre11 Rad50 Nbs1 (MRN) MRN protein complex plays a central role in 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74363 17174478 95370 14453 22948 NLRP2 NBS1 Nbs1 1 1.3 The Mre11/Rad50/Nbs1 Mre11 Rad50 Nbs1 (MRN) MRN protein complex plays a central role in repairing 2 JUMiner_v2.2 1 0 0 2 7652 TotalCon:2<>7652|NBN|4683|Complete__22948|NLRP2|55655|Complete__<>AvaiableGeneRif=2<>BEST:7652|NBN|0.00139471313639611<>ScoreDetail__22948|NLRP2|0.000579150579150579__7652|NBN|0.00139471313639611__ 0 0 0 0 0 74364 17174478 95373 13444 7230 MRE11A MRE11 Mre11 3 2.3 Mutations in the Mre11 component give rise to ataxia-telangiectasia-like disorder (ATLD), ATLD with its 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74365 17174478 95373 13444 7230 MRE11A ATLD ATLD 10 2.3 in the Mre11 component give rise to ataxia-telangiectasia-like disorder (ATLD), ATLD with its increased radiosensitivity and an increased level of spontaneously 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74366 17174478 95374 14453 22948 NLRP2 NBS1 Nbs1 2 1.3 Mutations in Nbs1 cause Nijmegen Breakage syndrome which displays similar symptoms to ATLD 2 JUMiner_v2.2 1 0 0 2 7652 TotalCon:2<>7652|NBN|4683|Complete__22948|NLRP2|55655|Complete__<>AvaiableGeneRif=2<>BEST:7652|NBN|0.00139471313639611<>ScoreDetail__22948|NLRP2|0.000579150579150579__7652|NBN|0.00139471313639611__ 0 0 0 0 0 74367 17174478 95374 13444 7230 MRE11A ATLD ATLD 12 2.3 Nbs1 cause Nijmegen Breakage syndrome which displays similar symptoms to ATLD and is characterized by microcephaly radiosensitivity immunodeficiency increased cancer risk 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74368 17174478 95376 1271 795 ATM ATM ATM 23 0.9 processing events and to cell cycle checkpoint signaling through both ATM checkpoint kinase ( D'Amours and Jackson 2002 van den Bosch 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74369 17174478 95376 8983 4739 H2AFX H2AX H2AX 48 1.6 al. 2003 Assenmacher and Hopfner 2004 and global genome histone H2AX ( Paull et al. 2000 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74370 17174478 95384 17886 9816 RAD50 RAD50 Rad50 11 0.6 head of the complex possesses ATP-stimulated nuclease activity where the Rad50 ATPase controls the Mre11 nuclease 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74371 17174478 95384 13444 7230 MRE11A MRE11 Mre11 15 2.3 possesses ATP-stimulated nuclease activity where the Rad50 ATPase controls the Mre11 nuclease 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74372 17174478 95385 14453 22948 NLRP2 NBS1 Nbs1 0 1.3 Nbs1 also appears to be part of the head through its 2 JUMiner_v2.2 1 0 0 2 7652 TotalCon:2<>7652|NBN|4683|Complete__22948|NLRP2|55655|Complete__<>AvaiableGeneRif=2<>BEST:7652|NBN|0.00139471313639611<>ScoreDetail__22948|NLRP2|0.000579150579150579__7652|NBN|0.00139471313639611__ 0 0 0 0 0 74373 17174478 95385 13444 7230 MRE11A MRE11 Mre11 13 2.3 to be part of the head through its interactions with Mre11 ( Zhang et al. 2006 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74374 17174478 95386 17886 9816 RAD50 RAD50 Rad50 31 0.6 form an interlocked hook/Zinc/hook hook Zinc hook bridges joining two Rad50 coiled-coils ( Hopfner et al. 2002a 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74375 17174478 95394 13444 7230 MRE11A MRE11 Mre11 3 2.3 Double-Strand Breaks and Mre11/Rad50/Nbs1 Mre11 Rad50 Nbs1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74376 17174478 95394 17886 9816 RAD50 RAD50 Rad50 3 0.6 Double-Strand Breaks and Mre11/Rad50/Nbs1 Mre11 Rad50 Nbs1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74377 17174478 95394 14453 22948 NLRP2 NBS1 Nbs1 3 1.3 Double-Strand Breaks and Mre11/Rad50/Nbs1 Mre11 Rad50 Nbs1 2 JUMiner_v2.2 1 0 0 2 7652 TotalCon:2<>7652|NBN|4683|Complete__22948|NLRP2|55655|Complete__<>AvaiableGeneRif=2<>BEST:7652|NBN|0.00139471313639611<>ScoreDetail__22948|NLRP2|0.000579150579150579__7652|NBN|0.00139471313639611__ 0 0 0 0 0 74378 17174478 95395 24250 12791 WRN WRN WRN 6 3.5 Double-Strand Breaks Base Excision Repair and WRN 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74379 17174478 95396 24250 12791 WRN WRN WRN 3 3.5 Hereditary mutations in WRN are associated with Werner syndrome (WS), WS a rare autosomal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74380 17174478 95401 24250 12791 WRN WRN WRN 0 3.5 WRN encodes a 1 432-residue protein that contains a C-terminal nuclear-localization 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74381 17174478 95403 24250 12791 WRN WRN WRN 0 3.5 WRN belongs to the RecQ helicase family that is widely distributed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74382 17174478 95404 18160 9948 RECQL RecQ1 RecQ1 11 1.3 human genome also contains four other RecQ helicase family members RecQ1 BLM RecQ4L and RecQ5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74383 17174478 95404 1675 1058 BLM BLM BLM 13 1.6 genome also contains four other RecQ helicase family members RecQ1 BLM RecQ4L and RecQ5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74384 17174478 95404 18162 9950 RECQL5 RecQ5 RecQ5 17 1.3 four other RecQ helicase family members RecQ1 BLM RecQ4L and RecQ5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74385 17174478 95405 1675 1058 BLM BLM BLM 2 1.6 Mutations in BLM and RecQ4L cause Bloom syndrome and Rothmund-Thomson syndrome respectively ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74386 17174478 95407 24250 12791 WRN WRN WRN 0 3.5 WRN has been implicated to function in multiple DNA metabolism steps 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74387 17174478 95408 24250 12791 WRN WRN WRN 3 3.5 Biochemical characterization of WRN helicase has shown ATPase activity and unwinding of partial-duplex DNA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74388 17174478 95410 24250 12791 WRN WRN WRN 5 3.5 Significantly a unique feature of WRN among all the human RecQ helicases is the addition of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74389 17174478 95412 24250 12791 WRN WRN WRN 0 3.5 WRN exonuclease functions on a variety of structured DNA substrates that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74390 17174478 95413 24250 12791 WRN WRN WRN 0 3.5 WRN 3_amp_#x02032 -5_amp_#x02032 exonuclease activity shows substrate specificity similar to that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74391 17174478 95413 24250 12791 WRN WRN WRN 17 3.5 similar to that for the helicase suggesting that the two WRN enzymatic activities may have coordinated functions on several classes of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74392 17174478 95414 24250 12791 WRN WRN WRN 0 3.5 WRN has been implicated in certain DNA repair events as WS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74393 17174478 95416 24250 12791 WRN WRN WRN 0 3.5 WRN links to BER include physical and functional interaction with pol_amp_#x003b2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74394 17174478 95416 18741 10289 RPA1 RPA RPA 27 0.6 pol_amp_#x003b4 ( Szekely et al. 2000 replication protein A (RPA)( RPA Brosh et al. 1999 flap endonuclease 1 (FEN-1) FEN-1 ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74395 17174478 95416 7490 3650 FEN1 FEN-1 FEN-1 36 1.9 (RPA)( RPA Brosh et al. 1999 flap endonuclease 1 (FEN-1) FEN-1 ( Brosh et al. 2001b PCNA ( Lebel et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74396 17174478 95416 16232 8729 PCNA PCNA PCNA 43 0.9 flap endonuclease 1 (FEN-1) FEN-1 ( Brosh et al. 2001b PCNA ( Lebel et al. 1999 and poly(ADP-ribose)polymerase poly ADP-ribose polymerase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74397 17174478 95416 16068 270 PARP1 PARP-1 PARP-1 53 3.4 et al. 1999 and poly(ADP-ribose)polymerase poly ADP-ribose polymerase 1 (PARP-1) PARP-1 ( von Kobbe et al. 2003a 1 JUMiner_v2.2 1 0 0 2 270 TotalCon:2<>23696|TIPARP|25976|Complete__270|PARP1|142|Complete__<>AvaiableGeneRif=2<>BEST:270|PARP1|0.000751389021936967<>ScoreDetail__23696|TIPARP|0__270|PARP1|0.000751389021936967__ 0 0 0 0 0 74398 17174478 95416 24185 29175 WDTC1 ADP ADP-ribose 51 0.1 2001b PCNA ( Lebel et al. 1999 and poly(ADP-ribose)polymerase poly ADP-ribose polymerase 1 (PARP-1) PARP-1 ( von Kobbe et al. 2003a 6 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74399 17174478 95417 17892 9824 RAD52 RAD52 Rad52 21 0.6 with the MRN complex ( Cheng et al. 2004 and Rad52 ( Baynton et al. 2003 and by colocalization with Rad51 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74400 17174478 95417 17887 9817 RAD51 RAD51 Rad51 32 1.6 Rad52 ( Baynton et al. 2003 and by colocalization with Rad51 in camptothecin-treated cells ( Sakamoto et al. 2001 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74401 17174478 95418 24250 12791 WRN WRN WRN 13 3.5 to the NHEJ pathway is indicated by in interactions of WRN with the NHEJ-essential protein kinase DNA-PK ( Yannone et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74402 17174478 95418 17319 9413 PRKDC DNAPK DNA-PK 19 1.2 by in interactions of WRN with the NHEJ-essential protein kinase DNA-PK ( Yannone et al. 2001 Karmakar et al. 2002a Li 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74403 17174478 95419 24250 12791 WRN WRN WRN 0 3.5 WRN activity is regulated by holo _amp_#x02013 DNA-PK ( Yannone et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74404 17174478 95419 17319 9413 PRKDC DNAPK DNA-PK 6 1.2 WRN activity is regulated by holo _amp_#x02013 DNA-PK ( Yannone et al. 2001 Karmakar et al. 2002a WRN 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74405 17174478 95419 24250 12791 WRN WRN WRN 18 3.5 DNA-PK ( Yannone et al. 2001 Karmakar et al. 2002a WRN is an in vivo substrate of DNA-PK ( Yannone et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74406 17174478 95419 17319 9413 PRKDC DNAPK DNA-PK 25 1.2 et al. 2002a WRN is an in vivo substrate of DNA-PK ( Yannone et al. 2001 Karmakar et al. 2002a and 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74407 17174478 95419 17319 9413 PRKDC DNAPK DNA-PK 39 1.2 Yannone et al. 2001 Karmakar et al. 2002a and the DNA-PK subunit Ku70/80 Ku70 80 stimulates WRN exonuclease activity in vitro 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74408 17174478 95419 24334 4055 XRCC6 KU70 Ku70 41 1.6 2001 Karmakar et al. 2002a and the DNA-PK subunit Ku70/80 Ku70 80 stimulates WRN exonuclease activity in vitro ( Cooper et 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74409 17174478 95419 24250 12791 WRN WRN WRN 43 3.5 al. 2002a and the DNA-PK subunit Ku70/80 Ku70 80 stimulates WRN exonuclease activity in vitro ( Cooper et al. 2000 Li 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74410 17174478 95420 24250 12791 WRN WRN WRN 1 3.5 Furthermore WRN has been observed in an endogenous complex with the Ku70/80 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74411 17174478 95420 24334 4055 XRCC6 KU70 Ku70 11 1.6 has been observed in an endogenous complex with the Ku70/80 Ku70 80 subunit and poly(ADP-ribose) poly ADP-ribose polymerase-1 (PARP-1) PARP-1 ( 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74412 17174478 95420 16068 270 PARP1 PARP-1 PARP-1 16 3.4 Ku70/80 Ku70 80 subunit and poly(ADP-ribose) poly ADP-ribose polymerase-1 (PARP-1) PARP-1 ( Li et al. 2004 1 JUMiner_v2.2 1 0 0 2 270 TotalCon:2<>23696|TIPARP|25976|Complete__270|PARP1|142|Complete__<>AvaiableGeneRif=2<>BEST:270|PARP1|0.000751389021936967<>ScoreDetail__23696|TIPARP|0__270|PARP1|0.000751389021936967__ 0 0 0 0 0 74413 17174478 95420 24185 29175 WDTC1 ADP ADP-ribose 14 0.1 complex with the Ku70/80 Ku70 80 subunit and poly(ADP-ribose) poly ADP-ribose polymerase-1 (PARP-1) PARP-1 ( Li et al. 2004 6 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74414 17174478 95421 16068 270 PARP1 PARP-1 PARP-1 1 3.4 Notably PARP-1 binds sites of SSBs and DSBs and is also implicated 1 JUMiner_v2.2 1 0 0 2 270 TotalCon:2<>23696|TIPARP|25976|Complete__270|PARP1|142|Complete__<>AvaiableGeneRif=2<>BEST:270|PARP1|0.000751389021936967<>ScoreDetail__23696|TIPARP|0__270|PARP1|0.000751389021936967__ 0 0 0 0 0 74415 17174478 95421 21298 11316 SSB SSB SSBs 5 0.3 Notably PARP-1 binds sites of SSBs and DSBs and is also implicated in the control of 13 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74416 17174478 95422 24250 12791 WRN WRN WRN 0 3.5 WRN has a modular composition ( Fig 6a and structural studies 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74417 17174478 95422 24250 12791 WRN WRN WRN 24 3.5 protein's domains and those of homologues are helping to define WRN mediated functions ( Killoran and Keck 2006 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74418 17174478 95423 24250 12791 WRN WRN WRN 3 3.5 The N-terminus of WRN contains the exonuclease domain the central core contains the helicase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74419 17174478 95424 24250 12791 WRN WRN WRN 8 3.5 Crystallographic and structure based mutational studies on the WRN exonuclease domain have revealed a high degree of structural and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74420 17174478 95425 24250 12791 WRN WRN WRN 5 3.5 These structural biochemistry studies on WRN exonuclease revealed a two metal ion mediated mechanism of nucleotide 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74421 17174478 95426 24250 12791 WRN WRN WRN 7 3.5 The lanthanide Eu 3 ions inhibit the WRN exonuclease activity probably due to either a greater charge state 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74422 17174478 95427 24334 4055 XRCC6 KU70 Ku70 0 1.6 Ku70/80 Ku70 80 specifically stimulates this WRN exonuclease activity but inhibits the 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74423 17174478 95427 24250 12791 WRN WRN WRN 4 3.5 Ku70/80 Ku70 80 specifically stimulates this WRN exonuclease activity but inhibits the Klenow fragment exonuclease its closest 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74424 17174478 95428 24250 12791 WRN WRN WRN 5 3.5 This also suggests that the WRN exonuclease domain may help impart functions mediated by WRN_amp_#x02013;Ku70/80 WRN_amp_#x02013 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74425 17174478 95428 24334 4055 XRCC6 KU70 Ku70 14 1.6 exonuclease domain may help impart functions mediated by WRN_amp_#x02013;Ku70/80 WRN_amp_#x02013 Ku70 80 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74426 17174478 95429 24250 12791 WRN WRN WRN 1 3.5 Additionally WRN exonuclease activity is required to fully compliment a Werner syndrome 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74427 17174478 95430 24250 12791 WRN WRN WRN 18 3.5 specific cellular pathway but the elevated microhomology-mediated repair observed in WRN exonuclease deficient cells is similar to the phenotypes associated with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74428 17174478 95430 24250 12791 WRN WRN WRN 45 3.5 Melek et al. 1998 Verkaik et al. 2002 possibly linking WRN to this pathway 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74429 17174478 95431 24250 12791 WRN WRN WRN 11 3.5 Werner syndrome cells have mild radiation sensitivity which rules out WRN as an essential DSB repair protein but WRN exonuclease may 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74430 17174478 95431 24250 12791 WRN WRN WRN 19 3.5 rules out WRN as an essential DSB repair protein but WRN exonuclease may nevertheless be used for resolution of a limited 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74431 17174478 95432 24250 12791 WRN WRN WRN 6 3.5 Double-Strand Breaks Base Excision Repair and WRN 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74432 17174478 95433 24250 12791 WRN WRN WRN 5 3.5 This substantial functional divergence between WRN exonuclease and its structural homologs such as Klenow fragment exonuclease 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74433 17174478 95434 24250 12791 WRN WRN WRN 1 3.5 The WRN exonuclease domain construct that was defined by crystallography studies is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74434 17174478 95435 24250 12791 WRN WRN WRN 3 3.5 However a similar WRN exonuclease construct forms homo-hexamers upon interaction with DNA or PCNA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74435 17174478 95435 16232 8729 PCNA PCNA PCNA 13 0.9 WRN exonuclease construct forms homo-hexamers upon interaction with DNA or PCNA ( Xue et al. 2002 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74436 17174478 95436 24250 12791 WRN WRN WRN 3 3.5 Also a larger WRN N-terminal construct residues 1-333 and containing the exonuclease domain forms 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74437 17174478 95437 24250 12791 WRN WRN WRN 11 3.5 potentially affects substrate specificities and enzymatic activities of the full-length WRN protein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74438 17174478 95438 24250 12791 WRN WRN WRN 4 3.5 The multimerization state of WRN homologues is still under debate ( Sharma et al. 2006 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74439 17174478 95438 1675 1058 BLM BLM BLM 20 1.6 debate ( Sharma et al. 2006 but the human homolog BLM has been observed to form hexameric and/or and or tetrameric 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74440 17174478 95439 24250 12791 WRN WRN WRN 1 3.5 A WRN exonuclease hexameric ring model ( Fig 6c has been built 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74441 17174478 95439 16266 8757 PDB1 PDB PDB 21 0.3 built based on a multimeric A thaliana structural homolog (PDB PDB code 1VK0 ( Perry et al. 2006 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74442 17174478 95440 24250 12791 WRN WRN WRN 1 3.5 This WRN exonuclease ring contains a positively charged central cavity with the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74443 17174478 95442 24250 12791 WRN WRN WRN 7 3.5 Important insights into the molecular mechanisms of WRN have also been discovered from the structure of the conserved 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74444 17174478 95446 19764 12950 SF1 SF1 SF1 45 0.3 al. 2003 ( Fig 6e and this is similar to SF1 _amp_#x00026 2 helicases 1 JUMiner_v2.2 1 0 0 2 7983 TotalCon:2<>12950|SF1|7536|Complete__7983|NR5A1|2516|Complete__<>AvaiableGeneRif=2<>BEST:7983|NR5A1|0.000497518012617236<>ScoreDetail__12950|SF1|0.000292740046838407__7983|NR5A1|0.000497518012617236__ 0 0 0 0 0 74445 17174478 95450 24250 12791 WRN WRN WRN 1 3.5 In WRN a mutation in Motif I in mice induces a Werner 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74446 17174478 95451 19764 12950 SF1 SF1 SF1 23 0.3 still undefined but the lobes likely use strategies similar to SF1 _amp_#x00026 2 proteins 1 JUMiner_v2.2 1 0 0 2 7983 TotalCon:2<>12950|SF1|7536|Complete__7983|NR5A1|2516|Complete__<>AvaiableGeneRif=2<>BEST:7983|NR5A1|0.000497518012617236<>ScoreDetail__12950|SF1|0.000292740046838407__7983|NR5A1|0.000497518012617236__ 0 0 0 0 0 74447 17174478 95452 19764 12950 SF1 SF1 SF1 23 0.3 Wang et al. 2000 and regions of sequence similarity to SF1 indicates that WRN helicase may function a base-flipping mechanism proposed 1 JUMiner_v2.2 1 0 0 2 7983 TotalCon:2<>12950|SF1|7536|Complete__7983|NR5A1|2516|Complete__<>AvaiableGeneRif=2<>BEST:7983|NR5A1|0.000497518012617236<>ScoreDetail__12950|SF1|0.000292740046838407__7983|NR5A1|0.000497518012617236__ 0 0 0 0 0 74448 17174478 95452 24250 12791 WRN WRN WRN 26 3.5 2000 and regions of sequence similarity to SF1 indicates that WRN helicase may function a base-flipping mechanism proposed in SF1 despite 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74449 17174478 95452 19764 12950 SF1 SF1 SF1 35 0.3 that WRN helicase may function a base-flipping mechanism proposed in SF1 despite overall sequence similarity to SF2 helicases ( Bernstein et 1 JUMiner_v2.2 1 0 0 2 7983 TotalCon:2<>12950|SF1|7536|Complete__7983|NR5A1|2516|Complete__<>AvaiableGeneRif=2<>BEST:7983|NR5A1|0.000497518012617236<>ScoreDetail__12950|SF1|0.000292740046838407__7983|NR5A1|0.000497518012617236__ 0 0 0 0 0 74450 17174478 95452 19787 10780 SFRS1 SF2 SF2 41 0.3 base-flipping mechanism proposed in SF1 despite overall sequence similarity to SF2 helicases ( Bernstein et al. 2003 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74451 17174478 95456 1675 1058 BLM BLM BLM 29 1.6 and are sufficient to cause Bloom syndrome when mutated in BLM ( Ellis et al. 1995 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74452 17174478 95457 24250 12791 WRN WRN WRN 32 3.5 a more recently determined NMR structure of this domain in WRN ( Hu et al. 2005 ( Fig 6g 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74453 17174478 95458 24250 12791 WRN WRN WRN 3 3.5 This domain in WRN binds several alternate DNA substructures including forks holding junctions 3_amp_#x02032 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74454 17174478 95459 24250 12791 WRN WRN WRN 2 3.5 Notably the WRN winged helix domain facilitates targeting of WRN to the nucleolus 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74455 17174478 95459 24250 12791 WRN WRN WRN 9 3.5 Notably the WRN winged helix domain facilitates targeting of WRN to the nucleolus ( von Kobbe and Bohr 2002 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74456 17174478 95459 24250 12791 WRN WRN WRN 30 3.5 and interactions of several of the potential protein partners of WRN have also been specifically mapped to this winged helix domain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74457 17174478 95459 24250 12791 WRN WRN WRN 57 3.5 indicating the critical and versatile nature of this domain in WRN 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74458 17174478 95460 24250 12791 WRN WRN WRN 5 3.5 The remaining C-terminal domain of WRN is the HRDC ( H elicase R Nase D C 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74459 17174478 95463 24250 12791 WRN WRN WRN 1 3.5 In WRN the HRDC domain preferentially binds to forked duplex DNA and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74460 17174478 95464 24250 12791 WRN WRN WRN 13 3.5 this domain is utilized in replication and recombination functions of WRN 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74461 17174478 95465 24250 12791 WRN WRN WRN 5 3.5 Significantly the interactions with the WRN C-terminus containing the winged helix and HRDC domains have been 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74462 17174478 95465 24250 12791 WRN WRN WRN 22 3.5 HRDC domains have been indicated to regulate the activity of WRN or of the partner protein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74463 17174478 95466 24250 12791 WRN WRN WRN 1 3.5 The WRN exonuclease domain activity is regulated through the interaction of its 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74464 17174478 95466 22671 11998 TP53 p53 p53 14 0.6 activity is regulated through the interaction of its C-terminus with p53 ( Blander et al. 1999 Ku70/80 Ku70 80 ( Cooper 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74465 17174478 95466 24334 4055 XRCC6 KU70 Ku70 21 1.6 its C-terminus with p53 ( Blander et al. 1999 Ku70/80 Ku70 80 ( Cooper et al. 2000 Li and Comai 2000 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74466 17174478 95466 16068 270 PARP1 PARP-1 PARP-1 44 3.4 2000 Brosh et al. 2001a Karmakar et al. 2002b and PARP-1 ( von Kobbe et al. 2004 1 JUMiner_v2.2 1 0 0 2 270 TotalCon:2<>23696|TIPARP|25976|Complete__270|PARP1|142|Complete__<>AvaiableGeneRif=2<>BEST:270|PARP1|0.000751389021936967<>ScoreDetail__23696|TIPARP|0__270|PARP1|0.000751389021936967__ 0 0 0 0 0 74467 17174478 95467 24250 12791 WRN WRN WRN 1 3.5 While WRN helicase activity is regulated by C-terminal interactions that include TRF2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74468 17174478 95467 21997 11729 TERF2 TRF2 TRF2 11 1.6 WRN helicase activity is regulated by C-terminal interactions that include TRF2 ( Opresko et al. 2002 Rad52 ( Baynton et al. 1 JUMiner_v2.2 1 0 0 2 11729 TotalCon:2<>11589|TBPL1|9519|Complete__11729|TERF2|7014|Complete__<>AvaiableGeneRif=2<>BEST:11729|TERF2|0.000743775101669656<>ScoreDetail__11729|TERF2|0.000743775101669656__11589|TBPL1|0.000207784019259429__ 0 0 0 0 0 74469 17174478 95467 17892 9824 RAD52 RAD52 Rad52 18 0.6 C-terminal interactions that include TRF2 ( Opresko et al. 2002 Rad52 ( Baynton et al. 2003 and PARP-1 ( von Kobbe 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74470 17174478 95467 16068 270 PARP1 PARP-1 PARP-1 26 3.4 et al. 2002 Rad52 ( Baynton et al. 2003 and PARP-1 ( von Kobbe et al. 2004 1 JUMiner_v2.2 1 0 0 2 270 TotalCon:2<>23696|TIPARP|25976|Complete__270|PARP1|142|Complete__<>AvaiableGeneRif=2<>BEST:270|PARP1|0.000751389021936967<>ScoreDetail__23696|TIPARP|0__270|PARP1|0.000751389021936967__ 0 0 0 0 0 74471 17174478 95468 24250 12791 WRN WRN WRN 3 3.5 An example of WRN stimulation of partner proteins includes the FEN-1 partner protein whose 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74472 17174478 95468 7490 3650 FEN1 FEN-1 FEN-1 10 1.9 An example of WRN stimulation of partner proteins includes the FEN-1 partner protein whose structures with DNA and PCNA have been 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74473 17174478 95468 16232 8729 PCNA PCNA PCNA 18 0.9 includes the FEN-1 partner protein whose structures with DNA and PCNA have been defined ( Hosfield et al. 1998 Chapados et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74474 17174478 95469 24250 12791 WRN WRN WRN 0 3.5 WRN interaction that was mapped to the winged helix domain stimulates 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74475 17174478 95469 7490 3650 FEN1 FEN-1 FEN-1 11 1.9 interaction that was mapped to the winged helix domain stimulates FEN-1 nucleolytic activity by more than 80-fold ( Brosh et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74476 17174478 95470 24250 12791 WRN WRN WRN 15 3.5 interesting to define how these interactions are able to regulate WRN catalytic activities how key DNA and/or and or protein interactions 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74477 17174478 95470 24250 12791 WRN WRN WRN 31 3.5 or protein interactions may potentially allow for controlled handoffs during WRN mediated pathway progression and how the breakdown of this pathway 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74478 17174478 95470 24250 12791 WRN WRN WRN 48 3.5 breakdown of this pathway progression in the absence of functioning WRN gives rise to the disease phenotype 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74479 17174478 95471 14635 7965 NR1H2 NER NER 0 1.3 NER and the XPB helicase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74480 17174478 95471 6736 3435 ERCC3 XPB XPB 3 2.4 NER and the XPB helicase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74481 17174478 95472 14635 7965 NR1H2 NER NER 0 1.3 NER functions to restore short segments of nucleotides containing DNA helix 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74482 17174478 95474 14635 7965 NR1H2 NER NER 28 1.3 generated by ionizing radiation can produce DNA lesions that require NER for repair ( Satoh et al. 1993 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74483 17174478 95475 14635 7965 NR1H2 NER NER 0 1.3 NER is a particularly versatile DNA repair system that is capable 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74484 17174478 95476 14635 7965 NR1H2 NER NER 3 1.3 Hereditary mutations in NER genes clearly demonstrate that the inherited DNA repair potential has 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74485 17174478 95477 14635 7965 NR1H2 NER NER 6 1.3 Moreover much of our understanding of NER has been derived from studies on cells from individuals with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74486 17174478 95477 14635 7965 NR1H2 NER NER 17 1.3 has been derived from studies on cells from individuals with NER defects that present clinical phenotypes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74487 17174478 95478 8901 21157 GTF2H5 TTD TTD 12 1.2 the rare genetic disorders xeroderma pigmentosum (XP), XP trichothiodystrophy (TTD) TTD and Cockayne syndrome (CS) CS 1 JUMiner_v2.2 1 2 UserEdit 0 2 21157 TotalCon:2<>21157|GTF2H5|404672|Complete__3434|ERCC2|2068|Complete__<>AvaiableGeneRif=2<>BEST:21157|GTF2H5|0.00104353482027836<>ScoreDetail__21157|GTF2H5|0.00104353482027836__3434|ERCC2|0.000283645881010553__ 1 1 0 0 0 74488 17174478 95482 8901 21157 GTF2H5 TTD TTD 1 1.2 The TTD individuals have characteristically brittle hair and nails and may also 1 JUMiner_v2.2 1 2 UserEdit 0 2 21157 TotalCon:2<>21157|GTF2H5|404672|Complete__3434|ERCC2|2068|Complete__<>AvaiableGeneRif=2<>BEST:21157|GTF2H5|0.00104353482027836<>ScoreDetail__21157|GTF2H5|0.00104353482027836__3434|ERCC2|0.000283645881010553__ 1 1 0 0 0 74489 17174478 95483 6736 3435 ERCC3 XPB XPB 12 2.4 gene that is associated with all three disorders is the XPB helicase ( Weeda et al. 1997 which is part of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74490 17174478 95483 6736 3435 ERCC3 TFIIH TFIIH 28 2.7 al. 1997 which is part of the general transcription factor TFIIH complex ( Schaeffer et al. 1993 1 JUMiner_v2.2 1 0 0 2 3435 TotalCon:5<>3435|ERCC3|2071|Complete__4656|GTF2H2|2966|Complete__4657|GTF2H3|2967|Complete__4655|GTF2H1|2965|Complete__4658|GTF2H4|2968|Complete__<>AvaiableGeneRif=5<>BEST:3435|ERCC3|0.00287469287469287<>ScoreDetail__4656|GTF2H2|0.0025974025974026__4658|GTF2H4|0.00176390773405699__4657|GTF2H3|0__3435|ERCC3|0.00287469287469287__4655|GTF2H1|0.00230055658627087__ 0 0 0 0 0 74491 17174478 95484 6736 3435 ERCC3 XPB XPB 1 2.4 The XPB ATPase and helicase activities are essential for promoter DNA melting 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74492 17174478 95485 6736 3435 ERCC3 XPB XPB 6 2.4 In addition to these transcriptional functions XPB also plays a role in NER 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74493 17174478 95485 14635 7965 NR1H2 NER NER 12 1.3 to these transcriptional functions XPB also plays a role in NER 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74494 17174478 95486 6736 3435 ERCC3 XPB XPB 8 2.4 Recent developments in structural and biochemical characterization of XPB helicase have begun to address some of the key questions 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74495 17174478 95486 6736 3435 ERCC3 XPB XPB 25 2.4 of the key questions on the underlying mechanisms of how XPB and TFIIH function in both transcription and NER ( Coin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74496 17174478 95486 6736 3435 ERCC3 TFIIH TFIIH 27 2.7 key questions on the underlying mechanisms of how XPB and TFIIH function in both transcription and NER ( Coin et al. 1 JUMiner_v2.2 1 0 0 2 3435 TotalCon:5<>3435|ERCC3|2071|Complete__4656|GTF2H2|2966|Complete__4657|GTF2H3|2967|Complete__4655|GTF2H1|2965|Complete__4658|GTF2H4|2968|Complete__<>AvaiableGeneRif=5<>BEST:3435|ERCC3|0.00287469287469287<>ScoreDetail__4656|GTF2H2|0.0025974025974026__4658|GTF2H4|0.00176390773405699__4657|GTF2H3|0__3435|ERCC3|0.00287469287469287__4655|GTF2H1|0.00230055658627087__ 0 0 0 0 0 74497 17174478 95486 14635 7965 NR1H2 NER NER 33 1.3 of how XPB and TFIIH function in both transcription and NER ( Coin et al. 2004 Coin et al. 2006 Fan 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74498 17174478 95487 6736 3435 ERCC3 XPB XPB 12 2.4 studies have been conducted on a homolog of the human XPB the archea Archaeoglobus fulgidus XPB ( Af XPB ( Fan 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74499 17174478 95487 6736 3435 ERCC3 XPB XPB 17 2.4 a homolog of the human XPB the archea Archaeoglobus fulgidus XPB ( Af XPB ( Fan et al. 2006a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74500 17174478 95487 6736 3435 ERCC3 XPB XPB 20 2.4 the human XPB the archea Archaeoglobus fulgidus XPB ( Af XPB ( Fan et al. 2006a 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74501 17174478 95488 6736 3435 ERCC3 XPB XPB 1 2.4 Af XPB shares 42% amino acid sequence similarity with the central region 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74502 17174478 95488 6736 3435 ERCC3 XPB XPB 14 2.4 amino acid sequence similarity with the central region of human XPB suggesting that the core XPB structure is conserved 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74503 17174478 95488 6736 3435 ERCC3 XPB XPB 19 2.4 the central region of human XPB suggesting that the core XPB structure is conserved 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74504 17174478 95489 6736 3435 ERCC3 XPB XPB 7 2.4 As indicated by sequence comparison the Af XPB structure contains two RecA-like helicase domains (HD1 HD1 and HD2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74505 17174478 95489 17887 9817 RAD51 RECA RecA-like 11 1.6 indicated by sequence comparison the Af XPB structure contains two RecA-like helicase domains (HD1 HD1 and HD2 that belong to helicase 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74506 17174478 95489 9122 4852 HDAC1 HD1 HD1 14 0.3 the Af XPB structure contains two RecA-like helicase domains (HD1 HD1 and HD2 that belong to helicase superfamily 2 1 JUMiner_v2.2 1 2 UserEdit 0 2 9069 TotalCon:2<>4852|HDAC1|3065|Complete__9069|PLEC1|5339|Complete__<>AvaiableGeneRif=2<>BEST:9069|PLEC1|0.000743006237796555<>ScoreDetail__9069|PLEC1|0.000743006237796555__4852|HDAC1|0.000271388197420876__ 1 1 0 0 0 74507 17174478 95490 6736 3435 ERCC3 XPB XPB 6 2.4 However several other functional regions in XPB were discovered that were not predicted either through sequence analysis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74508 17174478 95491 9122 4852 HDAC1 HD1 HD1 9 0.3 A small N-terminal domain is attached to helicase domain HD1 ( Fig 7 which shares structural similarity to the mismatch 1 JUMiner_v2.2 1 2 UserEdit 0 2 9069 TotalCon:2<>4852|HDAC1|3065|Complete__9069|PLEC1|5339|Complete__<>AvaiableGeneRif=2<>BEST:9069|PLEC1|0.000743006237796555<>ScoreDetail__9069|PLEC1|0.000743006237796555__4852|HDAC1|0.000271388197420876__ 1 1 0 0 0 74509 17174478 95492 6736 3435 ERCC3 XPB XPB 4 2.4 This domain in Af XPB has been demonstrated to interact with some types of damaged 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74510 17174478 95493 6736 3435 ERCC3 XPB XPB 0 2.4 XPB DRD differs from the MutS domain by lacking a critical 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74511 17174478 95494 6736 3435 ERCC3 XPB XPB 2 2.4 Instead Af XPB DRD likely recognizes distortions in the DNA typically caused by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74512 17174478 95494 14635 7965 NR1H2 NER NER 17 1.3 in the DNA typically caused by the broad spectrum of NER lesions 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74513 17174478 95495 14635 7965 NR1H2 NER NER 18 1.3 is located and linked to initiation of DNA unwinding during NER steps by XPB/TFIIH XPB TFIIH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74514 17174478 95495 6736 3435 ERCC3 XPB XPB 21 2.4 to initiation of DNA unwinding during NER steps by XPB/TFIIH XPB TFIIH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74515 17174478 95495 6736 3435 ERCC3 TFIIH TFIIH 21 2.7 initiation of DNA unwinding during NER steps by XPB/TFIIH XPB TFIIH 1 JUMiner_v2.2 1 0 0 2 3435 TotalCon:5<>3435|ERCC3|2071|Complete__4656|GTF2H2|2966|Complete__4657|GTF2H3|2967|Complete__4655|GTF2H1|2965|Complete__4658|GTF2H4|2968|Complete__<>AvaiableGeneRif=5<>BEST:3435|ERCC3|0.00287469287469287<>ScoreDetail__4656|GTF2H2|0.0025974025974026__4658|GTF2H4|0.00176390773405699__4657|GTF2H3|0__3435|ERCC3|0.00287469287469287__4655|GTF2H1|0.00230055658627087__ 0 0 0 0 0 74516 17174478 95496 6736 3435 ERCC3 XPB XPB-family 6 2.4 Also present is a highly conserved XPB-family specific RED amino acid motif located in domain HD1 ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74517 17174478 95496 9122 4852 HDAC1 HD1 HD1 15 0.3 conserved XPB-family specific RED amino acid motif located in domain HD1 ( Fig 7c 1 JUMiner_v2.2 1 2 UserEdit 0 2 9069 TotalCon:2<>4852|HDAC1|3065|Complete__9069|PLEC1|5339|Complete__<>AvaiableGeneRif=2<>BEST:9069|PLEC1|0.000743006237796555<>ScoreDetail__9069|PLEC1|0.000743006237796555__4852|HDAC1|0.000271388197420876__ 1 1 0 0 0 74518 17174478 95496 6277 3094 DYRK3 RED RED 8 0.1 Also present is a highly conserved XPB-family specific RED amino acid motif located in domain HD1 ( Fig 7c 6 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>3094|DYRK3|8444|Complete__5958|IK|3550|No_GeneRif__<>AvaiableGeneRif=1<> 1 1 0 0 0 74519 17174478 95497 6736 3435 ERCC3 XPB XPB 5 2.4 Mutational analysis suggests that this XPB RED motif has a critical role in DNA unwinding function 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74520 17174478 95497 6277 3094 DYRK3 RED RED 6 0.2 Mutational analysis suggests that this XPB RED motif has a critical role in DNA unwinding function ( 5 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>3094|DYRK3|8444|Complete__5958|IK|3550|No_GeneRif__<>AvaiableGeneRif=1<> 1 1 0 0 0 74521 17174478 95498 22116 11792 THM THM ThM 12 0.0 contains the helicase domain HD2 and a thumb domain (ThM) ThM insert 14 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 74522 17174478 95499 22116 11792 THM THM ThM 1 0.0 The ThM domain is predicted to bind DNA in a sequence independent 14 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 74523 17174478 95500 22116 11792 THM THM ThM 29 0.0 positively charged amino acid residues at the interface between the ThM and HD2 domains ( Fan et al. 2006a 14 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 74524 17174478 95501 14635 7965 NR1H2 NER NER 0 1.3 NER and the XPB helicase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74525 17174478 95501 6736 3435 ERCC3 XPB XPB 3 2.4 NER and the XPB helicase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74526 17174478 95503 6736 3435 ERCC3 XPB XPB 1 2.4 Af XPB seems to follow this general trend 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74527 17174478 95504 9122 4852 HDAC1 HD1 HD1 8 0.3 The relative orientation of the two helicase domains HD1 and HD2 observed in the full-length Af XPB is different 1 JUMiner_v2.2 1 2 UserEdit 0 2 9069 TotalCon:2<>4852|HDAC1|3065|Complete__9069|PLEC1|5339|Complete__<>AvaiableGeneRif=2<>BEST:9069|PLEC1|0.000743006237796555<>ScoreDetail__9069|PLEC1|0.000743006237796555__4852|HDAC1|0.000271388197420876__ 1 1 0 0 0 74528 17174478 95504 6736 3435 ERCC3 XPB XPB 16 2.4 helicase domains HD1 and HD2 observed in the full-length Af XPB is different than the _amp_#x0201c closed_amp_#x0201d conformation observed in crystal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74529 17174478 95506 6736 3435 ERCC3 XPB XPB 13 2.4 also lead to a proposed mechanism for the involvement of XPB in the unwinding of duplex DNA at sites of DNA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74530 17174478 95507 6736 3435 ERCC3 XPB XPB 1 2.4 When XPB is recruited to DNA the DRD domain is proposed to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74531 17174478 95508 6736 3435 ERCC3 XPB XPB 16 2.4 helicase domain HD2 via a rotation of ~170_amp_#x000b0 and allows XPB to wrap around the DNA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74532 17174478 95509 6736 3435 ERCC3 XPB XPB 13 2.4 such a conformational change may result from interaction of the XPB C-terminus (including including ThM and HD2 domains with 3'-overhanging DNA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74533 17174478 95509 22116 11792 THM THM ThM 16 0.0 may result from interaction of the XPB C-terminus (including including ThM and HD2 domains with 3'-overhanging DNA 14 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 74534 17174478 95510 6277 3094 DYRK3 RED RED 9 0.0 In both cases in this new _amp_#x0201c closed_amp_#x0201d configuration the RED motif would be ideally placed at the helicase active site 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>3094|DYRK3|8444|Complete__5958|IK|3550|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 74535 17174478 95511 22116 11792 THM THM ThM 1 0.0 The ThM domain now _amp_#x0201c grips_amp_#x0201d one strand of the DNA above 14 JUMiner_v2.2 1 0 1 0 0 0 0 0 0 0 74536 17174478 95511 6277 3094 DYRK3 RED RED 29 0.0 lie in the groove on the opposite side of the RED motif 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>3094|DYRK3|8444|Complete__5958|IK|3550|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 74537 17174478 95512 6736 3435 ERCC3 XPB XPB 19 2.4 _amp_#x0201c wedge_amp_#x0201d to unzip the DNA when ATP hydrolysis drives XPB to move along the duplex DNA during NER 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74538 17174478 95512 14635 7965 NR1H2 NER NER 27 1.3 hydrolysis drives XPB to move along the duplex DNA during NER 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74539 17174478 95512 6277 3094 DYRK3 RED RED 4 0.0 In this position the RED motif would function as a _amp_#x0201c wedge_amp_#x0201d to unzip the 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>3094|DYRK3|8444|Complete__5958|IK|3550|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 74540 17174478 95513 6736 3435 ERCC3 XPB XPB 8 2.4 However it is noticed that DNA melting by XPB during transcription initiation is possibly mediated through an unconventional helicase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74541 17174478 95513 6736 3435 ERCC3 XPB XPB 28 2.4 unconventional helicase mechanism ( Kim et al. 2000 in which XPB functions as a molecular _amp_#x0201c wrench_amp_#x0201d rotating downstream DNA relative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74542 17174478 95514 6736 3435 ERCC3 XPB XPB 7 2.4 Therefore the conformation observed in the Af XPB structure may represent a _amp_#x0201c transcriptional mode_amp_#x0201d of XPB tuned 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74543 17174478 95514 6736 3435 ERCC3 XPB XPB 15 2.4 Af XPB structure may represent a _amp_#x0201c transcriptional mode_amp_#x0201d of XPB tuned for this action whereas the domain reorientation described above 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74544 17174478 95514 14635 7965 NR1H2 NER NER-specific 27 0.3 for this action whereas the domain reorientation described above is NER-specific and only occurs upon the interactions of the DRD with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74545 17174478 95515 6736 3435 ERCC3 XPB XPB 8 2.4 If these mechanisms are true the conformation of XPB will decide whether TFIIH functions as a transcription factor or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74546 17174478 95515 6736 3435 ERCC3 TFIIH TFIIH 12 2.7 mechanisms are true the conformation of XPB will decide whether TFIIH functions as a transcription factor or a DNA repair factor 1 JUMiner_v2.2 1 0 0 2 3435 TotalCon:5<>3435|ERCC3|2071|Complete__4656|GTF2H2|2966|Complete__4657|GTF2H3|2967|Complete__4655|GTF2H1|2965|Complete__4658|GTF2H4|2968|Complete__<>AvaiableGeneRif=5<>BEST:3435|ERCC3|0.00287469287469287<>ScoreDetail__4656|GTF2H2|0.0025974025974026__4658|GTF2H4|0.00176390773405699__4657|GTF2H3|0__3435|ERCC3|0.00287469287469287__4655|GTF2H1|0.00230055658627087__ 0 0 0 0 0 74547 17174478 95516 6736 3435 ERCC3 XPB XPB 3 2.4 In other words XPB acts as a master key helping TFIIH switch pathway selection 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74548 17174478 95516 6736 3435 ERCC3 TFIIH TFIIH 10 2.7 In other words XPB acts as a master key helping TFIIH switch pathway selection for transcription or DNA repair whenever it 1 JUMiner_v2.2 1 0 0 2 3435 TotalCon:5<>3435|ERCC3|2071|Complete__4656|GTF2H2|2966|Complete__4657|GTF2H3|2967|Complete__4655|GTF2H1|2965|Complete__4658|GTF2H4|2968|Complete__<>AvaiableGeneRif=5<>BEST:3435|ERCC3|0.00287469287469287<>ScoreDetail__4656|GTF2H2|0.0025974025974026__4658|GTF2H4|0.00176390773405699__4657|GTF2H3|0__3435|ERCC3|0.00287469287469287__4655|GTF2H1|0.00230055658627087__ 0 0 0 0 0 74549 17174478 95517 14635 7965 NR1H2 NER NER 0 1.3 NER and the XPB helicase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74550 17174478 95517 6736 3435 ERCC3 XPB XPB 3 2.4 NER and the XPB helicase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74551 17174478 95518 6736 3435 ERCC3 XPB XPB 3 2.4 Defining the Af XPB structural biochemistry has uncovered some unexpected structural motifs and functions 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74552 17174478 95518 6736 3435 ERCC3 XPB XPB 15 2.4 biochemistry has uncovered some unexpected structural motifs and functions for XPB 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74553 17174478 95519 6736 3435 ERCC3 XPB XPB 2 2.4 However Af XPB only correlates to the central region of human XPB 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74554 17174478 95519 6736 3435 ERCC3 XPB XPB 11 2.4 Af XPB only correlates to the central region of human XPB 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74555 17174478 95520 6736 3435 ERCC3 XPB XPB 12 2.4 exclusively occur in the N- and C-terminal extensions of human XPB suggesting that mutation to the conserved XPB central region is 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74556 17174478 95520 6736 3435 ERCC3 XPB XPB 19 2.4 extensions of human XPB suggesting that mutation to the conserved XPB central region is lethal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74557 17174478 95521 6736 3435 ERCC3 XPB XPB 1 2.4 Af XPB reflects the basic structure and function of XPB helicases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74558 17174478 95521 6736 3435 ERCC3 XPB XPB 9 2.4 Af XPB reflects the basic structure and function of XPB helicases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74559 17174478 95522 6736 3435 ERCC3 XPB XPB 6 2.4 However the extensions to the human XPB are likely to contribute to a greater level of complexity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74560 17174478 95523 6736 3435 ERCC3 XPB XPB 10 2.4 Phosphorylation of residue S751 at the C-terminal extension of human XPB was reported to regulate TFIIH activity in NER reactions ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74561 17174478 95523 6736 3435 ERCC3 TFIIH TFIIH 15 2.7 the C-terminal extension of human XPB was reported to regulate TFIIH activity in NER reactions ( Coin et al. 2004 1 JUMiner_v2.2 1 0 0 2 3435 TotalCon:5<>3435|ERCC3|2071|Complete__4656|GTF2H2|2966|Complete__4657|GTF2H3|2967|Complete__4655|GTF2H1|2965|Complete__4658|GTF2H4|2968|Complete__<>AvaiableGeneRif=5<>BEST:3435|ERCC3|0.00287469287469287<>ScoreDetail__4656|GTF2H2|0.0025974025974026__4658|GTF2H4|0.00176390773405699__4657|GTF2H3|0__3435|ERCC3|0.00287469287469287__4655|GTF2H1|0.00230055658627087__ 0 0 0 0 0 74562 17174478 95523 14635 7965 NR1H2 NER NER 18 1.3 of human XPB was reported to regulate TFIIH activity in NER reactions ( Coin et al. 2004 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74563 17174478 95524 6736 3435 ERCC3 XPB XPB 6 2.4 The physical and functional interactions between XPB and other proteins within and outside of the TFIIH complex 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74564 17174478 95524 6736 3435 ERCC3 TFIIH TFIIH 15 2.7 between XPB and other proteins within and outside of the TFIIH complex have been investigated recently ( Jawhari et al. 2002 1 JUMiner_v2.2 1 0 0 2 3435 TotalCon:5<>3435|ERCC3|2071|Complete__4656|GTF2H2|2966|Complete__4657|GTF2H3|2967|Complete__4655|GTF2H1|2965|Complete__4658|GTF2H4|2968|Complete__<>AvaiableGeneRif=5<>BEST:3435|ERCC3|0.00287469287469287<>ScoreDetail__4656|GTF2H2|0.0025974025974026__4658|GTF2H4|0.00176390773405699__4657|GTF2H3|0__3435|ERCC3|0.00287469287469287__4655|GTF2H1|0.00230055658627087__ 0 0 0 0 0 74565 17174478 95525 6736 3435 ERCC3 TFIIH TFIIH 11 2.7 occur in the extensions and have profound effects on the TFIIH activities in transcription or DNA repair 1 JUMiner_v2.2 1 0 0 2 3435 TotalCon:5<>3435|ERCC3|2071|Complete__4656|GTF2H2|2966|Complete__4657|GTF2H3|2967|Complete__4655|GTF2H1|2965|Complete__4658|GTF2H4|2968|Complete__<>AvaiableGeneRif=5<>BEST:3435|ERCC3|0.00287469287469287<>ScoreDetail__4656|GTF2H2|0.0025974025974026__4658|GTF2H4|0.00176390773405699__4657|GTF2H3|0__3435|ERCC3|0.00287469287469287__4655|GTF2H1|0.00230055658627087__ 0 0 0 0 0 74566 17174478 95526 6736 3435 ERCC3 XPB XPB 13 2.4 that future studies will similarly uncover new functions for human XPB 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74567 17174478 95527 6736 3435 ERCC3 TFIIH TFIIH 23 2.7 features highlighted above will fit into the ring-structure of human TFIIH complex ( Chang and Kornberg 2000 Schultz et al. 2000 1 JUMiner_v2.2 1 0 0 2 3435 TotalCon:5<>3435|ERCC3|2071|Complete__4656|GTF2H2|2966|Complete__4657|GTF2H3|2967|Complete__4655|GTF2H1|2965|Complete__4658|GTF2H4|2968|Complete__<>AvaiableGeneRif=5<>BEST:3435|ERCC3|0.00287469287469287<>ScoreDetail__4656|GTF2H2|0.0025974025974026__4658|GTF2H4|0.00176390773405699__4657|GTF2H3|0__3435|ERCC3|0.00287469287469287__4655|GTF2H1|0.00230055658627087__ 0 0 0 0 0 74568 17174478 95531 18723 10261 ROS1 ROS ROS 46 0.0 through mutations in specific residues such as observed in the ROS controlling superoxide dismutases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74569 17174478 95534 14533 7872 NOS1 NOS NOS 11 2.7 significant example is the fine control of activities of the NOS holo-enzyme suggested to occur through either promoting or inhibiting a 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74570 17174478 95537 17887 9817 RAD51 RAD51 Rad51 9 1.6 A significant example of protein interface mimicry occurs in Rad51 filament formation which is central to HRR steps 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74571 17174478 95538 17887 9817 RAD51 RAD51 Rad51 14 1.6 that filament formation occurs by the sequential binding of adjacent Rad51 monomers mimicking a BRC repeat 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74572 17174478 95539 1755 1101 BRCA2 BRCA2 BRCA2 8 0.8 This BRC repeat is normally found in the BRCA2 partner that mediates critical functions of Rad51 ( Pellegrini et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74573 17174478 95539 17887 9817 RAD51 RAD51 Rad51 15 1.6 found in the BRCA2 partner that mediates critical functions of Rad51 ( Pellegrini et al. 2002 Shin et al. 2003 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74574 17174478 95543 18723 10261 ROS1 ROS ROS 32 0.0 progression that provide genomic stability and protection from insults from ROS and DNA damage agents 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74575 17174478 95547 24250 12791 WRN WRN WRN 6 3.5 This includes MRN complex or the WRN RecQ helicase which may prove to be suitable targets for 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74576 17174478 95548 14533 7872 NOS1 NOS NOS 1 2.7 The NOS isoforms also have multiple functions that may be targets for 11 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000765840848201864<>ScoreDetail__7873|NOS2A|0.000583943663295171__7872|NOS1|0.000765840848201864__ 0 0 0 0 0 74863 17191135 96081 18723 10261 ROS1 ROS ROS 6 0.6 However while excess reactive oxygen species (ROS) ROS are toxic regulated ROS play an important role in cell 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 74864 17191135 96081 18723 10261 ROS1 ROS ROS 10 0.6 while excess reactive oxygen species (ROS) ROS are toxic regulated ROS play an important role in cell signaling 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 74865 17191135 96082 6554 3309 ELA2 HNE HNE 20 0.0 of the product of polyunsaturated fatty acid peroxidation (hydroxynonenals, hydroxynonenals HNE or cholesterol oxidation can disrupt redox homeostasis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74866 17191135 96085 18723 10261 ROS1 ROS ROS 18 0.6 is generally associated with metabolic derangements and excessive production of ROS 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 74867 17191135 96093 122 80 ABP1 ABP ABP 8 0.3 Specifically any dietary components that inhibit inappropriate inflammation ABP oligomerization and consequent increased apoptosis are of particular interest with 1 JUMiner_v2.2 1 0 0 2 10839 TotalCon:2<>80|ABP1|26|Complete__10839|SHBG|6462|Complete__<>AvaiableGeneRif=2<>BEST:10839|SHBG|0.00042022616685875<>ScoreDetail__80|ABP1|0.000281036389679619__10839|SHBG|0.00042022616685875__ 0 0 0 0 0 74868 17191135 96096 926 620 APP amyloid amyloid 21 1.3 as a novel nutritional approach to reduce oxidative damage and amyloid pathology in AD 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 74869 17191135 96101 18723 10261 ROS1 ROS ROS 16 0.6 uptake by cells is converted into reactive oxygen species (ROS) ROS 1 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 74870 17191135 96103 18723 10261 ROS1 ROS ROS 9 0.6 In contrast to this physiological role pathological actions of ROS occur at an order of magnitude higher concentrations 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 74871 17191135 96106 18723 10261 ROS1 ROS ROS 5 0.6 Indeed continuous low concentrations of ROS induce expression of antioxidant enzymes and related defense mechanisms 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 74872 17191135 96107 20996 11179 SOD1 ALS ALS 13 1.9 s diseases (HD), HD but also amyotrophic lateral scelrosis (ALS) ALS and Friedreich_amp_#8217 s ataxia (FRDA) FRDA belong to the so-called 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000570340949044605<>ScoreDetail__5468|IGFALS|0.000429859285933318__11179|SOD1|0.000570340949044605__ 0 0 0 0 0 74873 17191135 96107 7975 3951 FXN FRDA FRDA 17 1.5 amyotrophic lateral scelrosis (ALS) ALS and Friedreich_amp_#8217 s ataxia (FRDA) FRDA belong to the so-called _amp_#8220 protein conformational diseases_amp_#8221 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74874 17191135 96111 18723 10261 ROS1 ROS ROS 20 0.6 stress which leads to mitochondrial dysfunction and excessive production of ROS thus inducing oxidative stress 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 74875 17191135 96112 18723 10261 ROS1 ROS ROS 9 0.6 The ability of a cell to deal with excessive ROS as well as excessive reactive nitrogen species (RNS) RNS requires 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 74876 17191135 96112 6981 22140 FAM20C RNS RNS 17 0.6 excessive ROS as well as excessive reactive nitrogen species (RNS) RNS requires the activation of pro-survival pathways as well as the 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74877 17191135 96113 9462 5013 HMOX1 HO-1 HO-1 2 6.5 Heme oxygenase-1 (HO-1), HO-1 also referred to as Hsp32 belongs to the Hsps family 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74878 17191135 96114 1681 1062 BLVRA BVR BVR 8 0.9 This latter is then reduced by biliverdin reductase (BVR) BVR into bilirubin (BR), BR a linear tetrapyrrole with antioxidant properties 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74879 17191135 96115 6981 22140 FAM20C RNS RNS 21 0.6 stress through its properties to bind and inactivate NO and RNS 11 -14 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74880 17191135 96116 9462 5013 HMOX1 HO-1 HO-1 12 6.5 1 ( A Cellular stress response and the interplay between HO-1 and TRXr 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74881 17191135 96118 9691 5232 HSPA1A HSP Hsp 0 1.9 Hsp response is also involved in cellular homeostasis during various physiological 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74882 17191135 96120 14345 7782 NFE2L2 NRF2 Nrf2 11 2.1 activation (via via acetylation of the redox sensitive transcription factor Nrf2 and its consequent binding to the antioxidant responsive element (ARE) 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.00155191154741079<>ScoreDetail__7782|NFE2L2|0.00155191154741079__4071|GABPA|0.000525009545628102__ 0 0 0 0 0 74883 17191135 96120 9462 5013 HMOX1 HO-1 HO-1 27 6.5 antioxidant responsive element (ARE) ARE in the HO gene up-regulates HO-1 and TRXr thus counteracting nitrosative stress and NO-mediated neurotoxicity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74884 17191135 96121 1493 14078 BACH2 BACH2 Bach-2 12 0.3 same figure are described the respective roles of protein factors Bach-2 (positive) positive and Keap (negative) negative in the Nrf2 activation 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74885 17191135 96121 14345 7782 NFE2L2 NRF2 Nrf2 19 2.1 factors Bach-2 (positive) positive and Keap (negative) negative in the Nrf2 activation as well as the redox cycling between Bilirubin and 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.00155191154741079<>ScoreDetail__7782|NFE2L2|0.00155191154741079__4071|GABPA|0.000525009545628102__ 0 0 0 0 0 74886 17191135 96121 1681 1062 BLVRA BVR BVR 34 0.9 the redox cycling between Bilirubin and biliverdin through the enzyme BVR 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74887 17191135 96122 9462 5013 HMOX1 HO-1 HO-1 3 6.5 OxS oxidative stress HO-1 heme oxygenase TRXr thioredoxin reductase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74888 17191135 96123 23454 12435 TXN TRX TRX 0 2.5 TRX Thioredoxin SH (reduced reduced form S-S oxidized form 1 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 74889 17191135 96124 9462 5013 HMOX1 HO-1 HO-1 5 6.5 ( B Regulation of HO-1 gene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74890 17191135 96125 14345 7782 NFE2L2 NRF2 Nrf2 5 2.1 Nuclear factor-erythroid 2-related factor 2 (Nrf2) Nrf2 is a transcription factor responsible for the induction of several 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.00155191154741079<>ScoreDetail__7782|NFE2L2|0.00155191154741079__4071|GABPA|0.000525009545628102__ 0 0 0 0 0 74891 17191135 96125 9462 5013 HMOX1 HO-1 HO-1 24 6.5 of several genes related to the cellular stress response including HO-1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74892 17191135 96126 14345 7782 NFE2L2 NRF2 Nrf2 3 2.1 Under normal conditions Nrf2 is sequestered in the cytoplasm by an actin-binding protein Kelch-like 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.00155191154741079<>ScoreDetail__7782|NFE2L2|0.00155191154741079__4071|GABPA|0.000525009545628102__ 0 0 0 0 0 74893 17191135 96126 10983 23177 KEAP1 KEAP1 Keap1 18 0.3 by an actin-binding protein Kelch-like ECH associating protein 1 (Keap1), Keap1 but upon exposure of cells to oxidative stress Nrf2 dissociates 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74894 17191135 96126 14345 7782 NFE2L2 NRF2 Nrf2 27 2.1 (Keap1), Keap1 but upon exposure of cells to oxidative stress Nrf2 dissociates from Keap1 translocates to the nucleus binds to antioxidant 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.00155191154741079<>ScoreDetail__7782|NFE2L2|0.00155191154741079__4071|GABPA|0.000525009545628102__ 0 0 0 0 0 74895 17191135 96126 10983 23177 KEAP1 KEAP1 Keap1 30 0.3 upon exposure of cells to oxidative stress Nrf2 dissociates from Keap1 translocates to the nucleus binds to antioxidant responsive elements (AREs), 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74896 17191135 96126 9462 5013 HMOX1 HO-1 HO-1 43 6.5 nucleus binds to antioxidant responsive elements (AREs), AREs and activates HO-1 gene This review will emphasize the role of free radicals 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74897 17191135 96127 9462 5013 HMOX1 HO-1 HO-1 14 6.5 role played by members of the vitagene system such as HO-1 and Thioredoxin (Fig Fig 1 A in modulating the onset 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74898 17191135 96135 18723 10261 ROS1 ROS ROS 6 0.6 As a consequence of this aggregation ROS formation increases and a pro-oxidant environment takes place 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 74899 17191135 96139 20997 11180 SOD2 Mn-SOD Mn-SOD 14 1.9 genes such as heme oxygenase thioredoxin and detoxificant enzymes (Mn-SOD, Mn-SOD glutathione S-transferase NADPH quinone reductase cytokine immunoreceptors and growth factors 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74900 17191135 96140 18723 10261 ROS1 ROS ROS 13 0.6 heme oxygenase could _amp_#8220 sense_amp_#8221 NO and thus protect against ROS and RNS insults is supported by the following findings (a) 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 74901 17191135 96140 6981 22140 FAM20C RNS RNS 15 0.6 could _amp_#8220 sense_amp_#8221 NO and thus protect against ROS and RNS insults is supported by the following findings (a) a NO 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74902 17191135 96140 9462 5013 HMOX1 HO-1 HO-1 29 6.5 the following findings (a) a NO and NO-related species induce HO-1 expression and increase heme oxygenase activity in human glioblastoma cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74903 17191135 96141 6981 22140 FAM20C RNS RNS 5 0.6 The conception that NO and RNS can be directly involved in the modulation of HO-1 expression 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74904 17191135 96141 9462 5013 HMOX1 HO-1 HO-1 14 6.5 and RNS can be directly involved in the modulation of HO-1 expression in eukaryotes is based on the evidence that different 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74905 17191135 96141 9462 5013 HMOX1 HO-1 HO-1 30 6.5 on the evidence that different NO-releasing agents can markedly increase HO-1 and Hsp70 in a variety of tissues including brain cells 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74906 17191135 96141 9691 5232 HSPA1A HSP70 Hsp70 32 3.5 evidence that different NO-releasing agents can markedly increase HO-1 and Hsp70 in a variety of tissues including brain cells 19 20 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74907 17191135 96142 10676 6121 IRF6 LPS LPS 7 0.6 In rat glial cells treatment with lipopolysaccaride (LPS) LPS and interferon-G (IFN-G) IFN-G promotes a rapid increase in both 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>12728|VWS||No_GeneRif__6121|IRF6|3664|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 74908 17191135 96142 9905 5438 IFNG IFNG IFN-G 10 0.8 glial cells treatment with lipopolysaccaride (LPS) LPS and interferon-G (IFN-G) IFN-G promotes a rapid increase in both iNOS expression and nitrite 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74909 17191135 96142 14535 7873 NOS2A iNOS iNOS 17 3.2 and interferon-G (IFN-G) IFN-G promotes a rapid increase in both iNOS expression and nitrite levels followed by enhancement of Hsp70 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74910 17191135 96142 9691 5232 HSPA1A HSP70 Hsp70 26 3.5 both iNOS expression and nitrite levels followed by enhancement of Hsp70 3 20 whereas the modulation of HO-1 mRNA expression by 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74911 17191135 96142 9462 5013 HMOX1 HO-1 HO-1 36 6.5 by enhancement of Hsp70 3 20 whereas the modulation of HO-1 mRNA expression by iNOS-derived NO following stimulation with LPS has 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74912 17191135 96142 14535 7873 NOS2A iNOS iNOS-derived 40 2.7 3 20 whereas the modulation of HO-1 mRNA expression by iNOS-derived NO following stimulation with LPS has also been reported in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74913 17191135 96142 10676 6121 IRF6 LPS LPS 45 0.6 of HO-1 mRNA expression by iNOS-derived NO following stimulation with LPS has also been reported in different brain regions particularly in 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>12728|VWS||No_GeneRif__6121|IRF6|3664|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 74914 17191135 96143 14535 7873 NOS2A iNOS iNOS 5 3.2 Moreover the early increase in iNOS protein levels observed in endothelial cells exposed to low oxygen 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74915 17191135 96143 9462 5013 HMOX1 HO-1 HO-1 23 6.5 to low oxygen tension seems to precede the stimulation of HO-1 expression and activity an effect that appears to be finely 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74916 17191135 96144 9462 5013 HMOX1 HO-1 HO-1 25 6.5 molecule which by triggering expression of cytoprotective genes such as HO-1 and Hsp70 may lead to adaptation and resistance of brain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74917 17191135 96144 9691 5232 HSPA1A HSP70 Hsp70 27 3.5 by triggering expression of cytoprotective genes such as HO-1 and Hsp70 may lead to adaptation and resistance of brain cells to 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74918 17191135 96145 9462 5013 HMOX1 HO-1 HO-1 20 6.5 sites within the promoter and distal enhancer regions of the HO-1 gene such as Fos/Jun Fos Jun activator protein-1 (AP-1)], AP-1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74919 17191135 96145 7683 3796 FOS FOS Fos 24 1.8 distal enhancer regions of the HO-1 gene such as Fos/Jun Fos Jun activator protein-1 (AP-1)], AP-1 nuclear factor-kB (NFkB) NFkB and 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74920 17191135 96145 10824 6204 JUN AP-1 AP-1 27 1.6 HO-1 gene such as Fos/Jun Fos Jun activator protein-1 (AP-1)], AP-1 nuclear factor-kB (NFkB) NFkB and the more recently identified Nrf2 1 JUMiner_v2.2 1 0 0 2 6204 TotalCon:5<>3796|FOS|2353|Complete__3797|FOSB|2354|Complete__6204|JUN|3725|Complete__6205|JUNB|3726|Complete__6206|JUND|3727|Complete__<>AvaiableGeneRif=5<>BEST:6204|JUN|0.00077545260429419<>ScoreDetail__3796|FOS|0.000631914674627876__3797|FOSB|0.000554782843078888__6205|JUNB|0.00063223039517478__6204|JUN|0.00077545260429419__6206|JUND|0.00070916977257676__ 0 0 0 0 0 74921 17191135 96145 14352 7794 NFKB1 NFKB NFkB 30 0.6 Fos/Jun Fos Jun activator protein-1 (AP-1)], AP-1 nuclear factor-kB (NFkB) NFkB and the more recently identified Nrf2 proteins 24 -26 (Fig 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74922 17191135 96145 14345 7782 NFE2L2 NRF2 Nrf2 36 2.1 AP-1 nuclear factor-kB (NFkB) NFkB and the more recently identified Nrf2 proteins 24 -26 (Fig Fig 1 B contain cysteine residues 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.00155191154741079<>ScoreDetail__7782|NFE2L2|0.00155191154741079__4071|GABPA|0.000525009545628102__ 0 0 0 0 0 74923 17191135 96147 9462 5013 HMOX1 HO-1 HO-1 22 6.5 and complex IV inhibition an effect associated with up-regulation of HO-1 and nuclear translocation of the transcription factor Nrf-2 27 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74924 17191135 96147 14345 7782 NFE2L2 NRF2 Nrf-2 30 1.6 up-regulation of HO-1 and nuclear translocation of the transcription factor Nrf-2 27 1 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.00155191154741079<>ScoreDetail__7782|NFE2L2|0.00155191154741079__4071|GABPA|0.000525009545628102__ 0 0 0 0 0 74925 17191135 96156 9726 5269 HSPE1 HSP10 Hsp10 7 1.9 Some of the known Hsps include ubiquitin Hsp10 Hsp27 Hsp32 (or or HO-1 Hsp47 Hsp60 Hsc70 Hsp70 (or 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74926 17191135 96156 9708 5247 HSPB2 HSP27 Hsp27 8 1.9 Some of the known Hsps include ubiquitin Hsp10 Hsp27 Hsp32 (or or HO-1 Hsp47 Hsp60 Hsc70 Hsp70 (or or 2 JUMiner_v2.2 1 0 0 2 5246 TotalCon:2<>5246|HSPB1|3315|Complete__5247|HSPB2|3316|Complete__<>AvaiableGeneRif=2<>BEST:5246|HSPB1|0.000908602424758586<>ScoreDetail__5246|HSPB1|0.000908602424758586__5247|HSPB2|0.000783297072361479__ 0 0 0 0 0 74927 17191135 96156 9462 5013 HMOX1 HO-1 HO-1 11 6.5 the known Hsps include ubiquitin Hsp10 Hsp27 Hsp32 (or or HO-1 Hsp47 Hsp60 Hsc70 Hsp70 (or or Hsp72 Hsp90 and Hsp100/105 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74928 17191135 96156 19730 1546 SERPINH1 HSP47 Hsp47 12 1.3 known Hsps include ubiquitin Hsp10 Hsp27 Hsp32 (or or HO-1 Hsp47 Hsp60 Hsc70 Hsp70 (or or Hsp72 Hsp90 and Hsp100/105 Hsp100 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74929 17191135 96156 9718 5261 HSPD1 HSP60 Hsp60 13 1.9 Hsps include ubiquitin Hsp10 Hsp27 Hsp32 (or or HO-1 Hsp47 Hsp60 Hsc70 Hsp70 (or or Hsp72 Hsp90 and Hsp100/105 Hsp100 105 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74930 17191135 96156 9700 5241 HSPA8 HSC70 Hsc70 14 1.9 include ubiquitin Hsp10 Hsp27 Hsp32 (or or HO-1 Hsp47 Hsp60 Hsc70 Hsp70 (or or Hsp72 Hsp90 and Hsp100/105 Hsp100 105 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74931 17191135 96156 9691 5232 HSPA1A HSP70 Hsp70 15 3.5 ubiquitin Hsp10 Hsp27 Hsp32 (or or HO-1 Hsp47 Hsp60 Hsc70 Hsp70 (or or Hsp72 Hsp90 and Hsp100/105 Hsp100 105 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74932 17191135 96156 9691 5232 HSPA1A HSP72 Hsp72 17 2.9 Hsp32 (or or HO-1 Hsp47 Hsp60 Hsc70 Hsp70 (or or Hsp72 Hsp90 and Hsp100/105 Hsp100 105 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74933 17191135 96156 9676 5253 HSP90AA1 Hsp90 Hsp90 18 3.4 (or or HO-1 Hsp47 Hsp60 Hsc70 Hsp70 (or or Hsp72 Hsp90 and Hsp100/105 Hsp100 105 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74934 17191135 96159 9700 5241 HSPA8 HSC70 Hsc70 5 1.9 Included in this family are Hsc70 (heat heat shock cognate the constitutive form Hsp70 (the the 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74935 17191135 96159 9691 5232 HSPA1A HSP70 Hsp70 12 3.5 family are Hsc70 (heat heat shock cognate the constitutive form Hsp70 (the the inducible form also referred to as Hsp72 GRP75 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74936 17191135 96159 9691 5232 HSPA1A HSP72 Hsp72 20 2.9 form Hsp70 (the the inducible form also referred to as Hsp72 GRP75 (a a constitutively expressed glucose-regulated protein found in the 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74937 17191135 96159 9701 5244 HSPA9 GRP75 GRP75 21 1.9 Hsp70 (the the inducible form also referred to as Hsp72 GRP75 (a a constitutively expressed glucose-regulated protein found in the endoplasmic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74938 17191135 96160 9691 5232 HSPA1A HSP70 Hsp70 9 3.5 After a variety of central nervous system (CNS) CNS insults Hsp70 is synthesized at high levels and is present in cytosol 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74939 17191135 96162 10463 6018 IL6 HSF HSFs 7 0.3 These denaturated proteins activate heat shock factors (HSFs) HSFs within the cytosol (or or ER by dissociating other Hsps 13 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74940 17191135 96162 10463 6018 IL6 HSF HSF 20 0.3 (or or ER by dissociating other Hsps normally bound to HSF 34 13 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74941 17191135 96163 10463 6018 IL6 HSF HSF 1 0.3 Freed HSF is phosphorylated and forms trimers which enter the nucleus and 13 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74942 17191135 96163 9652 23316 HSD17B6 HSE HSE 17 0.0 enter the nucleus and bind to heat shock elements (HSE) HSE within the promoters of different heat shock genes leading to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74943 17191135 96164 9691 5232 HSPA1A HSP70 Hsp70 5 3.5 After heat shock synthesis of Hsp70 may increase to become the most abundant protein in the 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74944 17191135 96165 9691 5232 HSPA1A HSP70 Hsp70 2 3.5 Once synthesized Hsp70 binds to denaturated proteins in an ATP-dependent manner 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74945 17191135 96168 9691 5232 HSPA1A HSP70 Hsp70 18 3.5 cytokine-induced nitrosative stress is associated with an increased synthesis of Hsp70 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74946 17191135 96169 9691 5232 HSPA1A HSP70 Hsp70 2 3.5 Increase in Hsp70 protein expression was also found after treatment of cells with 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74947 17191135 96169 9691 5232 HSPA1A HSP70 Hsp70 28 3.5 (SNP), SNP thus suggesting a role for NO in inducing Hsp70 proteins 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74948 17191135 96171 9691 5232 HSPA1A HSP72 Hsp72 2 2.9 Induction of Hsp72 under stress conditions is often accompanied by the induction of 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74949 17191135 96172 9462 5013 HMOX1 HO-1 HO-1 28 6.5 toxicity by acting at three different levels (i) i inducing HO-1 and Hsp72 proteins (ii) ii decreasing the neuronal 3-nitrotyrosine levels 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74950 17191135 96172 9691 5232 HSPA1A HSP72 Hsp72 30 2.9 acting at three different levels (i) i inducing HO-1 and Hsp72 proteins (ii) ii decreasing the neuronal 3-nitrotyrosine levels and therefore 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74951 17191135 96172 14535 7873 NOS2A NOS NOS 41 2.7 (ii) ii decreasing the neuronal 3-nitrotyrosine levels and therefore inducible NOS activity and (iii) iii by the well known direct free 1 JUMiner_v2.2 1 0 0 2 7873 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7873|NOS2A|0.000591049358800701<>ScoreDetail__7873|NOS2A|0.000591049358800701__7872|NOS1|0.000524055369725158__ 0 0 0 0 0 74952 17191135 96175 9691 5232 HSPA1A HSP70 Hsp70 6 3.5 During translocation this proteins interact with Hsp70 ATP-dependent binding and the release of Hsp70 provide the major 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74953 17191135 96175 9691 5232 HSPA1A HSP70 Hsp70 13 3.5 proteins interact with Hsp70 ATP-dependent binding and the release of Hsp70 provide the major driving force for complete transport of polypeptides 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74954 17191135 96176 9691 5232 HSPA1A HSP70 Hsp70 8 3.5 Although most imported polypeptides are released from soluble Hsp70 however a subset of aggregation-sensitive polypeptides must be transferred from 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74955 17191135 96176 9691 5232 HSPA1A HSP70 Hsp70 19 3.5 however a subset of aggregation-sensitive polypeptides must be transferred from Hsp70 to Hsp60 for folding 40 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74956 17191135 96176 9718 5261 HSPD1 HSP60 Hsp60 21 1.9 subset of aggregation-sensitive polypeptides must be transferred from Hsp70 to Hsp60 for folding 40 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74957 17191135 96177 9691 5232 HSPA1A HSP70 Hsp70 12 3.5 the close functional interaction between this chaperonin system and the Hsp70 system it is likely that up-regulation of Hsp60 may be 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74958 17191135 96177 9718 5261 HSPD1 HSP60 Hsp60 20 1.9 and the Hsp70 system it is likely that up-regulation of Hsp60 may be a fundamental site targeted by LAC action with 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74959 17191135 96177 11717 6530 LCT LAC LAC 28 0.0 up-regulation of Hsp60 may be a fundamental site targeted by LAC action with consequent restoration of complex IV function under conditions 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74960 17191135 96178 9462 5013 HMOX1 HO-1 HO-1 15 6.5 heme oxygenase (HO) HO isoforms were described an inducible isoform HO-1 and a constitutive isoform HO-2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74961 17191135 96178 9463 5014 HMOX2 HO-2 HO-2 20 1.9 were described an inducible isoform HO-1 and a constitutive isoform HO-2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74962 17191135 96183 9462 5013 HMOX1 HO-1 HO-1 11 6.5 from the identity between the active centers of the enzyme HO-1 and HO-2 broadly differ in cell and tissue regulation and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74963 17191135 96183 9463 5014 HMOX2 HO-2 HO-2 11 1.9 from the identity between the active centers of the enzyme HO-1 and HO-2 broadly differ in cell and tissue regulation and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74964 17191135 96183 9463 5014 HMOX2 HO-2 HO-2 13 1.9 identity between the active centers of the enzyme HO-1 and HO-2 broadly differ in cell and tissue regulation and distribution 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74965 17191135 96184 18723 10261 ROS1 ROS ROS 8 0.6 Heme oxygenase-1 is induced by various stimuli including ROS RNS ischemia heat shock LPS hemin and the neuroprotective agent 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 74966 17191135 96184 6981 22140 FAM20C RNS RNS 9 0.6 Heme oxygenase-1 is induced by various stimuli including ROS RNS ischemia heat shock LPS hemin and the neuroprotective agent Neotrofin 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 74967 17191135 96184 10676 6121 IRF6 LPS LPS 13 0.6 induced by various stimuli including ROS RNS ischemia heat shock LPS hemin and the neuroprotective agent Neotrofin 41 44 -46 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>12728|VWS||No_GeneRif__6121|IRF6|3664|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 74968 17191135 96185 9462 5013 HMOX1 HO-1 HO-1 5 6.5 Furthermore in cultured human cells HO-1 expression can be repressed by hypoxia or by the treatment 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74969 17191135 96186 9463 5014 HMOX2 HO-2 HO-2 3 1.9 On the contrary HO-2 the constitutive form is responsive to developmental factors adrenal glucocorticoids 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74970 17191135 96187 9462 5013 HMOX1 HO-1 HO-1 1 6.5 Although HO-1 and HO-2 catalyze the same reaction they play different roles 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74971 17191135 96187 9463 5014 HMOX2 HO-2 HO-2 1 1.9 Although HO-1 and HO-2 catalyze the same reaction they play different roles 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74972 17191135 96187 9463 5014 HMOX2 HO-2 HO-2 3 1.9 Although HO-1 and HO-2 catalyze the same reaction they play different roles in protecting 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74973 17191135 96188 9462 5013 HMOX1 HO-1 HO-1 5 6.5 The current hypothesis suggests that HO-1 induction is one of the earlier cellular responses to tissue 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74974 17191135 96189 9463 5014 HMOX2 HO-2 HO-2 3 1.9 On the contrary HO-2 constitutively expressed is primarily involved in maintaining cell heme homeostasis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74975 17191135 96191 9462 5013 HMOX1 HO-1 HO-1 3 6.5 The induction of HO-1 is regulated principally by two upstream enhancers E1 and E2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74976 17191135 96192 12203 6776 MAF MAF Maf 22 0.5 called ARE that also conform to the sequence of the Maf recognition element (MARE) MARE 53 with a consensus sequence (GCnnnGTA) 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74977 17191135 96193 14345 7782 NFE2L2 NRF2 Nrf2 12 2.1 evidence to suggest that heterodimers of NF-E2-related factors 2 (Nrf2) Nrf2 and one or another of the small Maf proteins (i.e 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.00155191154741079<>ScoreDetail__7782|NFE2L2|0.00155191154741079__4071|GABPA|0.000525009545628102__ 0 0 0 0 0 74978 17191135 96193 12203 6776 MAF MAF Maf 20 0.5 2 (Nrf2) Nrf2 and one or another of the small Maf proteins (i.e i.e MafK MafF and MafG are directly involved 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74979 17191135 96193 12211 6782 MAFK MAFK MafK 23 0.3 one or another of the small Maf proteins (i.e i.e MafK MafF and MafG are directly involved in induction of HO-1 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74980 17191135 96193 12209 6780 MAFF MAFF MafF 24 0.3 or another of the small Maf proteins (i.e i.e MafK MafF and MafG are directly involved in induction of HO-1 gene 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74981 17191135 96193 9462 5013 HMOX1 HO-1 HO-1 33 6.5 MafK MafF and MafG are directly involved in induction of HO-1 gene through these MAREs 53 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74982 17191135 96193 12210 6781 MAFG MAFG MafG 26 0.1 of the small Maf proteins (i.e i.e MafK MafF and MafG are directly involved in induction of HO-1 gene through these 6 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74983 17191135 96194 14345 7782 NFE2L2 NRF2 Nrf2 5 2.1 A possible model centered on Nrf2 activity suggests that the heme protein Bach1 works as a 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.00155191154741079<>ScoreDetail__7782|NFE2L2|0.00155191154741079__4071|GABPA|0.000525009545628102__ 0 0 0 0 0 74984 17191135 96194 1778 20473 BRIP1 BACH1 Bach1 12 2.4 model centered on Nrf2 activity suggests that the heme protein Bach1 works as a transcriptional repressor (Fig Fig 1 A B 2 JUMiner_v2.2 1 0 0 2 935 TotalCon:2<>935|BACH1|571|Complete__20473|BRIP1|83990|Complete__<>AvaiableGeneRif=2<>BEST:935|BACH1|0.00105162003880115<>ScoreDetail__935|BACH1|0.00105162003880115__20473|BRIP1|0.000321758489038601__ 0 0 0 0 0 74985 17191135 96195 9462 5013 HMOX1 HO-1 HO-1 3 6.5 Hence regulation of HO-1 gene expression by Bach1 and heme occurs through antagonism between 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74986 17191135 96195 1778 20473 BRIP1 BACH1 Bach1 7 2.4 Hence regulation of HO-1 gene expression by Bach1 and heme occurs through antagonism between transcription activators and the 2 JUMiner_v2.2 1 0 0 2 935 TotalCon:2<>935|BACH1|571|Complete__20473|BRIP1|83990|Complete__<>AvaiableGeneRif=2<>BEST:935|BACH1|0.00105162003880115<>ScoreDetail__935|BACH1|0.00105162003880115__20473|BRIP1|0.000321758489038601__ 0 0 0 0 0 74987 17191135 96195 1778 20473 BRIP1 BACH1 Bach1 19 2.4 heme occurs through antagonism between transcription activators and the repressor Bach1 2 JUMiner_v2.2 1 0 0 2 935 TotalCon:2<>935|BACH1|571|Complete__20473|BRIP1|83990|Complete__<>AvaiableGeneRif=2<>BEST:935|BACH1|0.00105162003880115<>ScoreDetail__935|BACH1|0.00105162003880115__20473|BRIP1|0.000321758489038601__ 0 0 0 0 0 74988 17191135 96196 9462 5013 HMOX1 HO-1 HO-1 6 6.5 Under normal physiological conditions expression of HO-1 is repressed by Bach1/Maf Bach1 Maf complex while increased levels 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74989 17191135 96196 1778 20473 BRIP1 BACH1 Bach1 10 2.4 normal physiological conditions expression of HO-1 is repressed by Bach1/Maf Bach1 Maf complex while increased levels of heme displace Bach1 from 2 JUMiner_v2.2 1 0 0 2 935 TotalCon:2<>935|BACH1|571|Complete__20473|BRIP1|83990|Complete__<>AvaiableGeneRif=2<>BEST:935|BACH1|0.00105162003880115<>ScoreDetail__935|BACH1|0.00105162003880115__20473|BRIP1|0.000321758489038601__ 0 0 0 0 0 74990 17191135 96196 12203 6776 MAF MAF Maf 10 0.5 physiological conditions expression of HO-1 is repressed by Bach1/Maf Bach1 Maf complex while increased levels of heme displace Bach1 from the 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74991 17191135 96196 1778 20473 BRIP1 BACH1 Bach1 18 2.4 Bach1/Maf Bach1 Maf complex while increased levels of heme displace Bach1 from the enhancers and allow activators such as heterodimer of 2 JUMiner_v2.2 1 0 0 2 935 TotalCon:2<>935|BACH1|571|Complete__20473|BRIP1|83990|Complete__<>AvaiableGeneRif=2<>BEST:935|BACH1|0.00105162003880115<>ScoreDetail__935|BACH1|0.00105162003880115__20473|BRIP1|0.000321758489038601__ 0 0 0 0 0 74992 17191135 96196 12203 6776 MAF MAF Maf 29 0.5 from the enhancers and allow activators such as heterodimer of Maf with NF-E2 related activators (Nrf2), Nrf2 to interact with the 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74993 17191135 96196 14345 7782 NFE2L2 NF-E2 NF-E2 31 1.6 enhancers and allow activators such as heterodimer of Maf with NF-E2 related activators (Nrf2), Nrf2 to interact with the transcriptional promotion 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 14343 7780 NFE2 0 74994 17191135 96196 14345 7782 NFE2L2 NRF2 Nrf2 34 2.1 such as heterodimer of Maf with NF-E2 related activators (Nrf2), Nrf2 to interact with the transcriptional promotion of HO-1 33 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.00155191154741079<>ScoreDetail__7782|NFE2L2|0.00155191154741079__4071|GABPA|0.000525009545628102__ 0 0 0 0 0 74995 17191135 96196 9462 5013 HMOX1 HO-1 HO-1 42 6.5 activators (Nrf2), Nrf2 to interact with the transcriptional promotion of HO-1 33 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74996 17191135 96197 1681 1062 BLVRA BVR BVR 7 0.9 Heme oxygenase activity is regulated also by BVR because this latter reduces biliverdin (BV), BV the inhibitory product 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74997 17191135 96198 1681 1062 BLVRA BVR BVR 4 0.9 The molecular mass of BVR ranges between 41-42 KDa (human) human and 33-34 KDa (rat), 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74998 17191135 96199 1681 1062 BLVRA BVR BVR 2 0.9 Until now BVR was considered a noninducible protein but recent data showed that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 74999 17191135 96199 10676 6121 IRF6 LPS LPS 19 0.6 recent data showed that the reductase can be induced by LPS and bromobenzene at a post-transcriptional level whereas heat shock has 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>12728|VWS||No_GeneRif__6121|IRF6|3664|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 75000 17191135 96200 1681 1062 BLVRA BVR BVR 4 0.9 In the rat brain BVR is co-expressed in cells that display HO-1 and/or and or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75001 17191135 96200 9462 5013 HMOX1 HO-1 HO-1 11 6.5 the rat brain BVR is co-expressed in cells that display HO-1 and/or and or HO-2 under normal conditions as well as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75002 17191135 96200 9463 5014 HMOX2 HO-2 HO-2 13 1.9 is co-expressed in cells that display HO-1 and/or and or HO-2 under normal conditions as well as in regions and cell 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75003 17191135 96200 9462 5013 HMOX1 HO-1 HO-1 33 6.5 cell types that have the potential to express heat shock-inducible HO-1 protein 57 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75004 17191135 96201 1681 1062 BLVRA BVR BVR 4 0.9 Further evidence demonstrated that BVR exhibited developmental changes with the activity increasing after birth and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75005 17191135 96202 1681 1062 BLVRA BVR BVR 9 0.9 Immunohistochemical analysis revealed age-related pattern of the expression of BVR in select rat brain areas such as the cortex substantia 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75006 17191135 96203 9463 5014 HMOX2 HO-2 HO-2 16 1.9 abundant in reticuloendothelial organs such as liver and spleen whereas HO-2 is localized in specific organs such as brain kidney and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75007 17191135 96204 9463 5014 HMOX2 HO-2 HO-2 16 1.9 high HO activity under basal conditions mostly accounted for by HO-2 the latter being expressed in neuronal populations in forebrain hippocampus 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75008 17191135 96206 9462 5013 HMOX1 HO-1 HO-1 7 6.5 This finding indicates that the activation of HO-1 and the following formation of CO can be induced by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75009 17191135 96207 4928 2355 CRH CRH CRH 14 0.3 within the parvicellular part of the paraventricular nucleus release both CRH and AVP the neuropeptides that initiate the endocrine response to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75010 17191135 96207 14455 16400 NLRP3 AVP AVP 16 0.3 parvicellular part of the paraventricular nucleus release both CRH and AVP the neuropeptides that initiate the endocrine response to a stressor 1 JUMiner_v2.2 1 0 0 2 894 TotalCon:3<>894|AVP|551|Complete__16400|NLRP3|114548|Complete__5432|IFNAR1|3454|Complete__<>AvaiableGeneRif=3<>BEST:894|AVP|0.000600449511871541<>ScoreDetail__5432|IFNAR1|0.000466924620201651__16400|NLRP3|0.00046775182975843__894|AVP|0.000600449511871541__ 0 0 0 0 0 75011 17191135 96207 16975 9201 POMC ACTH ACTH 32 1.0 endocrine response to a stressor stimulating the release of pituitary ACTH 44 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75012 17191135 96209 9027 4817 HARS2 HO3 HO-3 13 0.8 Maines and her group described a third HO isoform called HO-3 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75013 17191135 96211 9027 4817 HARS2 HO3 HO-3 13 0.8 paper Scapagnini et al investigated the regional brain expression of HO-3 and they found that this isoform is expressed mainly in 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75014 17191135 96212 9027 4817 HARS2 HO3 HO-3 3 0.8 The regulation of HO-3 gene expression and its synthesis is poorly understood and its 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75015 17191135 96213 23454 12435 TXN TRX Trx 5 2.5 The thioredoxin system The thioredoxin (Trx) Trx system (Trx Trx and Trx reductase has received a considerable 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75016 17191135 96213 23454 12435 TXN TRX Trx 7 2.5 The thioredoxin system The thioredoxin (Trx) Trx system (Trx Trx and Trx reductase has received a considerable attention in the 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75017 17191135 96213 23454 12435 TXN TRX Trx 9 2.5 thioredoxin system The thioredoxin (Trx) Trx system (Trx Trx and Trx reductase has received a considerable attention in the last years 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75018 17191135 96214 23454 12435 TXN TRX Trx 0 2.5 Trx is a ubiquitous thiol oxidoreductase system that regulates cellular redox 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75019 17191135 96215 23454 12435 TXN TRX Trx 19 2.5 a hydrogen donor for ribonucleotide reductase required for DNA synthesis Trx plays an essential role in cell function by limiting oxidative 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75020 17191135 96216 23454 12435 TXN TRX Trx 20 2.5 of many processes is provided by an interaction between the Trx and GSH systems 62 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75021 17191135 96217 23454 12435 TXN TRX Trx 2 2.5 In fact Trx and GSH systems are involved in a variety of redox-dependent 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75022 17191135 96220 23454 12435 TXN TRX Trx 1 2.5 The Trx system rather may play a critical role in the redox 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75023 17191135 96221 23454 12435 TXN TRX Trx 16 2.5 reduced form by TrxR and NADPH collectively known as the Trx system 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75024 17191135 96222 23454 12435 TXN TRX Trx 0 2.5 Trx reductase belongs to the flavoprotein family of pyridine nucleotide disulfide 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75025 17191135 96223 1755 1101 BRCA2 FAD FAD 14 0.3 which each monomer includes two prosthetic flavin adenine dinucleotide (FAD) FAD groups and a NADPH binding site 1 JUMiner_v2.2 1 2 nadph 0 2 3585 TotalCon:3<>1101|BRCA2|675|Complete__3585|FANCD2|2177|Complete__9508|PSEN1|5663|Complete__<>AvaiableGeneRif=3<>BEST:3585|FANCD2|0.000616414966919063<>ScoreDetail__1101|BRCA2|0.000291740765865872__9508|PSEN1|0.000550124664860037__3585|FANCD2|0.000616414966919063__ 0 0 0 0 0 75026 17191135 96224 1755 1101 BRCA2 FAD FAD 18 0.3 consisting of two cysteines adjacent to the flavin ring of FAD in the N-terminal part of the protein 1 JUMiner_v2.2 1 2 nadph 0 2 3585 TotalCon:3<>1101|BRCA2|675|Complete__3585|FANCD2|2177|Complete__9508|PSEN1|5663|Complete__<>AvaiableGeneRif=3<>BEST:3585|FANCD2|0.000616414966919063<>ScoreDetail__1101|BRCA2|0.000291740765865872__9508|PSEN1|0.000550124664860037__3585|FANCD2|0.000616414966919063__ 0 0 0 0 0 75027 17191135 96226 23454 12435 TXN TRX Trx 18 2.5 the catalytic activity of mammalian TrxR toward reduction of oxidized Trx and various antioxidant molecules such as lipoic acid ascorbic acid 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75028 17191135 96234 23454 12435 TXN TRX Trx 0 2.5 Trx which behaves as a soluble protein after disruption of cells 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75029 17191135 96234 23454 12435 TXN TRX1 Trx-1 18 3.0 of cells exists as one of the cytoplasmic proteins (Trx-1) Trx-1 and a mitochondrial (Trx-2) Trx-2 isoform 60 11 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75030 17191135 96234 23455 17772 TXN2 TRX2 Trx-2 22 1.3 of the cytoplasmic proteins (Trx-1) Trx-1 and a mitochondrial (Trx-2) Trx-2 isoform 60 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75031 17191135 96235 23454 12435 TXN TRX1 Trx-1 10 3.0 A growing number of studies report a striking association between Trx-1 up-regulation in the CNS and neuron survival following various injuries 11 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75032 17191135 96236 23454 12435 TXN TRX1 Trx-1 0 3.0 Trx-1 and TrxR the most extensively studied eukaryotic thioredoxin proteins were 11 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75033 17191135 96237 23454 12435 TXN TRX1 Trx-1 0 3.0 Trx-1 has been then found widely expressed in rat brain especially 11 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75034 17191135 96238 23454 12435 TXN TRX1 Trx-1 3 3.0 Immunohistochemical analysis of Trx-1 in human brain showed positive Trx1-like staining in white matter 11 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75035 17191135 96239 23454 12435 TXN TRX Trx 4 2.5 The promoter of the Trx gene contains a series of stress-responsive elements various transcription factor 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75036 17191135 96239 21038 11205 SP1 SP1 SP1 19 0.6 of stress-responsive elements various transcription factor binding sites such as SP1 GCF and WT-ZFP conferring constitutive expression inducible expression elements such 1 JUMiner_v2.2 1 0 0 2 11205 TotalCon:3<>11205|SP1|6667|Complete__26780|DAND5|199699|No_GeneRif__9514|PSG1|5669|Complete__<>AvaiableGeneRif=2<>BEST:11205|SP1|0.000794334123436801<>ScoreDetail__9514|PSG1|0.000307536098880178__11205|SP1|0.000794334123436801__ 0 0 0 0 0 75037 17191135 96239 2057 1317 C2orf3 GCF GCF 20 0.3 stress-responsive elements various transcription factor binding sites such as SP1 GCF and WT-ZFP conferring constitutive expression inducible expression elements such as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75038 17191135 96239 10824 6204 JUN AP-1 AP-1 31 1.6 and WT-ZFP conferring constitutive expression inducible expression elements such as AP-1 AP-2 NF-kB Oct-1 PEA-3 Myb and the antioxidant-responsive element (ARE) 1 JUMiner_v2.2 1 0 0 2 6204 TotalCon:5<>3796|FOS|2353|Complete__3797|FOSB|2354|Complete__6204|JUN|3725|Complete__6205|JUNB|3726|Complete__6206|JUND|3727|Complete__<>AvaiableGeneRif=5<>BEST:6204|JUN|0.00077545260429419<>ScoreDetail__3796|FOS|0.000631914674627876__3797|FOSB|0.000554782843078888__6205|JUNB|0.00063223039517478__6204|JUN|0.00077545260429419__6206|JUND|0.00070916977257676__ 0 0 0 0 0 75039 17191135 96239 22027 11742 TFAP2A AP-2 AP-2 32 1.6 WT-ZFP conferring constitutive expression inducible expression elements such as AP-1 AP-2 NF-kB Oct-1 PEA-3 Myb and the antioxidant-responsive element (ARE) ARE 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75040 17191135 96239 14352 7794 NFKB1 NF-kB NF-kB 33 0.6 conferring constitutive expression inducible expression elements such as AP-1 AP-2 NF-kB Oct-1 PEA-3 Myb and the antioxidant-responsive element (ARE) ARE 71 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75041 17191135 96239 20185 10963 SLC22A1 OCT1 Oct-1 34 0.3 constitutive expression inducible expression elements such as AP-1 AP-2 NF-kB Oct-1 PEA-3 Myb and the antioxidant-responsive element (ARE) ARE 71 11 JUMiner_v2.2 1 0 0 2 9212 TotalCon:2<>9212|POU2F1|5451|Complete__10963|SLC22A1|6580|Complete__<>AvaiableGeneRif=2<>BEST:9212|POU2F1|0.000801597851717757<>ScoreDetail__10963|SLC22A1|0.000501457087467555__9212|POU2F1|0.000801597851717757__ 0 0 0 0 0 75042 17191135 96239 6818 3493 ETV4 PEA3 PEA-3 35 0.3 expression inducible expression elements such as AP-1 AP-2 NF-kB Oct-1 PEA-3 Myb and the antioxidant-responsive element (ARE) ARE 71 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75043 17191135 96239 13916 7545 MYB MYB Myb 36 0.3 inducible expression elements such as AP-1 AP-2 NF-kB Oct-1 PEA-3 Myb and the antioxidant-responsive element (ARE) ARE 71 6 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75044 17191135 96240 23454 12435 TXN TRX1 Trx-1 1 3.0 ARE-mediated Trx-1 induction involves the transcription factor Nfr2 11 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75045 17191135 96241 23454 12435 TXN TRX Trx 6 2.5 Moreover it has been reported that Trx is constitutively present as a surface-associated sulfhydryl protein in plasma 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75046 17191135 96242 23454 12435 TXN TRX Trx 14 2.5 UV irradiation and hydrogen peroxide have been shown to induce Trx expression and secretion as a redox-sensitive molecule with cytokine-like and 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75047 17191135 96243 23454 12435 TXN TRX Trx 31 2.5 and hemin has been reported to cause the translocation of Trx from the cytoplasm to the nucleus where it regulates the 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75048 17191135 96243 10824 6204 JUN AP-1 AP-1 54 1.6 DNA binding activity of critical transcription factors such as the AP-1 family members NF-kB Jun Fos p53 CREB PEBP2/CBF, PEBP2 CBF 1 JUMiner_v2.2 1 0 0 2 6204 TotalCon:5<>3796|FOS|2353|Complete__3797|FOSB|2354|Complete__6204|JUN|3725|Complete__6205|JUNB|3726|Complete__6206|JUND|3727|Complete__<>AvaiableGeneRif=5<>BEST:6204|JUN|0.00077545260429419<>ScoreDetail__3796|FOS|0.000631914674627876__3797|FOSB|0.000554782843078888__6205|JUNB|0.00063223039517478__6204|JUN|0.00077545260429419__6206|JUND|0.00070916977257676__ 0 0 0 0 0 75049 17191135 96243 14352 7794 NFKB1 NF-kB NF-kB 57 0.6 of critical transcription factors such as the AP-1 family members NF-kB Jun Fos p53 CREB PEBP2/CBF, PEBP2 CBF Myb all involved 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75050 17191135 96243 7683 3796 FOS FOS Fos 59 1.8 transcription factors such as the AP-1 family members NF-kB Jun Fos p53 CREB PEBP2/CBF, PEBP2 CBF Myb all involved in fundamental 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75051 17191135 96243 22671 11998 TP53 p53 p53 60 0.6 factors such as the AP-1 family members NF-kB Jun Fos p53 CREB PEBP2/CBF, PEBP2 CBF Myb all involved in fundamental processes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75052 17191135 96243 4911 2345 CREB1 CREB CREB 61 1.9 such as the AP-1 family members NF-kB Jun Fos p53 CREB PEBP2/CBF, PEBP2 CBF Myb all involved in fundamental processes such 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75053 17191135 96243 13916 7545 MYB MYB Myb 63 0.1 family members NF-kB Jun Fos p53 CREB PEBP2/CBF, PEBP2 CBF Myb all involved in fundamental processes such as gene expression cell 6 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75054 17191135 96244 23454 12435 TXN TRX Trx 3 2.5 Plasma levels of Trx in normal individuals vary between 10 and 80 ng/ml; ng 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75055 17191135 96245 23454 12435 TXN TRX1 Trx-1 6 3.0 Of note several studies reported increased Trx-1 expression in many human primary cancers and tumor cell lines 11 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75056 17191135 96246 23454 12435 TXN TRX Trx 1 2.5 Elevated Trx levels may contribute to increased cancer cell proliferation and resistance 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75057 17191135 96247 23454 12435 TXN TRX1 Trx-1 4 3.0 Recent work suggests that Trx-1 play a key role in NGF signaling pathways 74 11 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75058 17191135 96247 14373 7808 NGF NGF NGF 10 0.6 Recent work suggests that Trx-1 play a key role in NGF signaling pathways 74 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75059 17191135 96248 14373 7808 NGF NGF NGF 0 0.6 NGF a neurotrophic factor regulating development maintenance and function of the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75060 17191135 96248 23454 12435 TXN TRX1 Trx-1 17 3.0 and function of the CNS has been shown to activate Trx-1 expression via cyclic AMP (cAMP)-response cAMP -response elements (CREs) CREs 11 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75061 17191135 96248 23454 12435 TXN TRX1 Trx-1 28 3.0 AMP (cAMP)-response cAMP -response elements (CREs) CREs present in the Trx-1 gene promoter and also to induce nuclear translocation of Trx1 11 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75062 17191135 96248 23454 12435 TXN TRX1 Trx1 38 2.5 Trx-1 gene promoter and also to induce nuclear translocation of Trx1 75 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75063 17191135 96249 23454 12435 TXN TRX Trx 17 2.5 to regulate the function of proteins through thiol-disulfide exchange reactions Trx may also have beneficial effects during oxidative stress by transcriptionally 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75064 17191135 96249 9462 5013 HMOX1 HO-1 HO-1 29 6.5 also have beneficial effects during oxidative stress by transcriptionally upregulating HO-1 with important cytoprotective pleiotropic effects deriving from heme degradation biliverdin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75065 17191135 96251 23454 12435 TXN TRX Trx 9 2.5 Besides the role as a source of reducing equivalents Trx by itself acts as antioxidant or ROS scavenger 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75066 17191135 96251 18723 10261 ROS1 ROS ROS 16 0.6 of reducing equivalents Trx by itself acts as antioxidant or ROS scavenger 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 75067 17191135 96252 23454 12435 TXN TRX Trx 2 2.5 In fact Trx eliminates singlet oxygen hydroxyl radical and hydrogen peroxide 78 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75068 17191135 96253 23454 12435 TXN TRX Trx 8 2.5 Another family of proteins acting in conjunction with Trx is the peroxide scavenger Peroxiredoxin (Prx) Prx 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75069 17191135 96253 17269 16753 PRDX6 PRX Prx 14 0.3 in conjunction with Trx is the peroxide scavenger Peroxiredoxin (Prx) Prx 2 JUMiner_v2.2 1 0 0 2 16753 TotalCon:2<>13797|PRX|57716|Complete__16753|PRDX6|9588|Complete__<>AvaiableGeneRif=2<>BEST:16753|PRDX6|0.000904407642412684<>ScoreDetail__16753|PRDX6|0.000904407642412684__13797|PRX|0.00074121081355502__ 0 0 0 0 0 75070 17191135 96254 23454 12435 TXN TRX Trx 23 2.5 antioxidant enzymes most of which use the reducing activity of Trx or other electron donors to catalyze the reduction of peroxides 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75071 17191135 96255 17269 16753 PRDX6 PRX Prx 8 0.3 A number of studies have shown that several Prx isoforms can be induced in brain in response to various 2 JUMiner_v2.2 1 0 0 2 16753 TotalCon:2<>13797|PRX|57716|Complete__16753|PRDX6|9588|Complete__<>AvaiableGeneRif=2<>BEST:16753|PRDX6|0.000904407642412684<>ScoreDetail__16753|PRDX6|0.000904407642412684__13797|PRX|0.00074121081355502__ 0 0 0 0 0 75072 17191135 96256 23454 12435 TXN TRX Trx 3 2.5 As for cytosolic Trx (Trx-1), Trx-1 the induction of Prx-1 appears to involve the 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75073 17191135 96256 23454 12435 TXN TRX1 Trx-1 4 3.0 As for cytosolic Trx (Trx-1), Trx-1 the induction of Prx-1 appears to involve the transcription factor 11 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75074 17191135 96256 17263 9352 PRDX1 PRX1 Prx-1 8 0.3 As for cytosolic Trx (Trx-1), Trx-1 the induction of Prx-1 appears to involve the transcription factor Nrf2 11 JUMiner_v2.2 1 0 0 2 9142 TotalCon:2<>9352|PRDX1|5052|Complete__9142|PRRX1|5396|Complete__<>AvaiableGeneRif=2<>BEST:9142|PRRX1|0.000865361317195306<>ScoreDetail__9352|PRDX1|0.000802147728292869__9142|PRRX1|0.000865361317195306__ 0 0 0 0 0 75075 17191135 96256 14345 7782 NFE2L2 NRF2 Nrf2 15 2.1 the induction of Prx-1 appears to involve the transcription factor Nrf2 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.00155191154741079<>ScoreDetail__7782|NFE2L2|0.00155191154741079__4071|GABPA|0.000525009545628102__ 0 0 0 0 0 75076 17191135 96257 17269 16753 PRDX6 PRX Prx 7 0.3 Recent studies have revealed aberrant patterns of Prx expression in the CNS of patients affected by neurodegenerative disorders 2 JUMiner_v2.2 1 0 0 2 16753 TotalCon:2<>13797|PRX|57716|Complete__16753|PRDX6|9588|Complete__<>AvaiableGeneRif=2<>BEST:16753|PRDX6|0.000904407642412684<>ScoreDetail__16753|PRDX6|0.000904407642412684__13797|PRX|0.00074121081355502__ 0 0 0 0 0 75077 17191135 96258 23454 12435 TXN TRX Trx 4 2.5 A second slightly larger Trx isoform (Trx-2), Trx-2 is also present in mammalian cells where 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75078 17191135 96258 23455 17772 TXN2 TRX2 Trx-2 6 1.3 A second slightly larger Trx isoform (Trx-2), Trx-2 is also present in mammalian cells where exhibits characteristics consistent 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75079 17191135 96259 23455 17772 TXN2 TRX2 Trx-2 0 1.3 Trx-2 inactivation studies in DT-40 chicken cells suggest that this mitochondrial 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75080 17191135 96259 23454 12435 TXN TRX Trx 11 2.5 inactivation studies in DT-40 chicken cells suggest that this mitochondrial Trx isoenzyme is essential for cell survival 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75081 17191135 96260 23455 17772 TXN2 TRX2 Trx-2 4 1.3 The homozygous disruption of Trx-2 generates a lethal embryonic phenotype in mice 81 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75082 17191135 96261 23455 17772 TXN2 TRX2 Trx-2 3 1.3 In support of Trx-2 protective function(s) function s against oxidative stress transfection of Trx2 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75083 17191135 96261 23455 17772 TXN2 TRX2 Trx2 11 1.3 Trx-2 protective function(s) function s against oxidative stress transfection of Trx2 reduced the sensitivity of human osteosarcoma and embryo kidney cells 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75084 17191135 96261 22000 11730 TERT TERT tert 29 0.3 embryo kidney cells to cell death induced by etopoxide or tert -butylhydroperoxide 82 14 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 75085 17191135 96262 23455 17772 TXN2 TRX2 Trx2 2 1.3 Mitochondrial isoform Trx2 is abundant and widely distributed in rat brain 83 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75086 17191135 96263 23455 17772 TXN2 TRX2 Trx-2 6 1.3 Brain regions showing highest expression of Trx-2 at the RNA and protein levels include the olfactory bulb 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75087 17191135 96264 23455 17772 TXN2 TRX2 Trx2 4 1.3 The expression pattern of Trx2 appears to be associated with brain regions producing high levels 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75088 17191135 96264 18723 10261 ROS1 ROS ROS 16 0.6 to be associated with brain regions producing high levels of ROS 83 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 75089 17191135 96266 926 620 APP amyloid amyloid 7 1.3 It is characterized pathologically by deposition of amyloid B-peptide (AB) AB in senile (neuritic) neuritic plaques and the 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 75090 17191135 96269 12369 6893 MAPT tau tau 42 1.8 ubiquitination clearing misfolded proteins to the proteasome and segregation of tau aggregates from the cellular machinery and recruitment of chaperone pairs 1 JUMiner_v2.2 1 2 35 0 0 0 0 0 0 0 0 75091 17191135 96269 9691 5232 HSPA1A HSP70 Hsp70 54 3.5 from the cellular machinery and recruitment of chaperone pairs including Hsp70 and Hsp27 endowed with anti-apoptotic properties 85 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75092 17191135 96269 9708 5247 HSPB2 HSP27 Hsp27 56 1.9 cellular machinery and recruitment of chaperone pairs including Hsp70 and Hsp27 endowed with anti-apoptotic properties 85 2 JUMiner_v2.2 1 0 0 2 5246 TotalCon:2<>5246|HSPB1|3315|Complete__5247|HSPB2|3316|Complete__<>AvaiableGeneRif=2<>BEST:5246|HSPB1|0.000908602424758586<>ScoreDetail__5246|HSPB1|0.000908602424758586__5247|HSPB2|0.000783297072361479__ 0 0 0 0 0 75093 17191135 96270 12369 6893 MAPT tau tau 3 1.8 Binding of phosphorylated tau to Hsp70 implies that the complex may be a substrate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75094 17191135 96270 9691 5232 HSPA1A HSP70 Hsp70 5 3.5 Binding of phosphorylated tau to Hsp70 implies that the complex may be a substrate for the 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75095 17191135 96270 7962 4012 FUT1 HSC Hsc 23 0.5 for the E3 ligase carboxyl terminus of heat-shock cognate (Hsc)70-interacting Hsc 70-interacting protein (CHIP) CHIP 86 -88 2 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 75096 17191135 96270 21493 11427 STUB1 CHIP CHIP 25 1.6 carboxyl terminus of heat-shock cognate (Hsc)70-interacting Hsc 70-interacting protein (CHIP) CHIP 86 -88 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75097 17191135 96272 9691 5232 HSPA1A HSP70 Hsp70 2 3.5 Together with Hsp70 CHIP can regulate tau ubiquitination and degradation in a cell 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75098 17191135 96272 21493 11427 STUB1 CHIP CHIP 3 1.6 Together with Hsp70 CHIP can regulate tau ubiquitination and degradation in a cell culture 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75099 17191135 96272 12369 6893 MAPT tau tau 6 1.8 Together with Hsp70 CHIP can regulate tau ubiquitination and degradation in a cell culture system 87 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75100 17191135 96273 21493 11427 STUB1 CHIP CHIP 3 1.6 Increased levels of CHIP and Hsp70 has ben detected in AD compared with normal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75101 17191135 96273 9691 5232 HSPA1A HSP70 Hsp70 5 3.5 Increased levels of CHIP and Hsp70 has ben detected in AD compared with normal controls 86 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75102 17191135 96274 21493 11427 STUB1 CHIP CHIP 7 1.6 In a JNPL3 mouse brain tauopathy model CHIP was widely distributed but weakly expressed in spinal cord which 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75103 17191135 96274 12369 6893 MAPT tau tau 24 1.8 in spinal cord which was the most prominent region for tau inclusions and neuronal loss 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75104 17191135 96275 21493 11427 STUB1 CHIP CHIP 3 1.6 Protein levels of CHIP in cerebellar regions (a a brain region highly resistant to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75105 17191135 96276 21493 11427 STUB1 CHIP CHIP 6 1.6 These findings suggest that increases in CHIP may protect against the formation of neurofibrillary tangles the major 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75106 17191135 96278 926 620 APP amyloid amyloid 26 1.3 intracellular immunoreactive deposits as well as the formation of intracellular amyloid 89 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 75107 17191135 96279 9691 5232 HSPA1A HSP70 Hsp70 16 3.5 specifically coimmunoprecipitate with AB has identified chaperone proteins such as Hsp70 and alpha B-crystallin-related small Hsp (Hsp16) Hsp16 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75108 17191135 96279 9691 5232 HSPA1A HSP Hsp 21 1.9 identified chaperone proteins such as Hsp70 and alpha B-crystallin-related small Hsp (Hsp16) Hsp16 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75109 17191135 96281 9462 5013 HMOX1 HO-1 HO-1 4 6.5 Recently the involvement of HO-1 in the antidegenerative mechanisms operating in AD has received considerable 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75110 17191135 96281 926 620 APP amyloid amyloid 23 1.3 received considerable attention as it has been demonstrated that the amyloid precursor protein (APP) APP decreases HO activity thus reducing the 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 75111 17191135 96281 926 620 APP APP APP 26 0.3 it has been demonstrated that the amyloid precursor protein (APP) APP decreases HO activity thus reducing the intracellular levels of bilirubin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75112 17191135 96282 9462 5013 HMOX1 HO-1 HO-1 0 6.5 HO-1 induction which occurs together with the induction of other stress 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75113 17191135 96283 9462 5013 HMOX1 HO-1 HO-1 6 6.5 Significant increases in the levels of HO-1 have been observed in AD brains in association with neurofibrillary 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75114 17191135 96283 9462 5013 HMOX1 HO-1 HO-1 20 6.5 in AD brains in association with neurofibrillary tangles and also HO-1 mRNA was found increased in AD neocortex and cerebral vessels 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75115 17191135 96284 9462 5013 HMOX1 HO-1 HO-1 0 6.5 HO-1 increase was not only in association with neurofibrillary tangles but 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75116 17191135 96285 9462 5013 HMOX1 HO-1 HO-1 9 6.5 In addition Takeda et al explored the relationship between HO-1 and tau protein this latter being the major component of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75117 17191135 96285 12369 6893 MAPT tau tau 11 1.8 addition Takeda et al explored the relationship between HO-1 and tau protein this latter being the major component of intraneuronal neurofibrillary 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75118 17191135 96286 9462 5013 HMOX1 HO-1 HO-1 5 6.5 In transfected neuroblastoma cells overexpressing HO-1 the activity of this enzyme was increased and conversely the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75119 17191135 96286 12369 6893 MAPT tau tau 18 1.8 of this enzyme was increased and conversely the level of tau protein was significantly decreased when compared with antisense HO-1 or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75120 17191135 96286 9462 5013 HMOX1 HO-1 HO-1 27 6.5 of tau protein was significantly decreased when compared with antisense HO-1 or vector transfected cells 93 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75121 17191135 96287 12369 6893 MAPT tau tau 3 1.8 The suppression of tau protein expression was almost completely counteracted by zinc-deuteroporphyrin a specific 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75122 17191135 96288 9462 5013 HMOX1 HO-1 HO-1 14 6.5 (extracellular extracellular signal-regulated kinases were also decreased in cells overexpressing HO-1 although no changes in the expression of total ERKs were 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75123 17191135 96288 12337 6871 MAPK1 ERK ERKs 4 0.0 The activated forms of ERKs (extracellular extracellular signal-regulated kinases were also decreased in cells overexpressing 13 JUMiner_v2.2 1 1 UserEdit 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.000741317599596616<>ScoreDetail__3393|EPHB2|0.000491692575393669__6871|MAPK1|0.000741317599596616__ 1 1 6697 3393 EPHB2 1 extracellular signal-regulated kinase 75124 17191135 96288 12337 6871 MAPK1 ERK ERKs 23 0.0 overexpressing HO-1 although no changes in the expression of total ERKs were observed 93 13 JUMiner_v2.2 1 1 UserEdit 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.000741317599596616<>ScoreDetail__3393|EPHB2|0.000491692575393669__6871|MAPK1|0.000741317599596616__ 1 1 6697 3393 EPHB2 1 extracellular signal-regulated kinase 75125 17191135 96290 23454 12435 TXN TRX Trx 10 2.5 Among the very few studies available on the expression of Trx cycle enzymes in neurodegenerative processes one report indicated increased Trx1 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75126 17191135 96290 23454 12435 TXN TRX1 Trx1 20 2.5 Trx cycle enzymes in neurodegenerative processes one report indicated increased Trx1 protein and RNA levels in the grey and white matter 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75127 17191135 96291 9462 5013 HMOX1 HO-1 HO-1 26 6.5 AD patients of a significant increase in the expression of HO-1 and TRXr whereas this latter was not increased in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75128 17191135 96294 9462 5013 HMOX1 HO-1 HO-1 13 6.5 lymphocytes showed an increased expression of inducible nitric oxide synthase HO-1 Hsp72 Hsp60 and TrxR 96 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75129 17191135 96294 9691 5232 HSPA1A HSP72 Hsp72 14 2.9 showed an increased expression of inducible nitric oxide synthase HO-1 Hsp72 Hsp60 and TrxR 96 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75130 17191135 96294 9718 5261 HSPD1 HSP60 Hsp60 15 1.9 an increased expression of inducible nitric oxide synthase HO-1 Hsp72 Hsp60 and TrxR 96 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75131 17191135 96295 23454 12435 TXN TRX Trx 13 2.5 that treatments of primary rat hippocampal cell cultures with exogenous Trx enhanced their survival against B-amyloid cytotoxicity 97 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75132 17191135 96296 23454 12435 TXN TRX Trx 6 2.5 Thus it has been suggested that Trx might play a protective role in AD and Trx-1 deficit 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75133 17191135 96296 23454 12435 TXN TRX1 Trx-1 15 3.0 that Trx might play a protective role in AD and Trx-1 deficit might eventually contribute to increased oxidative stress and subsequent 11 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75134 17191135 96297 23454 12435 TXN TRX1 Trx-1 4 3.0 In contrast to low Trx-1 protein levels TrxR activity was significantly elevated in the amygdala 11 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>7132|MLL|4297|Complete__12435|TXN|7295|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.000910069932883855<>ScoreDetail__12435|TXN|0.000910069932883855__7132|MLL|0.000511425008070683__ 0 0 0 0 0 75135 17191135 96298 20996 11179 SOD1 SOD1 SOD1 17 1.9 antioxidant enzymatic activities such as GPx GSSG reductase CAT and SOD1 were also found elevated in several regions of AD brain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75136 17191135 96298 3544 1516 CAT CAT CAT 15 0.1 other main antioxidant enzymatic activities such as GPx GSSG reductase CAT and SOD1 were also found elevated in several regions of 6 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>1516|CAT|847|Complete__13734|GLYAT|10249|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 75137 17191135 96300 23454 12435 TXN TRX Trx 8 2.5 It is likely that the expression of the Trx cycle enzymes must be tightly regulated in order to maintain 2 JUMiner_v2.2 1 0 0 2 12435 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:12435|TXN|0.00116607298420909<>ScoreDetail__12435|TXN|0.00116607298420909__25507|VAC14|0.000609444422600558__ 0 0 0 0 0 75138 17191135 96302 9462 5013 HMOX1 HO-1 HO-1 5 6.5 The protective role played by HO-1 in AD in fact raises new possibilities regarding the use 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75139 17191135 96302 9462 5013 HMOX1 HO-1 HO-1 24 6.5 the use of natural substances which are able to increase HO-1 levels as potential drugs for the treatment of AD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75140 17191135 96305 18723 10261 ROS1 ROS ROS 16 0.6 to inhibit lipid peroxidation and to effectively intercept and neutralize ROS and RNS 23 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 75141 17191135 96305 6981 22140 FAM20C RNS RNS 18 0.6 lipid peroxidation and to effectively intercept and neutralize ROS and RNS 23 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 75142 17191135 96306 9462 5013 HMOX1 HO-1 HO-1 9 6.5 In addition curcumin has been shown to significantly increase HO-1 in astrocytes and vascular endothelial cells 100 101 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75143 17191135 96307 9462 5013 HMOX1 HO-1 HO-1 4 6.5 This latter effect on HO-1 can explain at least in part the strong antioxidant properties 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75144 17191135 96307 18723 10261 ROS1 ROS ROS 32 0.6 that HO-1-derived BR has the ability to efficiently scavenge both ROS and RNS 8 11 -13 99 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 75145 17191135 96307 6981 22140 FAM20C RNS RNS 34 0.6 BR has the ability to efficiently scavenge both ROS and RNS 8 11 -13 99 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 75146 17191135 96309 16343 17468 PDLIM5 LIM Lim 4 0.3 Based on these findings Lim and colleagues have provided convincing evidence that dietary curcumin given 2 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 75147 17191135 96314 11717 6530 LCT LAC LAC 3 0.0 Acetyl-l -carnitine (LAC), LAC is a compound of great interest for its wide clinical 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75148 17191135 96322 9691 5232 HSPA1A HSP72 hsp72 40 2.9 modulates specific genes in the rat CNS such as the hsp72 gene the gene for the isoform of 14-3-3 protein and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75149 17191135 96322 11717 6530 LCT LAC LAC 29 0.0 often obscured by more abundant ones it has reported that LAC modulates specific genes in the rat CNS such as the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75150 17191135 96324 9718 5261 HSPD1 HSP60 Hsp60 14 1.9 for the first time that acetylcarnitine induces heme oxygenase-1 and Hsp60 heat-shock proteins with a mechanism involving activation and nuclear translocation 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75151 17191135 96324 14345 7782 NFE2L2 NRF2 Nrf2 29 2.1 mechanism involving activation and nuclear translocation of the transcription factor Nrf2 27 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.00155191154741079<>ScoreDetail__7782|NFE2L2|0.00155191154741079__4071|GABPA|0.000525009545628102__ 0 0 0 0 0 75152 17191135 96326 9462 5013 HMOX1 HO-1 HO-1 29 6.5 modulate ARE-mediated expression of stress-inducible genes 107 -124 such as HO-1 G-glutamylcysteine synthetase Mn-SOD and glutathione S-transferase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75153 17191135 96326 20997 11180 SOD2 Mn-SOD Mn-SOD 32 1.9 of stress-inducible genes 107 -124 such as HO-1 G-glutamylcysteine synthetase Mn-SOD and glutathione S-transferase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75154 17191135 96329 20996 11179 SOD1 ALS ALS 7 1.9 Protein conformational diseases such as AD PD ALS HD and MS affect a large portion of our aging 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000570340949044605<>ScoreDetail__5468|IGFALS|0.000429859285933318__11179|SOD1|0.000570340949044605__ 0 0 0 0 0 75155 17191135 96334 18723 10261 ROS1 ROS ROS 24 0.6 (mal)folding mal folding cycles and oxidative damage cycles sustaining excessive ROS production and oxidative stress 125 126 (Figs Figs 3 4 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 75156 17191135 96335 18723 10261 ROS1 ROS ROS 1 0.6 These ROS set in motion a lot of redox reactions which can 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 75157 17191135 96336 18723 10261 ROS1 ROS ROS 8 0.6 The ability of a cell to deal with ROS and oxidative stress requires functional chaperones antioxidant production protein degradation 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 75158 17191135 96337 18723 10261 ROS1 ROS ROS 20 0.6 susceptible to perturbations in the quality control system and that ROS play an important role in the development and/or and or 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 75159 17191135 96339 926 620 APP amyloid amyloid 12 1.3 s quality control system becomes overwhelmed conformational changes occur to amyloid polypeptide intermediates generating stable oligomers with an anti-parallel crossed B-pleated 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 75160 17191135 96341 926 620 APP amyloid amyloid 8 1.3 Although it is clear why mutant proteins form amyloid it is harder to rationalize why a wild-type protein adopts 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 75161 17191135 96342 926 620 APP amyloid amyloid 11 1.3 discrepancy suggests that another event likely triggers misfolding in sporadic amyloid disease 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 75162 17191135 96349 18723 10261 ROS1 ROS ROS 24 0.6 the altered membrane permeability results in Ca 2 leakage and ROS formation 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 75163 17191135 96351 18723 10261 ROS1 ROS ROS 0 0.6 ROS generated during and as a consequence of protein misfolding cause 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 75164 17191135 96352 18723 10261 ROS1 ROS ROS-induced 10 0.3 In these conditions chaperone proteins themselves can be target of ROS-induced alterations 1 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 75165 17191135 96354 9462 5013 HMOX1 HO-1 HO-1 13 6.5 phenolic compounds such as curcumin and ferulic acid can induce HO-1 and TRXr and thus reduce AD strongly indicates the therapeutic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75282 17192933 96379 10463 6018 IL6 IL-6 IL-6 13 1.3 secreted higher levels of nitric oxide interleukin (IL)-1beta, IL -1beta IL-6 and IL-12p70 and lower levels of vascular endothelial growth factor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75283 17192933 96380 10437 5992 IL1B IL1BETA IL-1beta 36 0.3 species scavenger vascular endothelial growth factor and neutralizing antibodies to IL-1beta IL-6 and IL-12 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 75284 17192933 96380 10463 6018 IL6 IL-6 IL-6 37 1.3 scavenger vascular endothelial growth factor and neutralizing antibodies to IL-1beta IL-6 and IL-12 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 67819 17317654 85964 78 61 ABCD1 adrenoleukodystrophy adrenoleukodystrophy 2 0.5 The X-linked adrenoleukodystrophy (X-ALD) X-ALD and oxidative stress 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 67820 17317654 85968 20996 11179 SOD1 ALS ALS 13 0.0 close resemblance to another neurodegenerative disease amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000787353801774373<>ScoreDetail__5468|IGFALS|0.000392433874892081__11179|SOD1|0.000787353801774373__ 0 0 0 0 0 67821 17317654 85969 20996 11179 SOD1 ALS ALS 6 0.0 One of the believed pathomechanisms of ALS is oxidative stress therefore this article's emphasis on the role 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000787353801774373<>ScoreDetail__5468|IGFALS|0.000392433874892081__11179|SOD1|0.000787353801774373__ 0 0 0 0 0 67822 17317654 85971 18723 10261 ROS1 ROS ROS 12 0.0 may point to a deficit in reactive oxygen species (ROS) ROS scavenging and/or and or ROS overproduction being involved in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 67823 17317654 85971 18723 10261 ROS1 ROS ROS 15 0.0 in reactive oxygen species (ROS) ROS scavenging and/or and or ROS overproduction being involved in the aetiopathology of these neurodegenerative diseases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70304 17365122 89703 18723 10261 ROS1 ROS ROS 31 0.0 is the oxidative stress induced by reactive oxygen species (ROS) ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70305 17365122 89708 18723 10261 ROS1 ROS ROS 5 0.0 When exposed to naphthazarin-induced cells ROS formation appeared to be reduced by colloidal silver 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70306 17365122 89709 18723 10261 ROS1 ROS ROS 2 0.0 However intracellular ROS formation in hydrogen peroxide-treated cells slightly reduced by colloidal silver 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70472 17368952 89802 20996 11179 SOD1 ALS ALS 16 2.8 the role of reactive species in amyotrophic lateral sclerosis (ALS), ALS the goal of this work is to explore the correlation 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70473 17368952 89802 20996 11179 SOD1 SOD1 SOD1 39 5.5 oxidation of proteins and mutation of Cu Zn-superoxide dismutase (SOD1) SOD1 in ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70474 17368952 89802 20996 11179 SOD1 ALS ALS 41 2.8 proteins and mutation of Cu Zn-superoxide dismutase (SOD1) SOD1 in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70475 17368952 89803 20996 11179 SOD1 SOD1 mSOD1 8 2.7 Transgenic mice overexpressing the mutant Cu Zn-superoxide dismutase (mSOD1) mSOD1 gene from humans with familial ALS wild-type mice overexpressing the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70476 17368952 89803 20996 11179 SOD1 ALS ALS 14 2.8 Cu Zn-superoxide dismutase (mSOD1) mSOD1 gene from humans with familial ALS wild-type mice overexpressing the normal human SOD1 gene and normal 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70477 17368952 89803 20996 11179 SOD1 SOD1 SOD1 21 5.5 humans with familial ALS wild-type mice overexpressing the normal human SOD1 gene and normal mice without gene overexpression were used 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70478 17368952 89805 20996 11179 SOD1 SOD1 mSOD1 10 2.7 Neurons containing nitrated and oxidized proteins were visualized only in mSOD1 mice in the motor cortex the cerebellar cortex and nucleus 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70479 17368952 89806 20996 11179 SOD1 SOD1 SOD1 4 5.5 This correlates mutation of SOD1 to nitration and oxidation of neurons in the movement regions 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70480 17368952 89807 20996 11179 SOD1 SOD1 mSOD1 28 2.7 the brain sections of both motor and sensory cortex in mSOD1 mice than in the corresponding regions of control mice (P=0.005 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70481 17368952 89807 20996 11179 SOD1 SOD1 SOD1 49 5.5 _amp_#x3c 0.001 further correlating nitration and oxidation of proteins to SOD1 mutation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70482 17368952 89808 20996 11179 SOD1 SOD1 mSOD1 17 2.7 in the motor cortex than in the sensory cortex in mSOD1 mice (P=0.002 P=0.002 and 0.02 respectively indicating enhanced susceptibility of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70483 17368952 89808 20996 11179 SOD1 ALS ALS 51 2.8 nitration of proteins in neurons of the motor cortex in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70484 17368952 89809 20996 11179 SOD1 SOD1 SOD1 22 5.5 in the brain tissues and in cerebrospinal fluid of mutant SOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70485 17368952 89810 20996 11179 SOD1 SOD1 SOD1 8 5.5 Our in vivo evidence correlates mutation of the SOD1 gene to increased nitric oxide nitration and oxidation of proteins 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70486 17368952 89810 20996 11179 SOD1 ALS ALS 20 2.8 to increased nitric oxide nitration and oxidation of proteins in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70487 17368952 89811 20996 11179 SOD1 ALS ALS 3 2.8 Amyotrophic lateral sclerosis (ALS) ALS is a progressive degenerative disorder of motor neurons in the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70488 17368952 89814 20996 11179 SOD1 ALS ALS 3 2.8 Approximately 10_amp_#x2013 15% of ALS cases are inherited 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70489 17368952 89815 20996 11179 SOD1 ALS ALS 11 2.8 number of mechanisms have been proposed for the pathogenesis of ALS including genetic factors oxidative stress protein aggregation glutamatergic toxicity mitochondrial 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70490 17368952 89816 20996 11179 SOD1 SOD1 SOD1 9 5.5 The discovery of mutation of the Cu Zn-superoxide dismutase (SOD1) SOD1 gene in familial ALS patients ( Deng et al 1993 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70491 17368952 89816 20996 11179 SOD1 ALS ALS 13 2.8 of the Cu Zn-superoxide dismutase (SOD1) SOD1 gene in familial ALS patients ( Deng et al 1993 and Rosen et al 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70492 17368952 89816 20996 11179 SOD1 ALS ALS 35 2.8 1993 was the first breakthrough in identifying causes of familial ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70493 17368952 89817 20996 11179 SOD1 SOD1 mSOD1 7 2.7 To explore how mutant Cu Zn-superoxide dismutase (mSOD1) mSOD1 causes ALS a transgenic mouse model was established by introducing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70494 17368952 89817 20996 11179 SOD1 ALS ALS 9 2.8 To explore how mutant Cu Zn-superoxide dismutase (mSOD1) mSOD1 causes ALS a transgenic mouse model was established by introducing a human 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70495 17368952 89817 20996 11179 SOD1 SOD1 SOD1 26 5.5 a human mutant (Gly Gly 93_amp_#x2192 Ala G93A of the SOD1 gene into the mouse ( Gurney et al. 1994 these 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70496 17368952 89817 20996 11179 SOD1 ALS ALS 46 2.8 1994 these transgenic mice developed symptoms resembling those of human ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70497 17368952 89818 20996 11179 SOD1 SOD1 SOD1 5 5.5 Since then over 100 different SOD1 mutants have been identified in ALS families and a number 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70498 17368952 89818 20996 11179 SOD1 ALS ALS 11 2.8 then over 100 different SOD1 mutants have been identified in ALS families and a number of transgenic mouse models with different 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70499 17368952 89819 20996 11179 SOD1 SOD1 mSOD1 10 2.7 A gain of function hypothesis currently explains the neurotoxicity of mSOD1 by two mechanisms 1 mSOD1 directly promotes generation of reactive 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70500 17368952 89819 20996 11179 SOD1 SOD1 mSOD1 15 2.7 currently explains the neurotoxicity of mSOD1 by two mechanisms 1 mSOD1 directly promotes generation of reactive species and causes oxidative damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70501 17368952 89819 20996 11179 SOD1 SOD1 mSOD1 31 2.7 species and causes oxidative damage to major cellular components 2 mSOD1 aggregation with itself and other important proteins leads to toxicity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70502 17368952 89820 20996 11179 SOD1 SOD SOD 2 1.9 Superoxide dismutase (SOD) SOD is a major antioxidative defense enzyme converting superoxide anion (O 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70503 17368952 89823 20996 11179 SOD1 SOD1 mSOD1 1 2.7 Using mSOD1 transgenic models we previously demonstrated in vivo that mutation of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70504 17368952 89823 20996 11179 SOD1 SOD1 SOD1 12 5.5 transgenic models we previously demonstrated in vivo that mutation of SOD1 elevates levels of H 2 O 2 _amp_#xb7 OH and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70505 17368952 89823 20996 11179 SOD1 SOD1 SOD1 46 5.5 protein oxidation 8-hydroxy-2-deoxyguanosine_amp_#x2014 a marker of DNA oxidation compared with SOD1 and normal control (Nc) Nc mice ( Liu et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70506 17368952 89824 18723 10261 ROS1 ROS ROS 5 0.3 Elevation of reactive oxygen species (ROS) ROS and oxidative damage has also been reported by others ( 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 70507 17368952 89825 20996 11179 SOD1 SOD1 SOD1 6 5.5 These results directly correlate mutation of SOD1 to generation of ROS and resulting oxidative damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70508 17368952 89825 18723 10261 ROS1 ROS ROS 10 0.3 These results directly correlate mutation of SOD1 to generation of ROS and resulting oxidative damage 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 70509 17368952 89826 18723 10261 ROS1 ROS ROS 1 0.3 Increased ROS and oxidation were also found in ALS patients ( Bowling 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 70510 17368952 89826 20996 11179 SOD1 ALS ALS 8 2.8 Increased ROS and oxidation were also found in ALS patients ( Bowling et al 1993 Ferrante et al 1997a 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70511 17368952 89826 18723 10261 ROS1 ROS ROS 32 0.3 Said Ahmed et al 2000 further supporting the involvement of ROS in ALS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 70512 17368952 89826 20996 11179 SOD1 ALS ALS 34 2.8 et al 2000 further supporting the involvement of ROS in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70513 17368952 89827 6981 22140 FAM20C RNS RNS 3 0.3 Reactive nitrogen species (RNS) RNS include nitric oxide ( _amp_#xb7 NO and peroxynitrite (ONOO ONOO 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 70514 17368952 89828 20996 11179 SOD1 SOD SOD 19 1.9 NO to form ONOO _amp_#x2212 which in turn reacts with SOD to form a nitronium-like intermediate that can nitrate tyrosine thereby 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70515 17368952 89829 20996 11179 SOD1 SOD1 SOD1 0 5.5 SOD1 mutation can disrupt the active-site pocket in the SOD1 dimer 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70516 17368952 89829 20996 11179 SOD1 SOD1 SOD1 9 5.5 SOD1 mutation can disrupt the active-site pocket in the SOD1 dimer to allow greater access of ONOO _amp_#x2212 to the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70517 17368952 89830 20996 11179 SOD1 ALS ALS 10 2.8 Genetically decreased spinal cord copper concentration prolongs life in familial ALS mice ( Kiaei et al. 2004 supporting copper_amp_#x2019 s involvement 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70518 17368952 89832 20996 11179 SOD1 ALS ALS 32 2.8 et al 1999 and Taskiran et al 2000 of sporadic ALS patients compared with the controls 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70519 17368952 89832 11629 6493 LAMC2 CSF CSF 16 0.0 nitrate and nitrite are significantly higher in cerebrospinal fluid (CSF) CSF and serum ( Tohgi et al 1999 and Taskiran et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70520 17368952 89833 14533 7872 NOS1 NOS NOS 7 1.2 Expression of inducible _amp_#xb7 nitric oxide synthase (NOS) NOS increases during the development of ALS in the G93A transgenic 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000763760294552083<>ScoreDetail__7873|NOS2A|0.00067699618071966__7872|NOS1|0.000763760294552083__ 0 0 0 0 0 70521 17368952 89833 20996 11179 SOD1 ALS ALS 13 2.8 nitric oxide synthase (NOS) NOS increases during the development of ALS in the G93A transgenic mice compared with normal SOD1 mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70522 17368952 89833 20996 11179 SOD1 SOD1 SOD1 22 5.5 of ALS in the G93A transgenic mice compared with normal SOD1 mice and Nc mice ( Almer et al. 1999 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70523 17368952 89834 20996 11179 SOD1 SOD1 mSOD1 9 2.7 On the other hand a transgenic cell line expressing mSOD1 releases less ONOO _amp_#x2212 than those expressing normal SOD1 ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70524 17368952 89834 20996 11179 SOD1 SOD1 SOD1 18 5.5 expressing mSOD1 releases less ONOO _amp_#x2212 than those expressing normal SOD1 ( Cookson et al. 2002 and pharmacological inhibition or genetic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70525 17368952 89834 14533 7872 NOS1 NOS NOS 33 1.2 al. 2002 and pharmacological inhibition or genetic manipulation of neuronal NOS does not alter the course of ALS ( Facchinetti et 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000763760294552083<>ScoreDetail__7873|NOS2A|0.00067699618071966__7872|NOS1|0.000763760294552083__ 0 0 0 0 0 70526 17368952 89834 20996 11179 SOD1 ALS ALS 40 2.8 manipulation of neuronal NOS does not alter the course of ALS ( Facchinetti et al 1999 and Upton-Rice et al 1999 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70527 17368952 89834 20996 11179 SOD1 ALS ALS 59 2.8 et al 1999 complicating the role of _amp_#xb7 NO in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70528 17368952 89836 20996 11179 SOD1 ALS ALS 6 2.8 Increased protein nitration also occurs in ALS patients ( Abe et al 1995 and Beal et al 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70529 17368952 89839 20996 11179 SOD1 SOD1 SOD1 0 5.5 SOD1 and NOS were colocalized at the foci of NF accumulation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70530 17368952 89839 14533 7872 NOS1 NOS NOS 2 1.2 SOD1 and NOS were colocalized at the foci of NF accumulation in motor 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000763760294552083<>ScoreDetail__7873|NOS2A|0.00067699618071966__7872|NOS1|0.000763760294552083__ 0 0 0 0 0 70531 17368952 89839 14282 7739 NEFL NFL NFL 44 0.6 of ONOO _amp_#x2212 at the light subunit of neurofilament (NFL) NFL 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70532 17368952 89840 14282 7739 NEFL NFL NFL 0 0.6 NFL is rich in tyrosine and therefore is a vulnerable site 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70533 17368952 89841 20996 11179 SOD1 ALS ALS 19 2.8 spinal cord and in brain regions related to movement in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70534 17368952 89842 20996 11179 SOD1 ALS ALS 39 2.8 oxidation of proteins contribute differently to different brain regions in ALS and controls 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70535 17368952 89844 20996 11179 SOD1 SOD1 SOD1 14 5.5 correlation between nitration and oxidation of proteins and mutation of SOD1 in this disease the present study using the G93A transgenic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70536 17368952 89844 20996 11179 SOD1 SOD1 mSOD1 46 2.7 brain regions particularly between motor and sensory cortex in the mSOD1 mice and controls 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70537 17368952 89845 6981 22140 FAM20C RNS RNS 18 0.3 measured biochemically to provide further support for the correlation between RNS and mutation of SOD1 in ALS 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 70538 17368952 89845 20996 11179 SOD1 SOD1 SOD1 22 5.5 further support for the correlation between RNS and mutation of SOD1 in ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70539 17368952 89845 20996 11179 SOD1 ALS ALS 24 2.8 for the correlation between RNS and mutation of SOD1 in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70540 17368952 89850 20996 11179 SOD1 SOD1 mSOD1 18 2.7 (Bar Bar Harbor ME USA were used mice overexpressing the mSOD1 gene (G93A) G93A from humans with familial ALS B6SJL-TgN(SOD1-G93A)1Gur, B6SJL-TgN 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70541 17368952 89850 20996 11179 SOD1 ALS ALS 25 2.8 overexpressing the mSOD1 gene (G93A) G93A from humans with familial ALS B6SJL-TgN(SOD1-G93A)1Gur, B6SJL-TgN SOD1-G93A 1Gur mice overexpressing normal human SOD1 gene 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70542 17368952 89850 20996 11179 SOD1 SOD1 SOD1 31 5.5 familial ALS B6SJL-TgN(SOD1-G93A)1Gur, B6SJL-TgN SOD1-G93A 1Gur mice overexpressing normal human SOD1 gene B6SJL-TgN(SOD1)2Gur, B6SJL-TgN SOD1 2Gur and Nc mice (B6SJLF1) B6SJLF1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70543 17368952 89850 20996 11179 SOD1 SOD1 SOD1 33 5.5 SOD1-G93A 1Gur mice overexpressing normal human SOD1 gene B6SJL-TgN(SOD1)2Gur, B6SJL-TgN SOD1 2Gur and Nc mice (B6SJLF1) B6SJLF1 without gene overexpression 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70544 17368952 89851 20996 11179 SOD1 ALS ALS 22 2.8 3-NY in nitrated proteins in brain tissues the onset of ALS symptoms of the mSOD1 mice that we used was delayed 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70545 17368952 89851 20996 11179 SOD1 SOD1 mSOD1 26 2.7 in brain tissues the onset of ALS symptoms of the mSOD1 mice that we used was delayed due to a small 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70546 17368952 89852 20996 11179 SOD1 SOD1 mSOD1 1 2.7 Therefore mSOD1 SOD1 and Nc mice were used at 6_amp_#x2013 6.5 months 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70547 17368952 89852 20996 11179 SOD1 SOD1 SOD1 2 5.5 Therefore mSOD1 SOD1 and Nc mice were used at 6_amp_#x2013 6.5 months of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70548 17368952 89853 20996 11179 SOD1 SOD1 mSOD1 1 2.7 The mSOD1 mice used for the immunohistochemical staining of oxidized or nitrated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70549 17368952 89853 20996 11179 SOD1 SOD1 mSOD1 36 2.7 by 4_amp_#x2013 5 months therefore 3 month_amp_#xb1 1 week old mSOD1 mice and age matched SOD1 and Nc mice were used 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70550 17368952 89853 20996 11179 SOD1 SOD1 SOD1 41 5.5 3 month_amp_#xb1 1 week old mSOD1 mice and age matched SOD1 and Nc mice were used while paralysis was developing in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70551 17368952 89855 14282 7739 NEFL NF68 NF-68 8 0.6 Neurons were immunohistochemically stained with an antibody to NF-68 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70552 17368952 89863 5176 2557 CUX1 CUT CUT 17 0.0 in rostral and caudal directions on a cryostat (IMEB IMEB CUT 4500 Leica Microsystems Bensheim Germany 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70553 17368952 89885 7625 3758 FLOT2 ESA ESA 51 0.0 were analyzed by HPLC with electrochemical detection (Coulochem Coulochem II ESA Laboratory Inc. Chelmsford MA USA as reported by Hensley et 1 JUMiner_v2.2 1 0 0 2 3758 TotalCon:2<>3758|FLOT2|2319|Complete__9204|PON1|5444|Complete__<>AvaiableGeneRif=2<>BEST:3758|FLOT2|0.000351458651576852<>ScoreDetail__9204|PON1|0.000347837246844954__3758|FLOT2|0.000351458651576852__ 0 0 0 0 0 70554 17368952 89888 11629 6493 LAMC2 CSF CSF 20 0.0 the intrathecal space of the mouse spinal cord to sample CSF from there to avoid damage to the spinal cord caused 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70555 17368952 89897 8255 4236 GFER HPO HPO 34 0.0 Ca 2 132 Cl _amp_#x2212 21.0 HCO 3 _amp_#x2212 2.5 HPO 4 2_amp_#x2212 and 3.5 glucose 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70556 17368952 89902 14533 7872 NOS1 NOS NOS 31 1.2 using a NO-selective electrode ( Liu et al. 2000 measuring NOS immuno-reactivity as an indicator of possible _amp_#xb7 NO synthesis by 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000763760294552083<>ScoreDetail__7873|NOS2A|0.00067699618071966__7872|NOS1|0.000763760294552083__ 0 0 0 0 0 70557 17368952 89917 20996 11179 SOD1 SOD1 mSOD1 8 2.7 3-NY- and DNP-positive neurons were only observed in mSOD1 mice in the movement-related brain regions 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70558 17368952 89919 20996 11179 SOD1 SOD1 mSOD1 14 2.7 of double immunofluorescence-stained 3-NY- and DNP-positive neurons in cross-sections of mSOD1 SOD1 and Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70559 17368952 89919 20996 11179 SOD1 SOD1 SOD1 15 5.5 double immunofluorescence-stained 3-NY- and DNP-positive neurons in cross-sections of mSOD1 SOD1 and Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70560 17368952 89920 14282 7739 NEFL NF68 NF-68 26 0.6 axons and large dendrites (white white arrow were immuno-stained for NF-68 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70561 17368952 89922 20996 11179 SOD1 SOD1 SOD1 9 5.5 There are no 3-NY-positive neurons in Nc (A) A and SOD1 (D) D mice but large neurons were 3-NY-positive in mSOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70562 17368952 89922 20996 11179 SOD1 SOD1 mSOD1 18 2.7 SOD1 (D) D mice but large neurons were 3-NY-positive in mSOD1 mice (G, G red arrowhead 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70563 17368952 89923 14282 7739 NEFL NF68 NF-68 4 0.6 Since staining was for NF-68 (green) green and 3-NY (red), red yellow fluorescence appeared in 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70564 17368952 89924 20996 11179 SOD1 SOD1 mSOD1 10 2.7 This demonstrates that more 3-NY-positive neurons were present in the mSOD1 mice compared with the Nc (A) A and SOD1 (D) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70565 17368952 89924 20996 11179 SOD1 SOD1 SOD1 18 5.5 the mSOD1 mice compared with the Nc (A) A and SOD1 (D) D mouse 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70566 17368952 89925 20996 11179 SOD1 SOD1 mSOD1 7 2.7 Similarly 3-NY-positive neurons appeared only in the mSOD1 mice (H) H in the motor cortex (B, B E 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70567 17368952 89925 20996 11179 SOD1 SOD1 mSOD1 21 2.7 motor cortex (B, B E and H and in the mSOD1 mice (I) I in the cortex of the cerebellum (C, 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70568 17368952 89925 20996 11179 SOD1 SOD1 SOD1 42 5.5 and I except a few 3-NY-positive neurons were observed in SOD1 mice (F) F 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70569 17368952 89926 20996 11179 SOD1 SOD1 mSOD1 21 2.7 the brain (J, J K and L red arrowhead of mSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70570 17368952 89928 20996 11179 SOD1 SOD1 mSOD1 14 2.7 higher in motor cortex than in sensory cortex of the mSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70571 17368952 89931 20996 11179 SOD1 SOD1 mSOD1 11 2.7 the motor cortex significantly more neurons were nitrated in the mSOD1 mice (48.8_amp_#xb1;5.6%, 48.8_amp_#xb1 5.6% S.D. than in the Nc (8.7_amp_#xb1;2.2, 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70572 17368952 89931 20996 11179 SOD1 SOD1 SOD1 22 5.5 S.D. than in the Nc (8.7_amp_#xb1;2.2, 8.7_amp_#xb1 2.2 S.D. and SOD1 (9.5_amp_#xb1;0.4, 9.5_amp_#xb1 0.4 S.D. mice ( P _amp_#x3c 0.001 Fig 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70573 17368952 89932 20996 11179 SOD1 SOD1 mSOD1 15 2.7 number of 3-NY-positive neurons was also significantly higher in the mSOD1 mice (19.6_amp_#xb1;3.3%, 19.6_amp_#xb1 3.3% S.D. than in Nc (9.3_amp_#xb1;3.7%, 9.3_amp_#xb1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70574 17368952 89932 20996 11179 SOD1 SOD1 SOD1 25 5.5 3.3% S.D. than in Nc (9.3_amp_#xb1;3.7%, 9.3_amp_#xb1 3.7% S.D. and SOD1 (9.6_amp_#xb1;0.6%, 9.6_amp_#xb1 0.6% S.D. mice ( P =0.008 Fig 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70575 17368952 89932 20996 11179 SOD1 SOD1 SOD1 44 5.5 B but the number was not different between Nc and SOD1 mice in either region 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70576 17368952 89933 20996 11179 SOD1 SOD1 mSOD1 19 2.7 cortex was significantly higher than in the sensory cortex in mSOD1 mice ( P =0.002 Fig 2 C demonstrating that neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70577 17368952 89933 20996 11179 SOD1 SOD1 mSOD1 47 2.7 to nitration than neurons in the sensory cortex in the mSOD1 mice or more ONOO _amp_#x2212 was produced in the motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70578 17368952 89934 20996 11179 SOD1 SOD1 mSOD1 15 2.7 oxidation in motor cortex than in sensory cortex of the mSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70579 17368952 89937 20996 11179 SOD1 SOD1 SOD1 21 5.5 and only a few DNP-positive neurons (1.38_amp_#xb1;0.39) 1.38_amp_#xb1 0.39 in SOD1 mice significantly more DNP-positive neurons appeared in the motor cortex 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70580 17368952 89937 20996 11179 SOD1 SOD1 mSOD1 34 2.7 more DNP-positive neurons appeared in the motor cortex in the mSOD1 mice (31.3_amp_#xb1;9.5%, 31.3_amp_#xb1 9.5% S.D. than in the Nc and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70581 17368952 89937 20996 11179 SOD1 SOD1 SOD1 43 5.5 mice (31.3_amp_#xb1;9.5%, 31.3_amp_#xb1 9.5% S.D. than in the Nc and SOD1 mice ( P =0.005 Fig 3 A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70582 17368952 89938 20996 11179 SOD1 SOD1 SOD1 20 5.5 and only a few DNP-positive neurons (0.79_amp_#xb1;0.7) 0.79_amp_#xb1 0.7 in SOD1 mice while significantly more DNP-positive neurons (11.4_amp_#xb1;0.7%, 11.4_amp_#xb1 0.7% S.D. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70583 17368952 89938 20996 11179 SOD1 SOD1 mSOD1 35 2.7 (11.4_amp_#xb1;0.7%, 11.4_amp_#xb1 0.7% S.D. appeared in the sensory cortex of mSOD1 mice than in the controls ( P _amp_#x3c 0.001 Fig 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70584 17368952 89939 20996 11179 SOD1 SOD1 mSOD1 41 2.7 the motor cortex than in the sensory cortex in the mSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70585 17368952 89940 20996 11179 SOD1 SOD1 mSOD1 6 2.7 Protein-bound nitrotyrosine is significantly higher in mSOD1 mice than in controls as measured by HPLC 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70586 17368952 89942 20996 11179 SOD1 SOD1 mSOD1 8 2.7 We demonstrated that the levels of 3-NY in mSOD1 mice are significantly higher than in SOD1 mice ( P 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70587 17368952 89942 20996 11179 SOD1 SOD1 SOD1 15 5.5 of 3-NY in mSOD1 mice are significantly higher than in SOD1 mice ( P =0.00003 and Nc mice ( P =0.00005 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70588 17368952 89942 20996 11179 SOD1 SOD1 SOD1 30 5.5 and Nc mice ( P =0.00005 but not different between SOD1 and Nc mice ( P =0.4 Fig 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70589 17368952 89943 20996 11179 SOD1 SOD1 mSOD1 5 2.7 The level of 3-NY in mSOD1 mice is about 2.5-fold higher than its level in SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70590 17368952 89943 20996 11179 SOD1 SOD1 SOD1 15 5.5 mSOD1 mice is about 2.5-fold higher than its level in SOD1 and Nc mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70591 17368952 89944 20996 11179 SOD1 SOD1 SOD1 11 5.5 clearly correlates elevated protein nitration to the mutation of the SOD1 enzyme 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70592 17368952 89945 20996 11179 SOD1 SOD1 mSOD1 7 2.7 Significantly higher levels of _amp_#xb7 NO in mSOD1 mice than in the controls 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70593 17368952 89948 20996 11179 SOD1 SOD1 mSOD1 9 2.7 We found a significantly higher citrulline level in the mSOD1 mice than in the SOD1 mice ( P =0.02 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70594 17368952 89948 20996 11179 SOD1 SOD1 SOD1 14 5.5 higher citrulline level in the mSOD1 mice than in the SOD1 mice ( P =0.02 and Nc mice ( P =0.03 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70595 17368952 89950 20996 11179 SOD1 SOD1 mSOD1 6 2.7 The elevation of _amp_#xb7 NO in mSOD1 mice and the failure of normal SOD1 gene overexpressed in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70596 17368952 89950 20996 11179 SOD1 SOD1 SOD1 13 5.5 _amp_#xb7 NO in mSOD1 mice and the failure of normal SOD1 gene overexpressed in the mouse to increase levels of _amp_#xb7 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70597 17368952 89950 20996 11179 SOD1 ALS ALS 33 2.8 _amp_#xb7 NO suggest that _amp_#xb7 NO may be associated with ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70598 17368952 89952 20996 11179 SOD1 SOD1 mSOD1 29 2.7 work revealed that 3-NY- and DNP-positive neurons were observed in mSOD1 mice in all movement-related brain regions that we examined (the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70599 17368952 89953 20996 11179 SOD1 SOD1 SOD1 4 5.5 This correlates mutation of SOD1 to nitration and oxidation of proteins in neurons in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70600 17368952 89954 20996 11179 SOD1 SOD1 mSOD1 28 2.7 the brain sections of both motor and sensory cortex in mSOD1 mice than in the corresponding regions of control mice ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70601 17368952 89954 20996 11179 SOD1 SOD1 SOD1 56 5.5 A B further correlating nitration and oxidation of proteins to SOD1 mutation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70602 17368952 89955 20996 11179 SOD1 SOD1 mSOD1 22 2.7 were significantly higher in both motor and sensory cortex in mSOD1 mice than in controls the motor cortex had significantly higher 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70603 17368952 89955 20996 11179 SOD1 SOD1 mSOD1 57 2.7 Fig 3 C neurons than did the sensory cortex in mSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70604 17368952 89956 20996 11179 SOD1 SOD1 mSOD1 31 2.7 cortex than in neurons in the sensory cortex of the mSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70605 17368952 89957 20996 11179 SOD1 ALS ALS 14 2.8 oxidation and nitration of proteins in motor cortex neurons in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70606 17368952 89958 20996 11179 SOD1 SOD1 SOD1 6 5.5 Our comparisons strongly correlate mutation of SOD1 to nitration and oxidation of proteins in the movement brain 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70607 17368952 89959 20996 11179 SOD1 SOD1 mSOD1 30 2.7 3-NY were significantly ( 2.5-fold higher in the brains of mSOD1 mice than in controls ( Fig 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70608 17368952 89960 20996 11179 SOD1 SOD1 mSOD1 28 2.7 Figs 2 demonstrated significantly higher levels of protein nitration in mSOD1 mice compared with the controls 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70609 17368952 89961 20996 11179 SOD1 ALS ALS 16 2.8 there are contradictions regarding the role of protein nitration in ALS the recent report that 3-NY-immunoactivity was higher in the spinal 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70610 17368952 89961 20996 11179 SOD1 SOD1 SOD1 58 5.5 analysis ( Casoni et al. 2005 confirms the correlation between SOD1 mutation and protein nitration 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70611 17368952 89962 20996 11179 SOD1 ALS ALS 18 2.8 support a role of protein nitration in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70612 17368952 89963 20996 11179 SOD1 SOD1 mSOD1 33 2.7 that the levels of _amp_#xb7 NO are significantly higher in mSOD1 transgenic mice than in their controls no difference was found 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70613 17368952 89963 20996 11179 SOD1 SOD1 SOD1 45 5.5 mice than in their controls no difference was found between SOD1 and Nc control groups ( Fig 5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70614 17368952 89964 20996 11179 SOD1 ALS ALS 8 2.8 This suggests that _amp_#xb7 NO is associated with ALS because overexpression of the normal SOD1 gene in the mouse 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70615 17368952 89964 20996 11179 SOD1 SOD1 SOD1 14 5.5 NO is associated with ALS because overexpression of the normal SOD1 gene in the mouse did not increase levels of citrulline 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70616 17368952 89964 20996 11179 SOD1 ALS ALS 26 2.8 in the mouse did not increase levels of citrulline in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70617 17368952 89965 20996 11179 SOD1 ALS ALS 4 2.8 Elevation of citrulline in ALS may not demonstrate that _amp_#xb7 NO contributes to the pathogenesis 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70618 17368952 89965 20996 11179 SOD1 ALS ALS 16 2.8 not demonstrate that _amp_#xb7 NO contributes to the pathogenesis of ALS because of the complexity of _amp_#xb7 NO functions as described 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70619 17368952 89967 14533 7872 NOS1 NOS NOS 5 1.2 Recent progress indicates that neuronal NOS is involved in a motoneuron-specific programmed cell death pathway ( 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000763760294552083<>ScoreDetail__7873|NOS2A|0.00067699618071966__7872|NOS1|0.000763760294552083__ 0 0 0 0 0 70620 17368952 89967 14533 7872 NOS1 NOS NOS 28 1.2 et al 2004 and Holasek et al 2005 and inducible NOS and _amp_#xb7 NO act as inflammatory markers in ALS ( 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000763760294552083<>ScoreDetail__7873|NOS2A|0.00067699618071966__7872|NOS1|0.000763760294552083__ 0 0 0 0 0 70621 17368952 89967 20996 11179 SOD1 ALS ALS 37 2.8 inducible NOS and _amp_#xb7 NO act as inflammatory markers in ALS ( Barbeito et al 2004 and Xie et al 2004 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70622 17368952 89968 20996 11179 SOD1 ALS ALS 14 2.8 this recent progress support involvement of elevated _amp_#xb7 NO in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70623 17368952 89969 20996 11179 SOD1 ALS ALS 33 2.8 may contribute to the selective damage of motor neurons in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70624 17368952 89970 20996 11179 SOD1 ALS ALS 8 2.8 However the excitatory amino acid levels measured from ALS patients and transgenic animals are another area of controversy the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70625 17368952 89970 20996 11179 SOD1 ALS ALS 37 2.8 aspartate are increased significantly in the CSF of patients with ALS ( Rothstein et al. 1990 and in the extracellular fluid 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70626 17368952 89970 20996 11179 SOD1 SOD1 SOD1 51 5.5 et al. 1990 and in the extracellular fluid in G93A SOD1 mice ( Alexander et al. 2000 but the glutamate concentration 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70627 17368952 89970 11629 6493 LAMC2 CSF CSF 33 0.0 amino acid glutamate and aspartate are increased significantly in the CSF of patients with ALS ( Rothstein et al. 1990 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70628 17368952 89970 11629 6493 LAMC2 CSF CSF 65 0.0 Alexander et al. 2000 but the glutamate concentration in the CSF of G93A mice was not different in 14- and 18-week 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70629 17368952 89971 20996 11179 SOD1 SOD1 mSOD1 13 2.7 that neither glutamate nor aspartate concentrations were significantly increased in mSOD1 mice compared with age-matched controls ( Fig 5 A consistent 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70630 17368952 89975 20996 11179 SOD1 ALS ALS 19 2.8 accurate conclusion regarding the involvement of excitatory amino acids in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70631 17368952 89977 20996 11179 SOD1 SOD1 mSOD1 11 2.7 summary using double immunohistochemical staining of brain sections from the mSOD1 mice and the controls this work reveals that 1 3-NY- 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70632 17368952 89977 20996 11179 SOD1 SOD1 mSOD1 29 2.7 that 1 3-NY- and DNP-positive neurons were observed only in mSOD1 mice 2 nitration and oxidation of proteins were significantly higher 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70633 17368952 89977 20996 11179 SOD1 SOD1 mSOD1 42 2.7 nitration and oxidation of proteins were significantly higher in the mSOD1 mice than in the controls 3 the number of 3-NY- 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70634 17368952 89977 20996 11179 SOD1 SOD1 mSOD1 67 2.7 significantly higher in motor cortex than in sensory cortex in mSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70635 17368952 89978 20996 11179 SOD1 SOD1 SOD1 5 5.5 These results correlate mutation of SOD1 to nitration and oxidation of proteins in neurons in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70636 17368952 89978 20996 11179 SOD1 SOD1 mSOD1 39 2.7 the motor cortex than of proteins in sensory cortex in mSOD1 mice 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70637 17368952 89979 20996 11179 SOD1 ALS ALS 15 2.8 oxidation of proteins to neuronal degeneration in motor cortex in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 70638 17368952 89980 20996 11179 SOD1 SOD1 mSOD1 29 2.7 the microdialysates and protein-bound nitrotyrosine in the brain tissue in mSOD1 SOD1 and Nc mice were measured 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70639 17368952 89980 20996 11179 SOD1 SOD1 SOD1 30 5.5 microdialysates and protein-bound nitrotyrosine in the brain tissue in mSOD1 SOD1 and Nc mice were measured 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70640 17368952 89981 20996 11179 SOD1 SOD1 mSOD1 15 2.7 both _amp_#xb7 NO and protein-bound 3-NY are significantly higher in mSOD1 mice than in control mice further supporting that RNS and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 70641 17368952 89981 6981 22140 FAM20C RNS RNS 24 0.3 in mSOD1 mice than in control mice further supporting that RNS and resulting protein nitration play a role in ALS 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 70642 17368952 89981 20996 11179 SOD1 ALS ALS 33 2.8 that RNS and resulting protein nitration play a role in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00161777181525835<>ScoreDetail__5468|IGFALS|0.000731819644310418__11179|SOD1|0.00161777181525835__ 0 0 0 0 0 54389 17496232 67628 12339 6877 MAPK3 ERK1 ERK1 34 2.7 to dual activation of proliferating and proapoptotic cascades like ERK1/2 ERK1 2 or p38 MAPK 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54390 17496232 67628 12337 6871 MAPK1 p38 p38 36 2.2 of proliferating and proapoptotic cascades like ERK1/2 ERK1 2 or p38 MAPK 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54391 17496232 67628 12337 6871 MAPK1 MAPK MAPK 37 2.2 proliferating and proapoptotic cascades like ERK1/2 ERK1 2 or p38 MAPK 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54392 17496232 67638 14533 7872 NOS1 nNOS nNOS 7 3.7 Transcriptional increase of neuronal nitric oxide synthase (nNOS) nNOS determines extensive binding to complex I and IV and contributes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54393 17496232 67639 14533 7872 NOS1 nNOS nNOS 10 3.7 3 3' 5-triiodothyronine (T T 3 levels there is increased nNOS transcription translation and translocation into mitochondria resulting in high mitochondrial 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54394 17496232 67639 14533 7872 NOS1 NOS NOS 21 2.7 transcription translation and translocation into mitochondria resulting in high mitochondrial NOS (mtNOS) mtNOS activity and increased nitric oxide (NO), NO ONOO 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54395 17496232 67641 20997 11180 SOD2 MnSOD MnSOD 3 1.9 MW molecular weight MnSOD manganese superoxide dismutase 2D two dimensional 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54396 17496232 67644 12339 6877 MAPK3 ERK1 ERK1 13 2.7 low NO and H 2 O 2 levels activate ERK1/2, ERK1 2 resulting in cyclin D 1 -increased expression and proliferation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54397 17496232 67645 12337 6871 MAPK1 p38 p38 15 2.2 higher NO ONOO and H 2 O 2 levels activate p38 MAPK which regulates cyclin D 1 expression negatively resulting in 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54398 17496232 67645 12337 6871 MAPK1 MAPK MAPK 16 2.2 NO ONOO and H 2 O 2 levels activate p38 MAPK which regulates cyclin D 1 expression negatively resulting in cell 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54399 17496232 67646 12337 6871 MAPK1 MAPK MAPKs 8 2.2 Representative Western blot of cyclin D 1 and MAPKs in tumoral cells (P07) P07 and in lysates of postnatal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54400 17496232 67646 3471 1473 CANX P90 P90 24 0.0 of postnatal day 2 (P2) P2 and day 90 (P90) P90 rat liver are included p Phosphorylated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54401 17496232 67648 22671 11998 TP53 p53 p53 21 1.6 programmed cell death via apoptotic protease-activating factor-1 and activation of p53 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54402 17496232 67649 22671 11998 TP53 p53 p53 8 1.6 Increased NO and ONOO result in DNA damage p53 accumulation increased Bax/Bcl-2, Bax Bcl-2 cytochrome c (cyt cyt c 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54403 17496232 67649 1576 990 BCL2 Bcl-2 Bcl-2 11 1.3 ONOO result in DNA damage p53 accumulation increased Bax/Bcl-2, Bax Bcl-2 cytochrome c (cyt cyt c release and caspase activation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54404 17496232 67655 24185 29175 WDTC1 ADP ADP-to-ATP 26 0.0 O 2 and substrate availabilities as well as by the ADP-to-ATP ratio likely the main mitochondrial modulator in response to cell 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54405 17496232 67656 4829 2294 COX8A COX COX 25 0.9 as resulting from its high-affinity binding to cytochrome oxidase (COX), COX the final electron acceptor ( 19 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54406 17496232 67657 14533 7872 NOS1 NOS NOS 16 2.7 and O 2 is catalyzed by nitric oxide synthases (NOS) NOS ( 92 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54407 17496232 67658 14533 7872 NOS1 NOS NOS 6 2.7 There exist three canonical isoforms neuronal (NOS NOS I or nNOS inducible (NOS NOS II and endothelial (NOS 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54408 17496232 67658 14533 7872 NOS1 nNOS nNOS 9 3.7 There exist three canonical isoforms neuronal (NOS NOS I or nNOS inducible (NOS NOS II and endothelial (NOS NOS III and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54409 17496232 67658 14533 7872 NOS1 NOS NOS 11 2.7 canonical isoforms neuronal (NOS NOS I or nNOS inducible (NOS NOS II and endothelial (NOS NOS III and a significant number 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54410 17496232 67658 14533 7872 NOS1 NOS NOS 15 2.7 I or nNOS inducible (NOS NOS II and endothelial (NOS NOS III and a significant number of spliced and posttranslationally modified 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54411 17496232 67659 14533 7872 NOS1 NOS NOS 8 2.7 In addition new isoforms or mitochondrial variants of NOS (mtNOS) mtNOS were recently described in rat liver ( 60 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54412 17496232 67659 4829 2294 COX8A COX COX 38 0.9 ( 119 mtNOS is bound to mitochondrial PDZ domains of COX ( 57 103 and to complex I ( 57 thus 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54413 17496232 67660 14533 7872 NOS1 NOS NOS 14 2.7 as extreme hypoxia mitochondrial NO could come either from stimulated NOS ( 116 142 or from the reduction of nitrite by 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54414 17496232 67660 4829 2294 COX8A COX COX 27 0.9 ( 116 142 or from the reduction of nitrite by COX ( 39 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54415 17496232 67661 14533 7872 NOS1 NOS NOS 0 2.7 NOS I and III ( 45 82 are constitutively expressed in 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54416 17496232 67662 5902 2903 DLG4 PSD95 PSD95 15 1.3 in cell membrane (caveolin) caveolin and in synaptic vesicles (PSD95) PSD95 in skeletal and cardiac muscles (dystrophin) dystrophin and to heat 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54417 17496232 67662 5927 2928 DMD dystrophin dystrophin 21 1.0 synaptic vesicles (PSD95) PSD95 in skeletal and cardiac muscles (dystrophin) dystrophin and to heat shock protein (HSP) HSP 90 or 70 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54418 17496232 67662 9691 5232 HSPA1A HSP HSP 27 0.9 cardiac muscles (dystrophin) dystrophin and to heat shock protein (HSP) HSP 90 or 70 chaperones ( 79 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54419 17496232 67663 5927 2928 DMD dystrophin dystrophin 23 1.0 decreased (caveolin-NOS) caveolin-NOS enzyme activity 2 modified subcellular traffic (dystrophin dystrophin impedes NOS I traffic to mitochondria ( 76 and 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54420 17496232 67663 14533 7872 NOS1 NOS NOS 25 2.7 caveolin-NOS enzyme activity 2 modified subcellular traffic (dystrophin dystrophin impedes NOS I traffic to mitochondria ( 76 and 3 participation in 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54421 17496232 67664 14533 7872 NOS1 NOS NOS 1 2.7 Constitutive NOS are activated by Ca pulses after activation of cell surface 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54422 17496232 67664 14533 7872 NOS1 NOS NOS 20 2.7 surface receptors by effectors like bradykinin or acetylcholine (endothelial endothelial NOS III or excitatory amino acids like glutamate (neuronal neuronal synaptic 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54423 17496232 67664 14533 7872 NOS1 NOS NOS 30 2.7 III or excitatory amino acids like glutamate (neuronal neuronal synaptic NOS I ( 45 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54424 17496232 67665 14533 7872 NOS1 NOS NOS 0 2.7 NOS I and III are characterized by fast and transient responses 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54425 17496232 67666 14533 7872 NOS1 NOS NOS 2 2.7 In contrast NOS II is not constitutive and does not depend on Ca 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54426 17496232 67666 14533 7872 NOS1 NOS NOS 14 2.7 is not constitutive and does not depend on Ca concentration NOS II gene expression is modulated by inflammatory mediators like cytokines 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54427 17496232 67666 22551 11892 TNF TNF-alpha TNF-alpha 25 0.8 II gene expression is modulated by inflammatory mediators like cytokines TNF-alpha IFN-gamma and LPS that activate transcription factors like NF-kappaB or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54428 17496232 67666 9905 5438 IFNG IFN-gamma IFN-gamma 27 0.8 gene expression is modulated by inflammatory mediators like cytokines TNF-alpha IFN-gamma and LPS that activate transcription factors like NF-kappaB or AP-1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54429 17496232 67666 10676 6121 IRF6 LPS LPS 30 0.3 is modulated by inflammatory mediators like cytokines TNF-alpha IFN-gamma and LPS that activate transcription factors like NF-kappaB or AP-1 ( 59 1 JUMiner_v2.2 1 2 UserEdit 0 1 0 TotalCon:2<>12728|VWS||No_GeneRif__6121|IRF6|3664|Complete__<>AvaiableGeneRif=1<> 1 1 0 0 0 54430 17496232 67666 7683 3796 FOS AP-1 AP-1 39 1.0 IFN-gamma and LPS that activate transcription factors like NF-kappaB or AP-1 ( 59 1 JUMiner_v2.2 1 0 0 2 6204 TotalCon:5<>3796|FOS|2353|Complete__3797|FOSB|2354|Complete__6204|JUN|3725|Complete__6205|JUNB|3726|Complete__6206|JUND|3727|Complete__<>AvaiableGeneRif=5<>BEST:6204|JUN|0.000678857475341454<>ScoreDetail__3796|FOS|0.000549948240165631__3797|FOSB|0.000366854496168705__6205|JUNB|0.000444690368035598__6204|JUN|0.000678857475341454__6206|JUND|0.00064045242526041__ 0 0 0 0 0 54431 17496232 67666 14352 7794 NFKB1 NF-kappaB NF-kappaB 36 0.0 cytokines TNF-alpha IFN-gamma and LPS that activate transcription factors like NF-kappaB or AP-1 ( 59 1 JUMiner_v2.2 1 1 nf-kappab; 0 0 0 0 0 0 0 0 54432 17496232 67668 14533 7872 NOS1 NOS NOS 4 2.7 The activities of classic NOS isoforms are able to sustain NO cytosolic concentrations large enough 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54433 17496232 67671 14533 7872 NOS1 NOS NOS 7 2.7 Therefore mitochondrial NO coming from classic cytosolic NOS results in a considerably lower concentration ~20-100 nM ( 18 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54434 17496232 67671 14533 7872 NOS1 NOS NOS 31 2.7 however it may increase by fivefold after induction of inducible NOS in endotoxemia ( 14 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54435 17496232 67674 14533 7872 NOS1 NOS NOS 11 2.7 is noteworthy that changes in the expression and activities of NOS isoforms particularly of intra-mtNOS will be followed by significant variations 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54436 17496232 67676 4829 2294 COX8A COX COX 37 0.9 ( 25 NO reversibly binds to Cu B center of COX and consequently inhibits electron transfer to O 2 and mitochondrial 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54437 17496232 67678 4829 2294 COX8A COX COX 27 0.9 concentrations 50-100 nM NO inhibits by half the activity of COX ( 108 110 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54438 17496232 67690 4829 2294 COX8A COX COX 21 0.9 represents a simple competition between NO and O 2 for COX the formation of the complex between COX and NO was 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54439 17496232 67690 4829 2294 COX8A COX COX 28 0.9 O 2 for COX the formation of the complex between COX and NO was followed by the authors after addition of 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54440 17496232 67692 4829 2294 COX8A COX COX 7 0.9 The time scale for the inhibition of COX by NO is given by k NOon x NO at 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54441 17496232 67693 4829 2294 COX8A COX COX 5 0.9 Therefore the fast inhibition of COX by NO is completely compatible with a direct competition between 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54442 17496232 67693 4829 2294 COX8A COX COX 21 0.9 with a direct competition between NO and O 2 for COX at the steady state and in the presence of NO 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54443 17496232 67693 4829 2294 COX8A COX COX 50 0.9 Eq 2 which describes a simple linear competitive inhibition of COX by NO with an inhibition constant ( K i given 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54444 17496232 67698 4829 2294 COX8A COX COX 6 0.9 These calculations are useful for isolated COX although they should be modified to include additional NO effects 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54445 17496232 67699 4829 2294 COX8A COX COX 3 0.9 Accordingly NO inhibits COX and increases the reduction levels of the components of the 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54446 17496232 67699 4829 2294 COX8A COX COX 26 0.9 chain including ubiquinol and ubisemiquinone on the substrate side of COX and reacts directly with ubiquinol to produce nitroxyl anion (NO 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54447 17496232 67705 20997 11180 SOD2 MnSOD MnSOD 8 1.9 In the presence of mitochondrial manganese superoxide dismutase (MnSOD), MnSOD most of O 2 is dismutated to H 2 O 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54448 17496232 67713 20997 11180 SOD2 MnSOD MnSOD 22 1.9 dismutates to H 2 O 2 a reaction catalized by MnSOD ( reactions 4 and 5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54449 17496232 67714 20997 11180 SOD2 MnSOD MnSOD 37 1.9 in mitochondrial metabolism will depend on NO concentration and on MnSOD level 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54450 17496232 67715 20996 11179 SOD1 SOD SOD 26 2.2 20-fold NO utilization in contrast addition of superoxide dismutase (SOD) SOD decreases NO utilization and prolongs its mean life and increases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54451 17496232 67716 20997 11180 SOD2 MnSOD MnSOD 24 1.9 decays by reaction 4 and 2 depending on NO and MnSOD concentrations mitochondrial utilization of NO involves the formation of H 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54452 17496232 67720 14533 7872 NOS1 NOS NOS 10 2.7 Our underlying proposal is that grading expression and activities of NOS isoforms and the concentration of matrix NO modulate H 2 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54453 17496232 67721 20997 11180 SOD2 MnSOD MnSOD 11 1.9 As described in cell transformation ( 71 concomitant changes in MnSOD have two effects to increase cytosolic H 2 O 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54454 17496232 67728 20997 11180 SOD2 MnSOD MnSOD 21 1.9 Cu ZnSOD whereas in mitochondria the reaction is catalyzed by MnSOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54455 17496232 67729 23454 12435 TXN TRX Trx 21 1.0 (GPx; GPx reactions 6 and 7 and thioredoxin peroxidase (Trx; Trx reaction 8 are preferentially distributed in cytosol and peroxisomes 2 JUMiner_v2.2 1 0 0 2 25507 TotalCon:2<>12435|TXN|7295|Complete__25507|VAC14|55697|Complete__<>AvaiableGeneRif=2<>BEST:25507|VAC14|0.00089464196473192<>ScoreDetail__12435|TXN|0.000763442133862406__25507|VAC14|0.00089464196473192__ 0 0 0 0 0 54456 17496232 67740 14533 7872 NOS1 NOS NOS 33 2.7 process including the concentration and activities of mtNOS cytosolic classic NOS isoforms MnSOD catalase and peroxidases 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54457 17496232 67740 20997 11180 SOD2 MnSOD MnSOD 35 1.9 the concentration and activities of mtNOS cytosolic classic NOS isoforms MnSOD catalase and peroxidases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54458 17496232 67742 18723 10261 ROS1 ROS ROS 7 0.3 Although high levels of reactive oxygen species (ROS) ROS are frequently associated with cytotoxicity H 2 O 2 mediates 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 54459 17496232 67750 14551 7889 NOX1 NOX1 Nox1 8 0.3 ( 7 showed that transfection of oxidase Nox1 to NIH/3T3 NIH 3T3 fibroblasts which increases cell H 2 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54460 17496232 67755 12337 6871 MAPK1 MAPK MAPKs 17 2.2 and H 2 O 2 are confluent on modulation of MAPKs and cyclin D 1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54461 17496232 67756 12337 6871 MAPK1 MAPK MAPKs 0 2.2 MAPKs including SAPK/JNK, SAPK JNK p38 MAPK and ERK are believed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54462 17496232 67756 12354 6886 MAPK9 SAPK SAPK 2 2.2 MAPKs including SAPK/JNK, SAPK JNK p38 MAPK and ERK are believed to be redox-dependent 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54463 17496232 67756 12349 6881 MAPK8 JNK JNK 2 2.7 MAPKs including SAPK/JNK, SAPK JNK p38 MAPK and ERK are believed to be redox-dependent biomolecules 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54464 17496232 67756 12337 6871 MAPK1 p38 p38 3 2.2 MAPKs including SAPK/JNK, SAPK JNK p38 MAPK and ERK are believed to be redox-dependent biomolecules that 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54465 17496232 67756 12337 6871 MAPK1 MAPK MAPK 4 2.2 MAPKs including SAPK/JNK, SAPK JNK p38 MAPK and ERK are believed to be redox-dependent biomolecules that modulate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54466 17496232 67756 12337 6871 MAPK1 ERK ERK 6 2.2 MAPKs including SAPK/JNK, SAPK JNK p38 MAPK and ERK are believed to be redox-dependent biomolecules that modulate cell proliferation 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.00240555376170488<>ScoreDetail__3393|EPHB2|0.00075331458417035__6871|MAPK1|0.00240555376170488__ 0 0 0 0 0 54467 17496232 67757 12337 6871 MAPK1 ERK ERKs 0 2.2 ERKs stimulate cell proliferation and induction of active cyclin D 1 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.00240555376170488<>ScoreDetail__3393|EPHB2|0.00075331458417035__6871|MAPK1|0.00240555376170488__ 0 0 0 0 0 54468 17496232 67757 7683 3796 FOS AP-1 AP-1 18 1.0 cyclin D 1 by different mechanisms including the enhancement of AP-1 activity 1 JUMiner_v2.2 1 0 0 2 6204 TotalCon:5<>3796|FOS|2353|Complete__3797|FOSB|2354|Complete__6204|JUN|3725|Complete__6205|JUNB|3726|Complete__6206|JUND|3727|Complete__<>AvaiableGeneRif=5<>BEST:6204|JUN|0.000678857475341454<>ScoreDetail__3796|FOS|0.000549948240165631__3797|FOSB|0.000366854496168705__6205|JUNB|0.000444690368035598__6204|JUN|0.000678857475341454__6206|JUND|0.00064045242526041__ 0 0 0 0 0 54469 17496232 67758 12337 6871 MAPK1 ERK ERKs 19 2.2 moderate elevation of intracellular Ca and leads to activation of ERKs and potentiates cell division functionally blocking Ca or inhibiting calmodulin 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.00240555376170488<>ScoreDetail__3393|EPHB2|0.00075331458417035__6871|MAPK1|0.00240555376170488__ 0 0 0 0 0 54470 17496232 67758 12337 6871 MAPK1 MAPK MAPK 31 2.2 potentiates cell division functionally blocking Ca or inhibiting calmodulin or MAPK activities prevents ERK activation and antagonizes the mitogenic effect of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54471 17496232 67758 12337 6871 MAPK1 ERK ERK 34 2.2 functionally blocking Ca or inhibiting calmodulin or MAPK activities prevents ERK activation and antagonizes the mitogenic effect of NO ( 90 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.00240555376170488<>ScoreDetail__3393|EPHB2|0.00075331458417035__6871|MAPK1|0.00240555376170488__ 0 0 0 0 0 54472 17496232 67759 12337 6871 MAPK1 p38 p38 4 2.2 On the other hand p38 SAPK transcriptionally downregulates cyclin D 1 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54473 17496232 67759 12354 6886 MAPK9 SAPK SAPK 5 2.2 On the other hand p38 SAPK transcriptionally downregulates cyclin D 1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54474 17496232 67761 12337 6871 MAPK1 p38 p38 20 2.2 cyclin D 1 activity and expression the former by activating p38 pathway ( 37 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54475 17496232 67763 12337 6871 MAPK1 p38 p38 21 2.2 8 who reported a temporal inverse correlation between activation of p38 MAPK and cyclin D 1 content during liver development or 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54476 17496232 67763 12337 6871 MAPK1 MAPK MAPK 22 2.2 who reported a temporal inverse correlation between activation of p38 MAPK and cyclin D 1 content during liver development or liver 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54477 17496232 67764 12337 6871 MAPK1 p38 p38 3 2.2 Similarly NO activates p38 MAPK and suppresses proliferation through the activation of JAK2-STAT5 and 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54478 17496232 67764 12337 6871 MAPK1 MAPK MAPK 4 2.2 Similarly NO activates p38 MAPK and suppresses proliferation through the activation of JAK2-STAT5 and cyclin 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54479 17496232 67764 4037 1773 CDK4 CDK4 cdk4 17 0.3 through the activation of JAK2-STAT5 and cyclin D 1 /cdk4 cdk4 ( 70 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54480 17496232 67765 12337 6871 MAPK1 p38 p38 25 2.2 signal pathways involving both production of NO and activation of p38 MAPK pathway ( 93 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54481 17496232 67765 12337 6871 MAPK1 MAPK MAPK 26 2.2 pathways involving both production of NO and activation of p38 MAPK pathway ( 93 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54482 17496232 67766 12337 6871 MAPK1 MAPK MAPKs 27 2.2 57 attempted to connect oxidative stress and NO levels to MAPKs D cyclins and cell proliferation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54483 17496232 67769 23515 29884 UBASH3B p70 p70 31 0.3 O 2 acts as a messenger in growth factor-induced p70(S6k) p70 S6k signaling pathway in mouse epidermal cells which plays an 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54484 17496232 67769 19050 10436 RPS6KB1 S6K S6k 31 0.3 2 acts as a messenger in growth factor-induced p70(S6k) p70 S6k signaling pathway in mouse epidermal cells which plays an important 4 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54485 17496232 67770 12339 6877 MAPK3 ERK1 ERK1 7 2.7 Finally our group ( 2 observed ERK1/2 ERK1 2 activation in brain mitochondria by very low concentrations of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54486 17496232 67771 12337 6871 MAPK1 MAPK MAPK 18 2.2 redox effect on the protein or actions on ERK-MEK (MAPK MAPK kinase interactions 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54487 17496232 67772 12337 6871 MAPK1 MAPK MAPK 9 2.2 In this way it was proposed that duration of MAPK activation determines whether a stimulus produces proliferation or differentiation ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54488 17496232 67773 12339 6877 MAPK3 ERK1 ERK1 20 2.7 factor induced only a transient activation of MEK and ERK1/2 ERK1 2 and 50% increase in cell proliferation whereas prolonged stimulation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54489 17496232 67773 23055 11812 TRIM24 TF1A TF-1a 7 0.0 Activation of a myeloid leukemia cell line (TF-1a) TF-1a by granulocyte/macrophage granulocyte macrophage colony-stimulating factor induced only a transient 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54490 17496232 67774 12339 6877 MAPK3 ERK1 ERK1 6 2.7 The findings gain significance considering that ERK1/2 ERK1 2 are activated by ROS ( 134 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54491 17496232 67774 18723 10261 ROS1 ROS ROS 10 0.3 gain significance considering that ERK1/2 ERK1 2 are activated by ROS ( 134 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 54492 17496232 67775 4059 1784 CDKN1A p21 p21 24 0.6 and to resulting changes in cell cycle regulators such as p21 p27 cyclins and retinoblastoma protein 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.000737768827857011<>ScoreDetail__1784|CDKN1A|0.000737768827857011__11616|TCEAL1|0.000535823637477036__ 0 0 0 0 0 54493 17496232 67775 17526 9567 PSMD9 p27 p27 25 0.3 to resulting changes in cell cycle regulators such as p21 p27 cyclins and retinoblastoma protein 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>9567|PSMD9|5715|Complete__11328|SSSCA1|10534|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 54494 17496232 67776 18723 10261 ROS1 ROS ROS 13 0.3 depend on translocation of Bax to mitochondria and generation of ROS and ultimately on the release of cytochrome c but in 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 54495 17496232 67777 12337 6871 MAPK1 p38 p38 4 2.2 For instance activation of p38 MAPK and cell cycle arrest may finally progress to apoptosis 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54496 17496232 67777 12337 6871 MAPK1 MAPK MAPK 5 2.2 For instance activation of p38 MAPK and cell cycle arrest may finally progress to apoptosis in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54497 17496232 67777 12337 6871 MAPK1 p38 p38 24 2.2 apoptosis in the presence of NO which may activate the p38 MAPK pathway 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54498 17496232 67777 12337 6871 MAPK1 MAPK MAPK 25 2.2 in the presence of NO which may activate the p38 MAPK pathway 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54499 17496232 67778 12337 6871 MAPK1 p38 p38 3 2.2 In accord the p38 inhibitor SB-203580 blocks proapoptotic effects of NO in SH-SY5Y neurons 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54500 17496232 67779 12337 6871 MAPK1 p38 p38 5 2.2 The activating NO effects and p38 MAPK signaling probably result in Bax translocation to mitochondria a 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54501 17496232 67779 12337 6871 MAPK1 MAPK MAPK 6 2.2 The activating NO effects and p38 MAPK signaling probably result in Bax translocation to mitochondria a well-known 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54502 17496232 67780 12337 6871 MAPK1 p38 p38 21 2.2 microM H 2 O 2 causes a rapid activation of p38 MAPK cascade with phosphorylation of MKK3/6 MKK3 6 and p38 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54503 17496232 67780 12337 6871 MAPK1 MAPK MAPK 22 2.2 H 2 O 2 causes a rapid activation of p38 MAPK cascade with phosphorylation of MKK3/6 MKK3 6 and p38 MAPK 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54504 17496232 67780 12301 6843 MAP2K3 MKK3 MKK3 27 2.2 rapid activation of p38 MAPK cascade with phosphorylation of MKK3/6 MKK3 6 and p38 MAPK and activating transcription factors (ATF)-1 ATF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54505 17496232 67780 12337 6871 MAPK1 p38 p38 29 2.2 p38 MAPK cascade with phosphorylation of MKK3/6 MKK3 6 and p38 MAPK and activating transcription factors (ATF)-1 ATF -1 (cAMP cAMP 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54506 17496232 67780 12337 6871 MAPK1 MAPK MAPK 30 2.2 MAPK cascade with phosphorylation of MKK3/6 MKK3 6 and p38 MAPK and activating transcription factors (ATF)-1 ATF -1 (cAMP cAMP response 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54507 17496232 67780 16734 9052 PLAU ATF ATF 35 0.6 MKK3 6 and p38 MAPK and activating transcription factors (ATF)-1 ATF -1 (cAMP cAMP response element-binding protein and ATF-2 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 54508 17496232 67780 1239 784 ATF2 ATF2 ATF-2 41 1.2 factors (ATF)-1 ATF -1 (cAMP cAMP response element-binding protein and ATF-2 11 JUMiner_v2.2 1 0 0 2 4232 TotalCon:2<>784|ATF2|1386|Complete__4232|GDNF|2668|Complete__<>AvaiableGeneRif=2<>BEST:4232|GDNF|0.000572391363054633<>ScoreDetail__784|ATF2|0.000531512277655335__4232|GDNF|0.000572391363054633__ 0 0 0 0 0 54509 17496232 67781 12337 6871 MAPK1 p38 p38 32 2.2 and were cancelled by N -acetylcysteine or SB-203580 a specific p38 MAPK inhibitor 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54510 17496232 67781 12337 6871 MAPK1 MAPK MAPK 33 2.2 were cancelled by N -acetylcysteine or SB-203580 a specific p38 MAPK inhibitor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54511 17496232 67783 12349 6881 MAPK8 JNK JNK 15 2.7 that H 2 O 2 -induced cellular injury depends on JNK activation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54512 17496232 67784 12337 6871 MAPK1 p38 p38 4 2.2 In this case also p38 and ERK were activated by H 2 O 2 however 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54513 17496232 67784 12337 6871 MAPK1 ERK ERK 6 2.2 In this case also p38 and ERK were activated by H 2 O 2 however only JNK-related 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.00240555376170488<>ScoreDetail__3393|EPHB2|0.00075331458417035__6871|MAPK1|0.00240555376170488__ 0 0 0 0 0 54514 17496232 67784 12349 6881 MAPK8 JNK JNK-related 17 2.7 ERK were activated by H 2 O 2 however only JNK-related injuring effects were inhibited by the MEK inhibitor PD-98059 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54515 17496232 67785 12349 6881 MAPK8 JNK JNK 1 2.7 Moreover JNK phosphorylation of p53 is important for the stabilization of proapoptotic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54516 17496232 67785 22671 11998 TP53 p53 p53 4 1.6 Moreover JNK phosphorylation of p53 is important for the stabilization of proapoptotic p53 protein ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54517 17496232 67785 22671 11998 TP53 p53 p53 12 1.6 phosphorylation of p53 is important for the stabilization of proapoptotic p53 protein ( 28 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54518 17496232 67786 12337 6871 MAPK1 p38 p38 3 2.2 Early activation of p38 MAPK and ERK does not seem to be dependent on 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54519 17496232 67786 12337 6871 MAPK1 MAPK MAPK 4 2.2 Early activation of p38 MAPK and ERK does not seem to be dependent on cytotoxic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54520 17496232 67786 12337 6871 MAPK1 ERK ERK 6 2.2 Early activation of p38 MAPK and ERK does not seem to be dependent on cytotoxic factors like 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.00240555376170488<>ScoreDetail__3393|EPHB2|0.00075331458417035__6871|MAPK1|0.00240555376170488__ 0 0 0 0 0 54521 17496232 67787 12337 6871 MAPK1 p38 p38 12 2.2 suggest that physiological H 2 O 2 -dependent activation of p38 MAPK may proceed many steps before a significant Ca release 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54522 17496232 67787 12337 6871 MAPK1 MAPK MAPK 13 2.2 that physiological H 2 O 2 -dependent activation of p38 MAPK may proceed many steps before a significant Ca release from 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54523 17496232 67787 12354 6886 MAPK9 SAPK SAPK 36 2.2 stores and that Ca -dependent tyrosine kinase-induced activation of SAPK/JNK SAPK JNK reflects the progression of cell injury ( 73 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54524 17496232 67787 12349 6881 MAPK8 JNK JNK 36 2.7 and that Ca -dependent tyrosine kinase-induced activation of SAPK/JNK SAPK JNK reflects the progression of cell injury ( 73 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54525 17496232 67789 20997 11180 SOD2 MnSOD MnSOD 6 1.9 The main mitochondrial antioxidant defense is MnSOD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54526 17496232 67790 20996 11179 SOD1 SOD SOD 3 2.2 At the same SOD level the production of ONOO (and and concurrent nitration at 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54527 17496232 67791 20996 11179 SOD1 SOD SOD 5 2.2 Dismutation of O 2 by SOD proceeds with an order of magnitude lower than formation of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54528 17496232 67793 9691 5232 HSPA1A HSP HSPs 12 0.9 effects include S -nitrosylation and inhibition of caspases increase of HSPs and Bcl-2 and activation of Akt/PKB, Akt PKB which induces 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54529 17496232 67793 1576 990 BCL2 Bcl-2 Bcl-2 14 1.3 S -nitrosylation and inhibition of caspases increase of HSPs and Bcl-2 and activation of Akt/PKB, Akt PKB which induces cytoprotective gene 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54530 17496232 67793 543 391 AKT1 AKT Akt 18 0.5 caspases increase of HSPs and Bcl-2 and activation of Akt/PKB, Akt PKB which induces cytoprotective gene expression through NF-kappaB activation ( 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54531 17496232 67793 543 391 AKT1 PKB PKB 18 0.5 increase of HSPs and Bcl-2 and activation of Akt/PKB, Akt PKB which induces cytoprotective gene expression through NF-kappaB activation ( 85 1 JUMiner_v2.2 1 0 0 2 9612 TotalCon:2<>391|AKT1|207|Complete__9612|PTK2B|2185|Complete__<>AvaiableGeneRif=2<>BEST:9612|PTK2B|0.000881513888667124<>ScoreDetail__391|AKT1|0.000774375994099823__9612|PTK2B|0.000881513888667124__ 0 0 0 0 0 54532 17496232 67793 14352 7794 NFKB1 NF-kappaB NF-kappaB 25 0.0 of Akt/PKB, Akt PKB which induces cytoprotective gene expression through NF-kappaB activation ( 85 1 JUMiner_v2.2 1 1 nf-kappab; 0 0 0 0 0 0 0 0 54533 17496232 67796 1576 990 BCL2 Bcl-2 Bcl-2 14 1.3 hand proapoptotic effects of NO include inhibition of NF-kappaB decreased Bcl-2 expression ( 87 -89 118 and increased p53 expression both 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54534 17496232 67796 22671 11998 TP53 p53 p53 25 1.6 NF-kappaB decreased Bcl-2 expression ( 87 -89 118 and increased p53 expression both by NO-mediated inhibition of proteasome degradation and by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54535 17496232 67796 14352 7794 NFKB1 NF-kappaB NF-kappaB 11 0.0 the other hand proapoptotic effects of NO include inhibition of NF-kappaB decreased Bcl-2 expression ( 87 -89 118 and increased p53 1 JUMiner_v2.2 1 1 nf-kappab; 0 0 0 0 0 0 0 0 54536 17496232 67801 18723 10261 ROS1 ROS ROS 23 0.3 however other mitochondrial enzymes like monoamino oxidase could contribute to ROS production ( 3 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 54537 17496232 67806 18723 10261 ROS1 ROS ROS 17 0.3 intact mitochondria rotenone inhibition of complex I did not increase ROS production with complex I substrates in myocardial ischemia ( 43 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 54538 17496232 67808 18723 10261 ROS1 ROS ROS 1 0.3 Therefore ROS production may differ substantially in mitochondria and corresponding submitochondrial particles 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 54539 17496232 67817 14533 7872 NOS1 nNOS nNOS 10 3.7 levels of 3 3' 5-triiodothyronine (T T 3 in hypothyroidism nNOS mRNA increased by threefold and nNOS translocation to mitochondria was 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54540 17496232 67817 14533 7872 NOS1 nNOS nNOS 16 3.7 T 3 in hypothyroidism nNOS mRNA increased by threefold and nNOS translocation to mitochondria was favored with concomitant increase of mtNOS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54541 17496232 67818 14533 7872 NOS1 nNOS nNOS 4 3.7 Two effects emerged from nNOS confinement 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54542 17496232 67819 14533 7872 NOS1 NOS NOS 14 2.7 consumption was more sensitive to L -arginine and to the NOS inhibitor N -monomethyl-L -arginine indicating the modulation of O 2 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54543 17496232 67821 12337 6871 MAPK1 MAPK MAPK 7 2.2 Mitochondrial redox contribution to the activation of MAPK cascades was also confirmed in the hypothyroid model 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54544 17496232 67822 12337 6871 MAPK1 p38 p38 22 2.2 2 O 2 and peroxynitrite with the concomitant activation of p38 MAPK and the inactivation of ERK1/2 ERK1 2 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54545 17496232 67822 12337 6871 MAPK1 MAPK MAPK 23 2.2 O 2 and peroxynitrite with the concomitant activation of p38 MAPK and the inactivation of ERK1/2 ERK1 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54546 17496232 67822 12339 6877 MAPK3 ERK1 ERK1 28 2.7 concomitant activation of p38 MAPK and the inactivation of ERK1/2 ERK1 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54547 17496232 67823 12337 6871 MAPK1 MAPK MAPK 4 2.2 As shown before this MAPK pattern is consistent with cell cycle arrest and inhibition of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54548 17496232 67824 14533 7872 NOS1 NOS NOS 5 2.7 A similar effect of a NOS inhibitor N -nitro-L -arginine methyl ester ( L -NAME or 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54549 17496232 67824 12337 6871 MAPK1 MAPK MAPK 33 2.2 hypothyroid cell signaling back to control status indicates that differential MAPK activation and cyclin D 1 expression should not depend on 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54550 17496232 67827 14533 7872 NOS1 nNOS nNOS 25 3.7 of complex I inhibition by NO-ONOO overproduced by increased translocated nNOS (mtNOS) mtNOS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54551 17496232 67828 14533 7872 NOS1 nNOS nNOS 9 3.7 It is interesting that lack of T 3 stimulates nNOS gene expression suggesting the existence of a tonic gene inhibition 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54552 17496232 67832 12337 6871 MAPK1 ERK ERK 28 2.2 cell types and its expression is positively regulated by the ERK pathway and antagonized by stress-activated p38 MAPK cascade ( 84 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.00240555376170488<>ScoreDetail__3393|EPHB2|0.00075331458417035__6871|MAPK1|0.00240555376170488__ 0 0 0 0 0 54553 17496232 67832 12337 6871 MAPK1 p38 p38 34 2.2 positively regulated by the ERK pathway and antagonized by stress-activated p38 MAPK cascade ( 84 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54554 17496232 67832 12337 6871 MAPK1 MAPK MAPK 35 2.2 regulated by the ERK pathway and antagonized by stress-activated p38 MAPK cascade ( 84 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54555 17496232 67833 12337 6871 MAPK1 p38 p38 11 2.2 liver development cyclin D 1 content is inversely related to p38 MAPK activity which in turn may be regulated by ROS 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54556 17496232 67833 12337 6871 MAPK1 MAPK MAPK 12 2.2 development cyclin D 1 content is inversely related to p38 MAPK activity which in turn may be regulated by ROS ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54557 17496232 67833 18723 10261 ROS1 ROS ROS 21 0.3 p38 MAPK activity which in turn may be regulated by ROS ( 81 and NO ( 104 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 54558 17496232 67834 16916 9175 POLD1 CDC2 cdc2 28 1.3 by inhibition of cyclin D 1 or by inhibition of cdc2 (cyclin cyclin E and A pathways ( 104 14 JUMiner_v2.2 1 0 0 2 1722 TotalCon:2<>1722|CDC2|983|Complete__9175|POLD1|5424|Complete__<>AvaiableGeneRif=2<>BEST:1722|CDC2|0.000829301768266925<>ScoreDetail__9175|POLD1|0.000356567747872096__1722|CDC2|0.000829301768266925__ 0 0 0 0 0 54559 17496232 67836 12337 6871 MAPK1 MAPK MAPK 15 2.2 observed that modulation of mtNOS and subsequent redox changes regulate MAPK cascades and cell cycle regulatory proteins in the sequence of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54560 17496232 67837 12339 6877 MAPK3 ERK1 ERK1 37 2.7 and high cyclin D 1 expression associated with high ERK1/2 ERK1 2 and low p38 MAPK activities 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54561 17496232 67837 12337 6871 MAPK1 p38 p38 40 2.2 1 expression associated with high ERK1/2 ERK1 2 and low p38 MAPK activities 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54562 17496232 67837 12337 6871 MAPK1 MAPK MAPK 41 2.2 expression associated with high ERK1/2 ERK1 2 and low p38 MAPK activities 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54563 17496232 67841 14533 7872 NOS1 NOS NOS 15 2.7 2 O 2 levels by controlled treatment with scavengers or NOS inhibitors like N -acetylcysteine glutathione or L -NAME increased proliferation 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54564 17496232 67842 12337 6871 MAPK1 MAPK MAPK 9 2.2 Moreover isolated hepatocyte proliferation rate may be modulated by MAPK inhibitors or stimulators like U-0126 (MEK MEK inhibitor SB-202190 (p38 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54565 17496232 67842 12337 6871 MAPK1 p38 p38 18 2.2 inhibitors or stimulators like U-0126 (MEK MEK inhibitor SB-202190 (p38 p38 inhibitor or anisomycin (p38 p38 activator suggesting that hepatocyte proliferation 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54566 17496232 67842 12337 6871 MAPK1 p38 p38 22 2.2 (MEK MEK inhibitor SB-202190 (p38 p38 inhibitor or anisomycin (p38 p38 activator suggesting that hepatocyte proliferation signaling is related to a 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54567 17496232 67851 1576 990 BCL2 Bcl-2 Bcl-2 14 1.3 that cleave specific aspartate residues in other regulatory proteins like Bcl-2 Bax and MEKK (for for review see Ref 83 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54568 17496232 67851 12306 6848 MAP3K1 MEKK MEKK 17 2.2 aspartate residues in other regulatory proteins like Bcl-2 Bax and MEKK (for for review see Ref 83 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54569 17496232 67852 22551 11892 TNF TNF-alpha TNF-alpha 9 0.8 In the extrinsic pathway binding of membrane ligands like TNF-alpha and Fas to membrane receptors triggers the activation of caspases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54570 17496232 67852 7333 11920 FAS FAS Fas 12 0.6 the extrinsic pathway binding of membrane ligands like TNF-alpha and Fas to membrane receptors triggers the activation of caspases and the 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000675502669018839<>ScoreDetail__11920|FAS|0.000675502669018839__3594|FASN|0.000565222966869989__ 0 0 0 0 0 54571 17496232 67856 22671 11998 TP53 p53 p53 3 1.6 For instance proapoptotic p53 protein induces gene transcription of redox-related genes encoding proteins that 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54572 17496232 67862 12349 6881 MAPK8 JNK JNK 13 2.7 NO induces apoptotic cell death with the activation of JNK/SAPK JNK SAPK and p38 MAPK and caspase 3 or inactivation of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54573 17496232 67862 12354 6886 MAPK9 SAPK SAPK 13 2.2 induces apoptotic cell death with the activation of JNK/SAPK JNK SAPK and p38 MAPK and caspase 3 or inactivation of NF-kappaB. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54574 17496232 67862 12337 6871 MAPK1 p38 p38 15 2.2 cell death with the activation of JNK/SAPK JNK SAPK and p38 MAPK and caspase 3 or inactivation of NF-kappaB. 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54575 17496232 67862 12337 6871 MAPK1 MAPK MAPK 16 2.2 death with the activation of JNK/SAPK JNK SAPK and p38 MAPK and caspase 3 or inactivation of NF-kappaB. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54576 17496232 67863 14533 7872 NOS1 NOS NOS 5 2.7 In this way increased inducible NOS expression and NO production act as a negative regulatory feedback 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54577 17496232 67863 14352 7794 NFKB1 NF-kappaB NF-kappaB 18 0.0 NO production act as a negative regulatory feedback modulator of NF-kappaB activity ( 102 1 JUMiner_v2.2 1 1 nf-kappab; 0 0 0 0 0 0 0 0 54578 17496232 67864 14352 7794 NFKB1 NF-kappaB NF-kappaB 5 0.0 The stimulation or inhibition of NF-kappaB may be related to proliferative or apoptotic effects 1 JUMiner_v2.2 1 1 nf-kappab; 0 0 0 0 0 0 0 0 54579 17496232 67865 14352 7794 NFKB1 NF-kappaB NF-kappaB 0 0.0 NF-kappaB is activated by several agents including cytokines oxidant free radicals 1 JUMiner_v2.2 1 1 nf-kappab; 0 0 0 0 0 0 0 0 54580 17496232 67866 14352 7794 NFKB1 NF-kappaB NF-kappaB 3 0.0 Inappropriate activation of NF-kappaB has been linked to inflammatory events associated with autoimmune arthritis 1 JUMiner_v2.2 1 1 nf-kappab; 0 0 0 0 0 0 0 0 54581 17496232 67867 14352 7794 NFKB1 NF-kappaB NF-kappaB 7 0.0 In contrast complete and persistent inhibition of NF-kappaB has been linked directly to apoptosis inappropriate immune cell development 1 JUMiner_v2.2 1 1 nf-kappab; 0 0 0 0 0 0 0 0 54582 17496232 67868 1576 990 BCL2 Bcl-2 Bcl-2 15 1.3 gene is associated with embryo lethality many antiapoptotic pathways like Bcl-2 are induced by NF-kappaB. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54583 17496232 67868 14352 7794 NFKB1 NF-kappaB NF-kappaB 3 0.0 Disruption of the NF-kappaB gene is associated with embryo lethality many antiapoptotic pathways like 1 JUMiner_v2.2 1 1 nf-kappab; 0 0 0 0 0 0 0 0 54584 17496232 67869 14352 7794 NFKB1 NF-kappaB NF-kappaB 14 0.0 have been developed in cancer treatment including inhibition of the NF-kappaB pathway ( 144 1 JUMiner_v2.2 1 1 nf-kappab; 0 0 0 0 0 0 0 0 54585 17496232 67871 22671 11998 TP53 p53 p53 24 1.6 the result of DNA damage which induces the accumulation of p53 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54586 17496232 67872 22671 11998 TP53 p53 p53 1 1.6 NO-mediated p53 accumulation induces cell cycle arrest by p21 upregulation or apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54587 17496232 67872 4059 1784 CDKN1A p21 p21 8 0.6 NO-mediated p53 accumulation induces cell cycle arrest by p21 upregulation or apoptosis by increase in Bax/Bcl-xL, Bax Bcl-xL cytochrome 1 JUMiner_v2.2 1 0 0 2 1784 TotalCon:2<>1784|CDKN1A|1026|Complete__11616|TCEAL1|9338|Complete__<>AvaiableGeneRif=2<>BEST:1784|CDKN1A|0.000737768827857011<>ScoreDetail__1784|CDKN1A|0.000737768827857011__11616|TCEAL1|0.000535823637477036__ 0 0 0 0 0 54588 17496232 67875 9691 5232 HSPA1A HSP70 Hsp70 26 0.9 antiapoptotic genes like that of heme oxygenase ( 127 and Hsp70 which protects hepatocytes from apoptosis induced by oxidative and nitrative 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54589 17496232 67878 9038 4827 HBB hemoglobin hemoglobin 8 1.0 Likewise in sickle cell anemia the sickle cell hemoglobin is deficient in the intramolecular and intermolecular transfer of NO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54590 17496232 67880 20996 11179 SOD1 ALS ALS 17 2.2 -nitrosylation contributes to the development of amyotrophic lateral sclerosis (ALS); ALS ALS is one of the most common adult-onset neurodegenerative diseases 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00054670412384765<>ScoreDetail__5468|IGFALS|0.000455259857037071__11179|SOD1|0.00054670412384765__ 0 0 0 0 0 54591 17496232 67880 20996 11179 SOD1 ALS ALS 18 2.2 contributes to the development of amyotrophic lateral sclerosis (ALS); ALS ALS is one of the most common adult-onset neurodegenerative diseases and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00054670412384765<>ScoreDetail__5468|IGFALS|0.000455259857037071__11179|SOD1|0.00054670412384765__ 0 0 0 0 0 54592 17496232 67880 20996 11179 SOD1 SOD1 SOD1 56 2.7 and 10-20% of cases are due to mutations in the SOD1 gene ( 122 123 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54593 17496232 67881 20996 11179 SOD1 SOD1 SOD1 2 2.7 Considering that SOD1 mutations lead to an increase of the denitrosylase activity of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54594 17496232 67881 8118 4141 GAPDH GAPDH GAPDH 35 0.3 of proteins that are regulated by this mechanism (like like GAPDH and that increased denitrosylase activity is a toxic gain of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54595 17496232 67881 20996 11179 SOD1 SOD1 SOD1 48 2.7 increased denitrosylase activity is a toxic gain of function of SOD1 mutants 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54596 17496232 67882 14533 7872 NOS1 NOS NOS 17 2.7 the mitochondrial field we previously reported the existence of defective NOS and mtNOS in mitochondria from tumor cells ( 58 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000854898005194548<>ScoreDetail__7873|NOS2A|0.00073791189877161__7872|NOS1|0.000854898005194548__ 0 0 0 0 0 54597 17496232 67883 12339 6877 MAPK3 ERK1 ERK1 18 2.7 O 2 yields high proliferation rate and activation of ERK1/2, ERK1 2 a pattern resembling that shown in embryonic development ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54598 17496232 67884 12337 6871 MAPK1 p38 p38 2 2.2 Because proapoptotic p38 or JNK1/2 JNK1 2 did not become phosphorylated we surmise 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:4<>1189|AHSA1|10598|Complete__6876|MAPK14|1432|Complete__6871|MAPK1|5594|Complete__6878|MAPK4|5596|Complete__<>AvaiableGeneRif=4<>BEST:6871|MAPK1|0.00253048487028415<>ScoreDetail__1189|AHSA1|0.000481695568400771__6878|MAPK4|0.00107349298100743__6871|MAPK1|0.00253048487028415__6876|MAPK14|0.00201587005614602__ 0 0 0 0 0 54599 17496232 67884 12349 6881 MAPK8 JNK1 JNK1 4 2.7 Because proapoptotic p38 or JNK1/2 JNK1 2 did not become phosphorylated we surmise the results are 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54600 17496232 67891 12337 6871 MAPK1 MAPK MAPKs 36 2.2 setting H 2 O 2 ss with differential activation of MAPKs Akt and cyclin D In this sense very low NO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54601 17496232 67891 543 391 AKT1 AKT Akt 37 0.5 H 2 O 2 ss with differential activation of MAPKs Akt and cyclin D In this sense very low NO inhibits 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 54602 17496232 67891 4829 2294 COX8A COX COX 48 0.9 and cyclin D In this sense very low NO inhibits COX and determines low H 2 O 2 yield 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>2294|COX8A|1351|No_GeneRif__2267|COX5A|9377|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 54603 17496232 67894 20996 11179 SOD1 ALS ALS 39 2.2 to the onset of diseases with high mortality rate like ALS or cancer 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00054670412384765<>ScoreDetail__5468|IGFALS|0.000455259857037071__11179|SOD1|0.00054670412384765__ 0 0 0 0 0 58549 17571960 73867 20996 11179 SOD1 ALS ALS 38 0.0 (PD), PD Huntington's (HD) HD diseases amyotrophic lateral sclerosis (ALS), ALS spinal muscular atrophy (SMA), SMA and diabetic encephalopathy 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000541264326850375<>ScoreDetail__5468|IGFALS|9.47957152336714e-05__11179|SOD1|0.000541264326850375__ 0 0 0 0 0 58550 17571960 73867 20478 11117 SMN1 SMA SMA 42 0.0 diseases amyotrophic lateral sclerosis (ALS), ALS spinal muscular atrophy (SMA), SMA and diabetic encephalopathy 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59582 17584954 75211 18723 10261 ROS1 ROS ROS 3 0.6 Reactive oxygen species (ROS), ROS especially mitochondrial ROS are postulated to play a significant role 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59583 17584954 75211 18723 10261 ROS1 ROS ROS 6 0.6 Reactive oxygen species (ROS), ROS especially mitochondrial ROS are postulated to play a significant role in muscle atrophy 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59584 17584954 75212 18723 10261 ROS1 ROS ROS 7 0.6 We report a dramatic increase in mitochondrial ROS generation in three conditions associated with muscle atrophy in aging 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59585 17584954 75212 20996 11179 SOD1 SOD1 Sod1 23 2.7 with muscle atrophy in aging in mice lacking CuZn-SOD ( Sod1 and in the neurodegenerative disease amyotrophic lateral sclerosis (ALS) ALS 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59586 17584954 75212 20996 11179 SOD1 ALS ALS 33 3.0 Sod1 and in the neurodegenerative disease amyotrophic lateral sclerosis (ALS) ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59587 17584954 75213 18723 10261 ROS1 ROS ROS 0 0.6 ROS generation in muscle mitochondria is nearly threefold higher in 28- 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59588 17584954 75214 20996 11179 SOD1 SOD1 Sod1 1 2.7 In Sod1 mice muscle mitochondrial ROS production is increased >100% in 20-mo 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59589 17584954 75214 18723 10261 ROS1 ROS ROS 5 0.6 In Sod1 mice muscle mitochondrial ROS production is increased >100% in 20-mo compared with 5-mo-old mice 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59590 17584954 75215 20996 11179 SOD1 ALS ALS 0 3.0 ALS G93A mutant mice show a 75% loss of muscle mass 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59591 17584954 75215 18723 10261 ROS1 ROS ROS 21 0.6 during disease progression and up to 12-fold higher muscle mitochondrial ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59592 17584954 75216 20996 11179 SOD1 ALS ALS 3 3.0 In a second ALS mutant model H46RH48Q mice ROS production is approximately fourfold higher 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59593 17584954 75216 18723 10261 ROS1 ROS ROS 8 0.6 In a second ALS mutant model H46RH48Q mice ROS production is approximately fourfold higher than in control mice and 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59594 17584954 75217 18723 10261 ROS1 ROS ROS 1 0.6 Thus ROS production is strongly correlated with the extent of muscle atrophy 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59595 17584954 75218 18723 10261 ROS1 ROS ROS 30 0.6 were interested in determining whether denervation plays a role in ROS generation in muscle mitochondria isolated from hindlimb muscle following surgical 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59596 17584954 75219 18723 10261 ROS1 ROS ROS 5 0.6 Seven days postdenervation muscle mitochondrial ROS production increased nearly 30-fold 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59597 17584954 75220 18723 10261 ROS1 ROS ROS 7 0.6 We conclude that enhanced generation of mitochondrial ROS may be a common factor in the mechanism underlying denervation-induced 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59598 17584954 75226 20996 11179 SOD1 ALS ALS 34 3.0 and in atrophic mouse muscle from amyotrophic lateral sclerosis (ALS) ALS transgenic mice ( 54 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59599 17584954 75227 18723 10261 ROS1 ROS ROS 10 0.6 mitochondria are an important source of reactive oxygen species (ROS) ROS in cells we were interested in delineating the role of 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59600 17584954 75227 18723 10261 ROS1 ROS ROS 23 0.6 we were interested in delineating the role of muscle mitochondrial ROS generation in muscle atrophy 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59601 17584954 75228 18723 10261 ROS1 ROS ROS 6 0.6 In this study we measured mitochondrial ROS production during aging in wild-type mice and in mutant mouse 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59602 17584954 75228 18723 10261 ROS1 ROS ROS 30 0.6 significant loss of muscle mass to assess the importance of ROS generation in the basic mechanism(s) mechanism s underlying muscle atrophy 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59603 17584954 75229 20996 11179 SOD1 SOD1 Sod1 18 2.7 is a knockout mouse lacking a major antioxidant enzyme CuZn-SOD Sod1 mice ( 67 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59604 17584954 75230 20996 11179 SOD1 SOD1 Sod1 8 2.7 In a recent study we reported that the Sod1 mice show a dramatic age-related loss of skeletal muscle mass 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59605 17584954 75231 20996 11179 SOD1 SOD1 Sod1 6 2.7 By 20 mo of age the Sod1 mice have lost nearly 50% of their hindlimb muscle mass 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59606 17584954 75234 20996 11179 SOD1 SOD1 Sod1 1 2.7 The Sod1 mice are also characterized by very high levels of oxidative 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59607 17584954 75235 20996 11179 SOD1 ALS ALS 29 3.0 CuZn-SOD that are found in humans with the neurodegenerative disease ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59608 17584954 75236 20996 11179 SOD1 ALS ALS 0 3.0 ALS is characterized by selective loss of upper and lower motor 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59609 17584954 75237 20996 11179 SOD1 ALS ALS 15 3.0 of the CuZn-SOD protein develop a disease strikingly similar to ALS ( 31 including paralysis and significant loss of muscle mass 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59610 17584954 75238 18723 10261 ROS1 ROS ROS 2 0.6 We measured ROS production in skeletal muscle mitochondria from two different CuZn-SOD mutant 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59611 17584954 75243 18723 10261 ROS1 ROS ROS 7 0.6 In this study we propose that mitochondrial ROS is a critical factor in the mechanism underlying muscle atrophy 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59612 17584954 75244 18723 10261 ROS1 ROS ROS 15 0.6 in all three models we observed a significant increase in ROS generation that correlated to the extent of muscle atrophy i.e. 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59613 17584954 75244 18723 10261 ROS1 ROS ROS 27 0.6 that correlated to the extent of muscle atrophy i.e. greater ROS generation in models exhibiting greater atrophy 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59614 17584954 75245 20996 11179 SOD1 SOD1 Sod1 12 2.7 that occurs in the three conditions we studied (aging, aging Sod1 mice and ALS is largely the result of loss of 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59615 17584954 75245 20996 11179 SOD1 ALS ALS 15 3.0 the three conditions we studied (aging, aging Sod1 mice and ALS is largely the result of loss of innervation we asked 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59616 17584954 75245 18723 10261 ROS1 ROS ROS 30 0.6 of loss of innervation we asked whether mitochondrial generation of ROS would be induced by surgical denervation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59617 17584954 75246 18723 10261 ROS1 ROS ROS 18 0.6 rapid muscle mass loss and a dramatic increase in mitochondria ROS production 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59618 17584954 75247 18723 10261 ROS1 ROS ROS 18 0.6 loss of innervation in the induction of skeletal muscle mitochondrial ROS generation oxidative stress and loss of muscle mass 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59619 17584954 75249 20996 11179 SOD1 SOD1 Sod1 1 2.7 The Sod1 mice used in this study were generated by Dr Charles 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59620 17584954 75250 20996 11179 SOD1 SOD1 Sod1 9 2.7 The mice were maintained in the heterozygous state ( Sod1 and backcrossed with C57Bl/6J C57Bl 6J females (Jackson Jackson Laboratory 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59621 17584954 75251 20996 11179 SOD1 ALS ALS 2 3.0 Two different ALS mouse models were employed 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59622 17584954 75263 18723 10261 ROS1 ROS ROS 1 0.6 Mitochondrial ROS production was measured with the Amplex red-horseradish peroxidase (HRP) HRP 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59623 17584954 75266 18723 10261 ROS1 ROS ROS 20 0.6 H 2 O 2 production and are referred to as ROS rather than H 2 O 2 production ( 55 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59624 17584954 75272 8255 4236 GFER HPO HPO 21 0.3 HEPES 5 mM MgCl 2 and 2 mM K 2 HPO 4 pH 7.44 1 JUMiner_v2.2 1 2 k 2 hpo 0 0 0 0 0 0 0 0 59625 17584954 75275 8255 4236 GFER HPO HPO 21 0.3 HEPES 5 mM MgCl 2 and 2 mM K 2 HPO 4 pH 7.44 with 0.3% BSA 1 JUMiner_v2.2 1 2 k 2 hpo 0 0 0 0 0 0 0 0 59626 17584954 75276 24185 29175 WDTC1 ADP ADP 11 0.0 3 respiration was induced with the addition of 0.3 mM ADP 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59627 17584954 75287 18723 10261 ROS1 ROS ROS 0 0.6 ROS production is increased in muscle mitochondria during aging and is 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59628 17584954 75288 18723 10261 ROS1 ROS ROS 23 0.6 of muscle mass is associated with alterations in muscle mitochondrial ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59629 17584954 75291 18723 10261 ROS1 ROS ROS 8 0.6 The major finding of this study is that ROS production was elevated in skeletal muscle mitochondria isolated from mice 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59630 17584954 75291 20996 11179 SOD1 SOD1 Sod1 33 2.7 associated with significant loss of muscle mass age-related muscle atrophy Sod1 mice (a a mouse model of accelerated sarcopenia and two 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59631 17584954 75291 20996 11179 SOD1 ALS ALS 43 3.0 mice (a a mouse model of accelerated sarcopenia and two ALS mutant mouse models differing in the time course and extent 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59632 17584954 75292 18723 10261 ROS1 ROS ROS 5 0.6 Thus as Fig 6 illustrates ROS production was lowest during normal aging (when when the extent 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59633 17584954 75292 20996 11179 SOD1 SOD1 Sod1 25 2.7 of muscle atrophy is lowest higher in muscle from the Sod1 mice and increased nearly 10-fold in G93A ALS mutant mice 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59634 17584954 75292 20996 11179 SOD1 ALS ALS 33 3.0 from the Sod1 mice and increased nearly 10-fold in G93A ALS mutant mice which showed the most dramatic muscle atrophy 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59635 17584954 75293 18723 10261 ROS1 ROS ROS 12 0.6 also holds within each of the models studied i.e. both ROS production and loss of muscle mass were higher in 32-mo-old 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59636 17584954 75293 18723 10261 ROS1 ROS ROS 28 0.6 mass were higher in 32-mo-old than in 27-mo-old normal mice ROS production and atrophy were higher in 20-mo-old than in 5-mo-old 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59637 17584954 75293 20996 11179 SOD1 SOD1 Sod1 39 2.7 production and atrophy were higher in 20-mo-old than in 5-mo-old Sod1 mice and ROS generation was higher in the G93A compared 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59638 17584954 75293 18723 10261 ROS1 ROS ROS 42 0.6 were higher in 20-mo-old than in 5-mo-old Sod1 mice and ROS generation was higher in the G93A compared with the H46RH48Q 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59639 17584954 75293 20996 11179 SOD1 ALS ALS 54 3.0 was higher in the G93A compared with the H46RH48Q mutant ALS models and in agreement with more atrophy in G93A 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59640 17584954 75296 20996 11179 SOD1 ALS ALS 5 3.0 Denervation is extensively documented in ALS caused by the degeneration of lower motor neurons ( 75 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59641 17584954 75296 20996 11179 SOD1 SOD1 Sod1 33 2.7 to denervation (caused caused by breakdown of neuromuscular junctions in Sod1 mice ( 25 57 70 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59642 17584954 75299 20996 11179 SOD1 SOD1 Sod1 9 2.7 Thus one common characteristic of the three models (aging, aging Sod1 mice and ALS mutant mice is alterations in innervation of 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59643 17584954 75299 20996 11179 SOD1 ALS ALS 12 3.0 characteristic of the three models (aging, aging Sod1 mice and ALS mutant mice is alterations in innervation of muscle fibers ( 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59644 17584954 75300 18723 10261 ROS1 ROS ROS 10 0.6 To test whether denervation contributes to an increase in mitochondrial ROS we measured ROS generation in mouse muscle following sciatic nerve 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59645 17584954 75300 18723 10261 ROS1 ROS ROS 13 0.6 denervation contributes to an increase in mitochondrial ROS we measured ROS generation in mouse muscle following sciatic nerve transection 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59646 17584954 75301 18723 10261 ROS1 ROS ROS 0 0.6 ROS generation was dramatically increased in surgically denervated muscle demonstrating a 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59647 17584954 75301 18723 10261 ROS1 ROS ROS 19 0.6 demonstrating a direct role for denervation in increased muscle mitochondrial ROS production 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59648 17584954 75302 18723 10261 ROS1 ROS ROS 4 0.6 Thus an elevation in ROS generation is a common event in skeletal muscle mitochondria under 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59649 17584954 75303 18723 10261 ROS1 ROS ROS 9 0.6 What is the connection between denervation and altered mitochondrial ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59650 17584954 75306 20996 11179 SOD1 ALS ALS 19 3.0 inhibition of neural signaling occurs in many neuromuscular diseases including ALS or spinal cord injury ( 75 spinal muscular atrophy ( 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59651 17584954 75311 18723 10261 ROS1 ROS ROS 23 0.6 loss of innervation that leads to muscle mitochondrial dysfunction increased ROS generation and an increase in oxidative stress the consequences of 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59652 17584954 75311 18723 10261 ROS1 ROS ROS 58 0.6 additional neurons or neuromuscular junctions exacerbating the increase in muscle ROS generation even further and continuing the cycle of damage 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59653 17584954 75315 18723 10261 ROS1 ROS ROS 15 0.6 subjected to nerve transaction also reported an increase in mitochondrial ROS generation that was associated with an increase in the mitochondrial 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59654 17584954 75317 18723 10261 ROS1 ROS ROS 6 0.6 How might the increase in mitochondrial ROS production contribute to the loss of muscle mass 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59655 17584954 75319 18723 10261 ROS1 ROS ROS 7 0.6 We can propose several ways that mitochondrial ROS generation might contribute to muscle atrophy 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59656 17584954 75320 18723 10261 ROS1 ROS ROS 7 0.6 It is possible that the increased in ROS directly or indirectly damages proteins increasing their turnover which could 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59657 17584954 75321 18723 10261 ROS1 ROS ROS 2 0.6 Alternatively increased ROS may damage critical enzymes such as those involved in energy 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59658 17584954 75322 18723 10261 ROS1 ROS ROS 3 0.6 In fact increased ROS production following denervation is mirrored by decreases in surface hydrophobicity 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59659 17584954 75323 18723 10261 ROS1 ROS ROS 2 0.6 Increased mitochondrial ROS may also play a signaling role 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59660 17584954 75324 18723 10261 ROS1 ROS ROS 7 0.6 Another good candidate for an effect of ROS on signaling is NF-kappaB. 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59661 17584954 75325 14352 7794 NFKB1 NF-kappaB NF-kappaB 0 0.0 NF-kappaB is known to play a role in muscle atrophy ( 1 JUMiner_v2.2 1 1 nf-kappab; 0 0 0 0 0 0 0 0 59662 17584954 75326 18723 10261 ROS1 ROS ROS 15 0.6 a central role in intrinsic pathway of apoptosis and mitochondrial ROS generation and atrophy could also be linked through apoptosis ( 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59663 17584954 75327 18723 10261 ROS1 ROS ROS 1 0.6 Mitochondrial ROS has also been shown to lead to upregulation of the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59664 17584954 75327 7405 16731 FBXO32 ATROGIN1 Atrogin-1 16 1.5 lead to upregulation of the expression of ubiquitin ligase Atrogin-1/MAFbx Atrogin-1 MAFbx ( 53 and could therefore contribute to atrophy through 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59665 17584954 75327 7405 16731 FBXO32 MAFbx MAFbx 16 1.5 to upregulation of the expression of ubiquitin ligase Atrogin-1/MAFbx Atrogin-1 MAFbx ( 53 and could therefore contribute to atrophy through increased 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59666 17584954 75328 18723 10261 ROS1 ROS ROS 15 0.6 whether the loss of innervation precedes the increase in mitochondrial ROS generation or vice versa 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59667 17584954 75329 20996 11179 SOD1 SOD1 Sod1 11 2.7 on our experiments in young and old wild-type mice the Sod1 model and the ALS mouse models we cannot be certain 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59668 17584954 75329 20996 11179 SOD1 ALS ALS 15 3.0 young and old wild-type mice the Sod1 model and the ALS mouse models we cannot be certain whether the increase in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59669 17584954 75329 18723 10261 ROS1 ROS ROS 26 0.6 mouse models we cannot be certain whether the increase in ROS generation precedes or follows changes in innervation especially in the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59670 17584954 75329 20996 11179 SOD1 SOD1 Sod1 37 2.7 generation precedes or follows changes in innervation especially in the Sod1 mice and in the case of aging in which the 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59671 17584954 75330 18723 10261 ROS1 ROS ROS 13 0.6 however is that in each situation both muscle atrophy and ROS production increase over time 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59672 17584954 75331 20996 11179 SOD1 ALS ALS 1 3.0 In ALS mice muscle atrophy occurs over weeks rather than months and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59673 17584954 75331 18723 10261 ROS1 ROS ROS 31 0.6 roughly correlate the timing of loss of muscle mass and ROS increase 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59674 17584954 75332 20996 11179 SOD1 ALS ALS 19 3.0 begins as early as 30-40 days of age in G93A ALS mice ( 24 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59675 17584954 75333 18723 10261 ROS1 ROS ROS 17 0.6 we had already detected a small but significant increase in ROS production supporting the fact that denervation and muscle ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59676 17584954 75333 18723 10261 ROS1 ROS ROS 26 0.6 in ROS production supporting the fact that denervation and muscle ROS generation are closely related and suggesting denervation precedes the increase 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59677 17584954 75333 18723 10261 ROS1 ROS ROS 38 0.6 are closely related and suggesting denervation precedes the increase in ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59678 17584954 75335 18723 10261 ROS1 ROS ROS 0 0.6 ROS generation was significantly increased 2 days after nerve transaction but 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59679 17584954 75336 18723 10261 ROS1 ROS ROS 15 0.6 the loss of innervation precedes the increase in muscle mitochondrial ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59680 17584954 75337 18723 10261 ROS1 ROS ROS 10 0.6 Furthermore the sciatic nerve transection demonstrated that an elevation in ROS generation precedes a significant loss in muscle mass (by by 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59681 17584954 75338 18723 10261 ROS1 ROS ROS 1 0.6 Although ROS production was increased as early as 5 days after sciatic 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59682 17584954 75339 18723 10261 ROS1 ROS ROS 6 0.6 The fact that dramatic changes in ROS were present before the loss of muscle mass supports the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59683 17584954 75339 18723 10261 ROS1 ROS ROS 19 0.6 before the loss of muscle mass supports the hypothesis that ROS may in fact contribute to muscle mass loss 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59684 17584954 75340 20996 11179 SOD1 ALS ALS 18 3.0 of muscle mass loss were quite different in these two ALS animal models and that these changes correlated with muscle mitochondrial 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59685 17584954 75340 18723 10261 ROS1 ROS ROS 29 0.6 animal models and that these changes correlated with muscle mitochondrial ROS generation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59686 17584954 75342 20996 11179 SOD1 ALS ALS 6 3.0 In effect the H46RH48Q mice developed ALS despite remarkably little muscle mass loss 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59687 17584954 75343 20996 11179 SOD1 ALS ALS 1 3.0 Incidentally ALS patients with the H46R mutation have a very long survival 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59688 17584954 75344 20996 11179 SOD1 ALS ALS 23 3.0 insight into the role of denervation in the etiology of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59689 17584954 75345 20996 11179 SOD1 ALS ALS 0 3.0 ALS has been proposed to be more than a strict neuropathy 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59690 17584954 75346 20996 11179 SOD1 ALS ALS 7 3.0 A converging line of argument suggests that ALS is a distal axonopathy ( 24 that is the disease 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59691 17584954 75349 20996 11179 SOD1 ALS ALS 6 3.0 The fact that H46RH48Q mice develop ALS with only mild muscle mass loss (and and that occurs 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59692 17584954 75350 18723 10261 ROS1 ROS ROS 40 0.6 which is reflected in the extent of the elevation of ROS production 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59693 17584954 75351 18723 10261 ROS1 ROS ROS 20 0.6 whereas muscle atrophy was associated with significant increases in mitochondrial ROS production in state 1 and with the substrates glutamate and 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59694 17584954 75351 18723 10261 ROS1 ROS ROS 41 0.6 malate the exact opposite occurred with the substrate succinate succinate-supported ROS release was significantly decreased in conditions in which the loss 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59695 17584954 75352 18723 10261 ROS1 ROS ROS 11 0.6 example although there was no statistically significant difference in succinate-supported ROS release with age succinate-supported H 2 O 2 release was 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59696 17584954 75352 20996 11179 SOD1 SOD1 Sod1 27 2.7 2 O 2 release was in fact lower in old Sod1 and late-stage G93A ALS skeletal muscle mitochondria conditions that are 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59697 17584954 75352 20996 11179 SOD1 ALS ALS 31 3.0 was in fact lower in old Sod1 and late-stage G93A ALS skeletal muscle mitochondria conditions that are associated with losses in 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59698 17584954 75353 18723 10261 ROS1 ROS ROS 6 0.6 The mechanism(s) mechanism s driving this decrease in ROS production and the potential physiological relevance of this phenomenon are 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59699 17584954 75356 18723 10261 ROS1 ROS ROS 7 0.6 We therefore conclude that the increases in ROS observed in state 1 that occurred in the presence of 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59700 17584954 75357 18723 10261 ROS1 ROS ROS 28 0.6 innervation are associated with dramatic increases in mitochondrial production of ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59701 17584954 75358 18723 10261 ROS1 ROS ROS 29 0.6 the downstream targets and effects of the increase in mitochondrial ROS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59702 17584954 75361 18723 10261 ROS1 ROS ROS 1 0.6 Increased ROS generation in skeletal muscle mitochondria from young and old mice 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59703 17584954 75362 18723 10261 ROS1 ROS ROS 7 0.6 Skeletal muscle mitochondria were isolated and mitochondrial ROS generation was measured as described in EXPERIMENTAL PROCEDURES 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59704 17584954 75365 18723 10261 ROS1 ROS ROS 13 0.6 are mean (_amp_#177;SE) _amp_#177 SE expressed as rates of mitochondrial ROS release measured in male mice killed at 10 mo (open 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59705 17584954 75367 18723 10261 ROS1 ROS ROS 0 0.6 ROS production in D was measured in the presence of 5 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59706 17584954 75369 18723 10261 ROS1 ROS ROS 1 0.6 Increased ROS generation in skeletal muscle mitochondria from Sod1 mice 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59707 17584954 75369 20996 11179 SOD1 SOD1 Sod1 8 2.7 Increased ROS generation in skeletal muscle mitochondria from Sod1 mice 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59708 17584954 75370 20996 11179 SOD1 SOD1 Sod1 12 2.7 of gastrocnemius muscle isolated from female wild-type (WT) WT and Sod1 mice at 5 and 20 mo of age 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59709 17584954 75371 20996 11179 SOD1 SOD1 Sod1 23 2.7 substrate in isolated muscle mitochondria from 8 WT and 8 Sod1 mice at 20 mo of age * P _lt_ 0.05 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59710 17584954 75372 20996 11179 SOD1 SOD1 Sod1 13 2.7 open bars represent 5-mo-old WT light shaded bars represent 5-mo-old Sod1 dark shaded bars represent 20-mo-old WT and solid bars represent 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59711 17584954 75372 20996 11179 SOD1 SOD1 Sod1 26 2.7 shaded bars represent 20-mo-old WT and solid bars represent 20-mo-old Sod1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59712 17584954 75373 18723 10261 ROS1 ROS ROS 4 0.6 C and D ROS generation from skeletal muscle mitochondria isolated from the hindlimb of 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59713 17584954 75374 18723 10261 ROS1 ROS ROS 13 0.6 _amp_#177 SE for state 1 and glutamate (Glut)/malate-supported Glut malate-supported ROS generation in mitochondria from 5-mo-old WT ( n = 21 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59714 17584954 75374 20996 11179 SOD1 SOD1 Sod1 25 2.7 in mitochondria from 5-mo-old WT ( n = 21 and Sod1 mice ( n = 10 and 20-mo-old WT ( n 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59715 17584954 75374 20996 11179 SOD1 SOD1 Sod1 40 2.7 10 and 20-mo-old WT ( n = 16 and old Sod1 mice ( n = 16 values in D are means 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59716 17584954 75374 18723 10261 ROS1 ROS ROS 54 0.6 = 16 values in D are means _amp_#177 SE for ROS generation in the presence of succinate alone antimycin A succinate 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59717 17584954 75374 20996 11179 SOD1 SOD1 Sod1 82 2.7 in H 2 O 2 release in muscle mitochondria from Sod1 mice compared with mitochondria from age-matched WT mice (ANOVA ANOVA 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59718 17584954 75376 20996 11179 SOD1 ALS ALS 7 3.0 Muscle mass loss during amyotrophic lateral sclerosis (ALS) ALS in the G93A and H46RH48Q mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59719 17584954 75380 18723 10261 ROS1 ROS ROS 1 0.6 Increased ROS generation in skeletal muscle mitochondria isolated from ALS transgenic mice 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59720 17584954 75380 20996 11179 SOD1 ALS ALS 9 3.0 Increased ROS generation in skeletal muscle mitochondria isolated from ALS transgenic mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59721 17584954 75381 18723 10261 ROS1 ROS ROS 0 0.6 ROS production was measured in skeletal muscle mitochondria of female ALS 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59722 17584954 75381 20996 11179 SOD1 ALS ALS 10 3.0 ROS production was measured in skeletal muscle mitochondria of female ALS transgenic mouse models G93A ( A and B and H46R/H48Q 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59723 17584954 75385 18723 10261 ROS1 ROS ROS 0 0.6 ROS production was measured in mitochondria isolated from hindlimb muscle of 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59724 17584954 75389 18723 10261 ROS1 ROS ROS 0 0.6 ROS production is dramatically increased following surgical denervation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59725 17584954 75392 18723 10261 ROS1 ROS ROS 7 0.6 Mice were killed tissues were harvested and ROS production was measured in isolated muscle mitochondria at 2 ( 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59726 17584954 75393 18723 10261 ROS1 ROS ROS 8 0.6 A time course of the rate of ROS production in state 1 following denervation (filled filled squares denervated 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59727 17584954 75395 18723 10261 ROS1 ROS ROS 2 0.6 C ROS generation in mitochondria from the control (open open bars and 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59728 17584954 75396 18723 10261 ROS1 ROS ROS 19 0.6 = 5 mice * P _lt_ 0.05 significant difference in ROS generation in muscle mitochondria following denervation compared with mitochondria from 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59729 17584954 75399 18723 10261 ROS1 ROS ROS 5 0.6 Correlation between muscle atrophy and ROS production 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59730 17584954 75400 18723 10261 ROS1 ROS ROS 0 0.6 ROS production data in state 1 are plotted vs gastrocnemius muscle 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59731 17584954 75401 18723 10261 ROS1 ROS ROS 3 0.6 Muscle mass and ROS production are expressed as the increase relative to young wild-type 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59732 17584954 75405 18723 10261 ROS1 ROS ROS 0 0.6 ROS production and mitochondrial respiration were measured in muscle mitochondria isolated 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59733 17584954 75408 18723 10261 ROS1 ROS ROS 3 0.6 Measurement of mitochondrial ROS production in isolated mitochondria is most traditionally done in the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59734 17584954 75408 18723 10261 ROS1 ROS ROS 23 0.6 the presence of added substrates largely because the levels of ROS with endogenous (state state 1 substrates are too low to 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59735 17584954 75409 18723 10261 ROS1 ROS ROS 17 0.6 the fluorogenic probe Amplex red is sensitive enough to detect ROS produced in mitochondria even during state 1 in the absence 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59736 17584954 75410 18723 10261 ROS1 ROS ROS 12 0.6 we previously found that the age-related increase in state 1 ROS generation is greater than in mitochondria exposed to glutamate/malate glutamate 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59737 17584954 75411 18723 10261 ROS1 ROS ROS 9 0.6 As shown in Fig 1 C state 1 ROS production was increased nearly twofold in mitochondria isolated from hindlimb 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59738 17584954 75412 18723 10261 ROS1 ROS ROS 7 0.6 In 32-mo-old animals the increase in ROS generation was even greater reaching levels approximately threefold higher than 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59739 17584954 75414 18723 10261 ROS1 ROS ROS 8 0.6 In mitochondria isolated from muscle of 10-mo-old mice ROS generation was about five times higher with glutamate/malate glutamate malate 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59740 17584954 75415 18723 10261 ROS1 ROS ROS 0 0.6 ROS generation in mitochondria respiring on glutamate/malate glutamate malate occurs primarily 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59741 17584954 75416 18723 10261 ROS1 ROS ROS 0 0.6 ROS production using glutamate/malate glutamate malate was increased with age and 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59742 17584954 75417 18723 10261 ROS1 ROS ROS 3 0.6 The difference in ROS production with 5 mM glutamate/malate glutamate malate as a substrate 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59743 17584954 75418 18723 10261 ROS1 ROS ROS 1 0.6 When ROS generation with glutamate/malate glutamate malate was stimulated by the addition 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59744 17584954 75418 18723 10261 ROS1 ROS ROS 19 0.6 addition of the complex I inhibitor rotenone the rate of ROS generation was increased ~10-fold but any effect of age disappeared 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59745 17584954 75419 18723 10261 ROS1 ROS ROS 0 0.6 ROS release with the substrate succinate exhibited quite different trends from 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59746 17584954 75422 18723 10261 ROS1 ROS ROS 28 0.6 interest in succinate-driven reverse electron transfer because this source of ROS is so much greater than any others at least under 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59747 17584954 75423 18723 10261 ROS1 ROS ROS 5 0.6 We compared the rates of ROS generation in young and old skeletal muscle mitochondria with succinate 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59748 17584954 75424 18723 10261 ROS1 ROS ROS 17 0.6 III inhibitor resulted in a seven- to eightfold increase in ROS generation that similar to the production of ROS in response 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59749 17584954 75424 18723 10261 ROS1 ROS ROS 25 0.6 increase in ROS generation that similar to the production of ROS in response to the complex I inhibitor rotenone was not 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59750 17584954 75425 18723 10261 ROS1 ROS ROS 3 0.6 Skeletal muscle mitochondrial ROS production is increased in Sod1 null mice and is associated 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59751 17584954 75425 20996 11179 SOD1 SOD1 Sod1 8 2.7 Skeletal muscle mitochondrial ROS production is increased in Sod1 null mice and is associated with the degree of muscle 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59752 17584954 75426 20996 11179 SOD1 SOD1 Sod1 7 2.7 In agreement with our previous report on Sod1 mice ( 57 the gastrocnemius mass was significantly decreased in 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59753 17584954 75426 20996 11179 SOD1 SOD1 Sod1 27 2.7 both young (5 5 mo and older (20 20 mo Sod1 mice compared with the age-matched wild-type mice ( Fig 2 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59754 17584954 75430 20996 11179 SOD1 SOD1 Sod1 19 2.7 was decreased ~36% in mitochondria isolated from muscle of 20-mo-old Sod1 mice compared with mitochondria from muscle of age-matched wild-type mice 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59755 17584954 75431 18723 10261 ROS1 ROS ROS 2 0.6 State 1 ROS production was increased over 30% in mitochondria from Sod1 mice 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59756 17584954 75431 20996 11179 SOD1 SOD1 Sod1 11 2.7 1 ROS production was increased over 30% in mitochondria from Sod1 mice at as early as 5 mo of age compared 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59757 17584954 75432 18723 10261 ROS1 ROS ROS 5 0.6 By 20 mo of age ROS production in mitochondria from Sod1 mice was threefold higher than 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59758 17584954 75432 20996 11179 SOD1 SOD1 Sod1 10 2.7 By 20 mo of age ROS production in mitochondria from Sod1 mice was threefold higher than in the age-matched wild-type mice 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59759 17584954 75433 18723 10261 ROS1 ROS ROS 9 0.6 In mitochondria incubated with glutamate malate as respiratory substrates ROS release was increased ~35% (30.89 30.89 _amp_#177 4.77 pmol H 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59760 17584954 75433 20996 11179 SOD1 SOD1 Sod1 29 2.7 2 _amp_#183 min _amp_#183 mg protein in mitochondria from 5-mo-old Sod1 compared with 19.77 _amp_#177 1.78 pmol H 2 O 2 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59761 17584954 75434 20996 11179 SOD1 SOD1 Sod1 2 2.7 In 20-mo-old Sod1 mice the increase in ROS generation with the substrates glutamate 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59762 17584954 75434 18723 10261 ROS1 ROS ROS 7 0.6 In 20-mo-old Sod1 mice the increase in ROS generation with the substrates glutamate and malate was >100% ( 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59763 17584954 75435 18723 10261 ROS1 ROS ROS 6 0.6 There was no significant difference in ROS production in state 1 or in response to glutamate/malate glutamate 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59764 17584954 75436 18723 10261 ROS1 ROS ROS 5 0.6 This is consistent with increased ROS being specifically associated with age-associated muscle loss since wild-type mice 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59765 17584954 75437 20996 11179 SOD1 SOD1 Sod1 22 2.7 the substrate succinate was significantly lower in mitochondria from the Sod1 mice compared with wild-type controls especially in mitochondria from the 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59766 17584954 75437 20996 11179 SOD1 SOD1 Sod1 34 2.7 compared with wild-type controls especially in mitochondria from the 20-mo-old Sod1 mice ( Fig 2 D 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59767 17584954 75439 18723 10261 ROS1 ROS ROS 0 0.6 ROS production is increased in muscle mitochondria in mouse models of 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59768 17584954 75439 20996 11179 SOD1 ALS ALS 11 3.0 production is increased in muscle mitochondria in mouse models of ALS and is correlated with the extent of muscle atrophy 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59769 17584954 75440 18723 10261 ROS1 ROS ROS 5 0.6 We next measured state 1 ROS production in mitochondria in another mouse model associated with significant 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59770 17584954 75441 20996 11179 SOD1 ALS ALS 4 3.0 We studied two different ALS mutant models the well-characterized G93A mutant ( 31 and mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59771 17584954 75445 20996 11179 SOD1 SOD1 Sod1 43 2.7 the G93A mutants and in the 20-mo-old (late late stage Sod1 mice 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59772 17584954 75447 18723 10261 ROS1 ROS ROS 11 0.6 pattern of muscle atrophy correlated closely with increases in mitochondrial ROS production 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59773 17584954 75448 18723 10261 ROS1 ROS ROS 2 0.6 State 1 ROS release during the disease course in G93A mice was increased 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59774 17584954 75448 20996 11179 SOD1 SOD1 Sod1 28 2.7 the mitochondria from wild-type mice much higher than in the Sod1 mice or in old wild-type mice which had relatively less 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59775 17584954 75449 18723 10261 ROS1 ROS ROS 13 0.6 mutant mice there was an up to fourfold increase in ROS release at late stage but virtually no change at early 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59776 17584954 75450 18723 10261 ROS1 ROS ROS 10 0.6 stage G93A mice with glutamate/malate glutamate malate as respiratory substrate ROS release was increased over sixfold ( Fig 4 A and 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59777 17584954 75450 18723 10261 ROS1 ROS ROS 31 0.6 A and E but in contrast in the H46RH48Q mice ROS release was only ~75% higher compared with the age-matched wild-type 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59778 17584954 75451 20996 11179 SOD1 SOD1 Sod1 8 2.7 As we had observed in mitochondria from the Sod1 mice ROS production with succinate as a substrate was lower 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59779 17584954 75451 18723 10261 ROS1 ROS ROS 10 0.6 As we had observed in mitochondria from the Sod1 mice ROS production with succinate as a substrate was lower in G93A 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59780 17584954 75451 20996 11179 SOD1 SOD1 Sod1 42 2.7 an even greater decrease than had been observed in the Sod1 mice approaching levels close to that measured in state 1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59781 17584954 75452 18723 10261 ROS1 ROS ROS 13 0.6 in Fig 4 C in addition to the increase in ROS the RCR was decreased 46% in mitochondria isolated from muscle 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59782 17584954 75453 18723 10261 ROS1 ROS ROS 0 0.6 ROS production is increased in muscle mitochondria following surgical denervation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59783 17584954 75454 18723 10261 ROS1 ROS ROS 13 0.6 denervation might be a factor in the increase in mitochondrial ROS in the three models of muscle atrophy studied here we 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59784 17584954 75454 18723 10261 ROS1 ROS ROS 28 0.6 of muscle atrophy studied here we measured mitochondrial state 1 ROS generation in the gastrocnemius and tibialis anterior muscles following denervation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59785 17584954 75455 18723 10261 ROS1 ROS ROS 0 0.6 ROS release was increased dramatically 5 days after sciatic nerve transection 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59786 17584954 75456 18723 10261 ROS1 ROS ROS 21 0.6 the loss of muscle mass was minimal yet state 1 ROS production was nearly 30-fold higher in mitochondria isolated from the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59787 17584954 75457 18723 10261 ROS1 ROS ROS 0 0.6 ROS release with glutamate/malate glutamate malate was 11-fold higher in the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59788 17584954 75458 18723 10261 ROS1 ROS ROS 9 0.6 There was no significant difference in the rates of ROS production in response to denervation with the use of succinate 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59789 17584954 75460 18723 10261 ROS1 ROS ROS 8 0.6 The relationship between muscle atrophy and induction of ROS generation by skeletal muscle mitochondria isolated from young and old 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 59790 17584954 75460 20996 11179 SOD1 SOD1 Sod1 22 2.7 muscle mitochondria isolated from young and old wild-type mice 20-mo-old Sod1 mice and the two ALS mouse models is illustrated in 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 59791 17584954 75460 20996 11179 SOD1 ALS ALS 27 3.0 and old wild-type mice 20-mo-old Sod1 mice and the two ALS mouse models is illustrated in Fig 6 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00158202037855057<>ScoreDetail__5468|IGFALS|0.000571371434285143__11179|SOD1|0.00158202037855057__ 0 0 0 0 0 59792 17584954 75461 18723 10261 ROS1 ROS ROS 18 0.6 greater loss of muscle mass show relatively higher levels of ROS production 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 49054 17634371 61544 14373 7808 NGF NGF NGF 3 1.2 Nerve growth factor (NGF) NGF can induce apoptosis by signaling through the p75 neurotrophin receptor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49055 17634371 61544 22562 11917 TNFRSF1B p75 p75 11 2.1 factor (NGF) NGF can induce apoptosis by signaling through the p75 neurotrophin receptor (p75 p75 in several nerve cell populations 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49056 17634371 61544 22562 11917 TNFRSF1B p75 p75 14 2.1 induce apoptosis by signaling through the p75 neurotrophin receptor (p75 p75 in several nerve cell populations 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49057 17634371 61545 22562 11917 TNFRSF1B p75 p75 5 2.1 Cultured embryonic motor neurons expressing p75 are not vulnerable to NGF unless they are exposed to 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49058 17634371 61545 14373 7808 NGF NGF NGF 10 1.2 Cultured embryonic motor neurons expressing p75 are not vulnerable to NGF unless they are exposed to an exogenous flux of nitric 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49059 17634371 61546 22562 11917 TNFRSF1B p75 p75 7 2.1 In the present study we show that p75 -mediated apoptosis in motor neurons involved neutral sphingomyelinase activation increased 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49060 17634371 61547 14373 7808 NGF NGF NGF-induced 16 1.2 prevented neuronal loss further evidencing the role of mitochondria in NGF-induced apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49061 17634371 61548 20996 11179 SOD1 ALS ALS 8 1.7 In motor neurons overexpressing the amyotrophic lateral sclerosis (ALS)-linked ALS -linked superoxide dismutase 1 (SOD1 SOD1 mutation NGF induced apoptosis 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00263912306447868<>ScoreDetail__5468|IGFALS|0.000345527577419773__11179|SOD1|0.00263912306447868__ 0 0 0 0 0 49062 17634371 61548 20996 11179 SOD1 SOD1 SOD1 12 1.7 amyotrophic lateral sclerosis (ALS)-linked ALS -linked superoxide dismutase 1 (SOD1 SOD1 mutation NGF induced apoptosis even in the absence of an 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49063 17634371 61548 14373 7808 NGF NGF NGF 15 1.2 sclerosis (ALS)-linked ALS -linked superoxide dismutase 1 (SOD1 SOD1 mutation NGF induced apoptosis even in the absence of an external source 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49064 17634371 61549 20996 11179 SOD1 SOD1 SOD1 4 1.7 The increased susceptibility of SOD1 motor neurons to NGF was associated to decreased nuclear factor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49065 17634371 61549 14373 7808 NGF NGF NGF 8 1.2 The increased susceptibility of SOD1 motor neurons to NGF was associated to decreased nuclear factor erythroid 2-related factor 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49066 17634371 61549 14345 7782 NFE2L2 NRF2 Nrf2 19 3.1 associated to decreased nuclear factor erythroid 2-related factor 2 (Nrf2) Nrf2 expression and downregulation of the enzymes involved in glutathione biosynthesis 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49067 17634371 61550 20996 11179 SOD1 SOD1 SOD1 13 1.7 of glutathione in nontransgenic motor neurons reproduced the effect of SOD1 expression increasing their sensitivity to NGF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49068 17634371 61550 14373 7808 NGF NGF NGF 19 1.2 reproduced the effect of SOD1 expression increasing their sensitivity to NGF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49069 17634371 61551 14345 7782 NFE2L2 NRF2 Nrf2 6 3.1 In contrast rising antioxidant defenses by Nrf2 activation prevented NGF-induced apoptosis 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49070 17634371 61551 14373 7808 NGF NGF NGF-induced 9 1.2 In contrast rising antioxidant defenses by Nrf2 activation prevented NGF-induced apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49071 17634371 61552 22562 11917 TNFRSF1B p75 p75 5 2.1 Together our data indicate that p75 -mediated motor neuron apoptosis involves ceramide-dependent increased mitochondrial superoxide production 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49072 17634371 61553 20996 11179 SOD1 ALS ALS-linked 9 1.7 This apoptotic pathway is facilitated by the expression of ALS-linked SOD1 mutations and critically modulated by Nrf2 activity 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00263912306447868<>ScoreDetail__5468|IGFALS|0.000345527577419773__11179|SOD1|0.00263912306447868__ 0 0 0 0 0 49073 17634371 61553 20996 11179 SOD1 SOD1 SOD1 10 1.7 This apoptotic pathway is facilitated by the expression of ALS-linked SOD1 mutations and critically modulated by Nrf2 activity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49074 17634371 61553 14345 7782 NFE2L2 NRF2 Nrf2 16 3.1 the expression of ALS-linked SOD1 mutations and critically modulated by Nrf2 activity 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49075 17634371 61554 14345 7782 NFE2L2 NRF2 Nrf2 11 3.1 words amyotrophic lateral sclerosis mitochondria motor neurons nerve growth factor Nrf2 p75 superoxide 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49076 17634371 61554 22562 11917 TNFRSF1B p75 p75 12 2.1 amyotrophic lateral sclerosis mitochondria motor neurons nerve growth factor Nrf2 p75 superoxide 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49077 17634371 61555 14373 7808 NGF NGF NGF 3 1.2 Nerve growth factor (NGF) NGF has a key role on the development and function of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49078 17634371 61556 14373 7808 NGF NGF NGF 8 1.2 In addition to promoting neuronal differentiation and survival NGF can induce apoptosis of neurons during development and may also 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49079 17634371 61557 14373 7808 NGF NGF NGF 0 1.2 NGF exerts its actions through two nonhomologous transmembrane receptors the tyrosine 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49080 17634371 61557 14738 8031 NTRK1 TRKA TrkA 13 1.9 actions through two nonhomologous transmembrane receptors the tyrosine kinase receptor TrkA and the p75 neurotrophin receptor (p75 p75 p75 is a 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49081 17634371 61557 22562 11917 TNFRSF1B p75 p75 16 2.1 nonhomologous transmembrane receptors the tyrosine kinase receptor TrkA and the p75 neurotrophin receptor (p75 p75 p75 is a member of the 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49082 17634371 61557 22562 11917 TNFRSF1B p75 p75 19 2.1 tyrosine kinase receptor TrkA and the p75 neurotrophin receptor (p75 p75 p75 is a member of the tumor necrosis factor receptor 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49083 17634371 61557 22562 11917 TNFRSF1B p75 p75 21 2.1 kinase receptor TrkA and the p75 neurotrophin receptor (p75 p75 p75 is a member of the tumor necrosis factor receptor superfamily 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49084 17634371 61558 14373 7808 NGF NGF NGF 10 1.2 Adult motor neurons had been thought to be unresponsive to NGF because they lack both TrkA and p75 receptors (Henderson Henderson 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49085 17634371 61558 14738 8031 NTRK1 TRKA TrkA 15 1.9 thought to be unresponsive to NGF because they lack both TrkA and p75 receptors (Henderson Henderson et al. 1993 Yan et 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49086 17634371 61558 22562 11917 TNFRSF1B p75 p75 17 2.1 be unresponsive to NGF because they lack both TrkA and p75 receptors (Henderson Henderson et al. 1993 Yan et al. 1993 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49087 17634371 61559 22562 11917 TNFRSF1B p75 p75 6 2.1 However adult motor neurons can reexpress p75 after nerve injury (Koliatsos Koliatsos et al. 1991 Rende et 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49088 17634371 61559 20996 11179 SOD1 ALS ALS 30 1.7 Ferri et al. 1998 and in amyotrophic lateral sclerosis (ALS) ALS (Seeburger Seeburger et al. 1993 Lowry et al. 2001b 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00263912306447868<>ScoreDetail__5468|IGFALS|0.000345527577419773__11179|SOD1|0.00263912306447868__ 0 0 0 0 0 49089 17634371 61560 22562 11917 TNFRSF1B p75 p75 2 2.1 Induction of p75 renders motor neurons vulnerable to NGF-induced apoptosis p75 has been 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49090 17634371 61560 14373 7808 NGF NGF NGF-induced 8 1.2 Induction of p75 renders motor neurons vulnerable to NGF-induced apoptosis p75 has been implicated in motor neuron death occurring 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49091 17634371 61560 22562 11917 TNFRSF1B p75 p75 10 2.1 Induction of p75 renders motor neurons vulnerable to NGF-induced apoptosis p75 has been implicated in motor neuron death occurring in transgenic 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49092 17634371 61560 20996 11179 SOD1 SOD1 SOD1 27 1.7 occurring in transgenic mice overexpressing mutant Cu-Zn superoxide dismutase (SOD1) SOD1 (Lowry Lowry et al. 2001b Copray et al. 2003 Kust 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49093 17634371 61561 22562 11917 TNFRSF1B p75 p75 5 2.1 Pure motor neuron cultures expressing p75 are sensitive to NGF-induced apoptosis only when physiological concentrations of 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49094 17634371 61561 14373 7808 NGF NGF NGF-induced 9 1.2 Pure motor neuron cultures expressing p75 are sensitive to NGF-induced apoptosis only when physiological concentrations of exogenous nitric oxide ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49095 17634371 61562 22562 11917 TNFRSF1B p75 p75 10 2.1 These motor neurons also become immunoreactive for nitrotyrosine suggesting that p75 activation may be inducing a source of superoxide that converts 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49096 17634371 61563 22562 11917 TNFRSF1B p75 p75 6 2.1 Astrocytes can protect motor neurons against p75 -induced apoptosis by the activation of the transcription factor nuclear 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49097 17634371 61563 14345 7782 NFE2L2 NRF2 Nrf2 22 3.1 the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), Nrf2 which increases antioxidant defenses (Vargas Vargas et al. 2006 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49098 17634371 61564 22562 11917 TNFRSF1B p75 p75 6 2.1 Thus the signaling pathway induced by p75 and its final outcome differs depending on the cell type 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49099 17634371 61565 10824 6204 JUN c-Jun c-Jun 13 1.3 is not completely elucidated but is associated with activation of c-Jun N-terminal kinase (JNK), JNK release of cytochrome c from mitochondria 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49100 17634371 61565 12349 6881 MAPK8 JNK JNK 16 0.6 but is associated with activation of c-Jun N-terminal kinase (JNK), JNK release of cytochrome c from mitochondria and subsequent activation of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49101 17634371 61566 22562 11917 TNFRSF1B p75 p75 8 2.1 Ceramide production may also be a mediator of p75 -induced apoptosis (Dobrowsky Dobrowsky et al. 1994 Casaccia-Bonnefil et al. 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49102 17634371 61568 18723 10261 ROS1 ROS ROS 30 0.0 promote cytochrome c release and induce reactive oxygen species (ROS) ROS production (Garcia-Ruiz Garcia-Ruiz et al. 1997 Gudz et al. 1997 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49103 17634371 61568 12393 6899 MAS1 MAS Mas 48 0.0 1997 Gudz et al. 1997 Quillet-Mary et al. 1997 Mansat-de Mas et al. 1999 Birbes et al. 2002 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49104 17634371 61569 22562 11917 TNFRSF1B p75 p75 5 2.1 We have previously shown that p75 -induced motor neuron death involves increased production of ROS and 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49105 17634371 61569 6981 22140 FAM20C RNS RNS 19 0.6 involves increased production of ROS and reactive nitrogen species (RNS) RNS (Pehar Pehar et al. 2004 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 49106 17634371 61569 18723 10261 ROS1 ROS ROS 14 0.0 that p75 -induced motor neuron death involves increased production of ROS and reactive nitrogen species (RNS) RNS (Pehar Pehar et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49107 17634371 61570 22562 11917 TNFRSF1B p75 p75 10 2.1 However the source of the increased ROS production induced by p75 activation in motor neurons is currently unknown 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49108 17634371 61570 18723 10261 ROS1 ROS ROS 6 0.0 However the source of the increased ROS production induced by p75 activation in motor neurons is currently 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49109 17634371 61571 22562 11917 TNFRSF1B p75 p75 11 2.1 the present study we investigated the apoptotic pathway mediated by p75 in motor neurons and the impact of ALS-linked SOD1 expression 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49110 17634371 61571 20996 11179 SOD1 ALS ALS-linked 19 1.7 mediated by p75 in motor neurons and the impact of ALS-linked SOD1 expression 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00263912306447868<>ScoreDetail__5468|IGFALS|0.000345527577419773__11179|SOD1|0.00263912306447868__ 0 0 0 0 0 49111 17634371 61571 20996 11179 SOD1 SOD1 SOD1 20 1.7 by p75 in motor neurons and the impact of ALS-linked SOD1 expression 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49112 17634371 61572 20486 11121 SMPD2 nSMase nSMase 8 1.9 We show that this pathway involved neutral sphingomyelinase (nSMase) nSMase activation and increased mitochondrial superoxide production 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49113 17634371 61573 20996 11179 SOD1 ALS ALS-linked 3 1.7 Motor neurons overexpressing ALS-linked SOD1 mutation showed greater susceptibility to the p75 -activated apoptotic 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00263912306447868<>ScoreDetail__5468|IGFALS|0.000345527577419773__11179|SOD1|0.00263912306447868__ 0 0 0 0 0 49114 17634371 61573 20996 11179 SOD1 SOD1 SOD1 4 1.7 Motor neurons overexpressing ALS-linked SOD1 mutation showed greater susceptibility to the p75 -activated apoptotic pathway 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49115 17634371 61573 22562 11917 TNFRSF1B p75 p75 11 2.1 neurons overexpressing ALS-linked SOD1 mutation showed greater susceptibility to the p75 -activated apoptotic pathway which was associated to decreased Nrf2 expression 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49116 17634371 61573 14345 7782 NFE2L2 NRF2 Nrf2 20 3.1 the p75 -activated apoptotic pathway which was associated to decreased Nrf2 expression and the consequent reduction in antioxidant defenses 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49117 17634371 61576 14373 7808 NGF NGF NGF 1 1.2 Mouse NGF (2.5S) 2.5S was obtained from Harlan (Madison, Madison WI recombinant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49118 17634371 61576 7333 11920 FAS FAS Fas 12 0.3 was obtained from Harlan (Madison, Madison WI recombinant human soluble Fas ligand and tert -butylhydroquinone (tBHQ) tBHQ from Alexis (San San 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000840215821746618<>ScoreDetail__11920|FAS|0.000840215821746618__3594|FASN|0.000403033744916279__ 0 0 0 0 0 49119 17634371 61576 22000 11730 TERT TERT tert 15 0.3 Harlan (Madison, Madison WI recombinant human soluble Fas ligand and tert -butylhydroquinone (tBHQ) tBHQ from Alexis (San San Diego CA and 14 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 49120 17634371 61577 14373 7808 NGF NGF NGF 3 1.2 Blocking antibodies to NGF and p75 were from Chemicon (Temecula, Temecula CA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49121 17634371 61577 22562 11917 TNFRSF1B p75 p75 5 2.1 Blocking antibodies to NGF and p75 were from Chemicon (Temecula, Temecula CA 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49122 17634371 61582 22562 11917 TNFRSF1B p75 p75 28 2.1 gradient centrifugation and immunopanning with the monoclonal antibody IgG192 against p75 as described previously (Henderson Henderson et al. 1995 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49123 17634371 61583 20996 11179 SOD1 SOD1 SOD1 1 1.7 Transgenic SOD1 and nontransgenic motor neurons were prepared in the same way 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49124 17634371 61584 20996 11179 SOD1 SOD1 SOD1 2 1.7 Sprague Dawley SOD1 L26H rats were kindly provided by Dr David S Howland 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49125 17634371 61586 13439 1304 MRAP B27 B-27 27 0.0 micro M 2-mercaptoethanol 0.5 m M L -glutamine and 2% B-27 supplement (Invitrogen) Invitrogen 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49126 17634371 61587 8240 4232 GDNF GDNF GDNF 14 1.2 by the addition of glial cell line-derived neurotrophic factor (GDNF) GDNF (1 1 ng/ml; ng ml Sigma to the culture media 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49127 17634371 61588 8240 4232 GDNF GDNF GDNF 10 1.2 neuron death induced by trophic factor deprivation (NONE; NONE without GDNF was determined in all experiments as a control and never 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49128 17634371 61590 20996 11179 SOD1 SOD1 SOD1 7 1.7 As a control the expression of human SOD1 was determined in the spinal cord of E15 embryos and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49129 17634371 61591 19573 10691 SDS SDS SDS-polyacrylamide 19 0.0 microg of spinal cord extract were resolved on a 12% SDS-polyacrylamide gel and transferred to nitrocellulose membrane 11 JUMiner_v2.2 1 0 0 2 19440 TotalCon:2<>10691|SDS|10993|Complete__19440|SBDS|51119|Complete__<>AvaiableGeneRif=2<>BEST:19440|SBDS|0.000280628304019052<>ScoreDetail__10691|SDS|0.000107700592353258__19440|SBDS|0.000280628304019052__ 0 0 0 0 0 49130 17634371 61592 20996 11179 SOD1 SOD1 SOD1 10 1.7 Anti-SOD1 antibodies were developed in rabbit using recombinant pure human SOD1 as immunogen (kindly kindly provided by Dr M Marin University 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49131 17634371 61595 14373 7808 NGF NGF NGF 2 1.2 Treatments with NGF and inhibitors were performed 3 h after motor neuron plating 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49132 17634371 61597 7333 11920 FAS FAS Fas 1 0.3 Soluble Fas ligand was added in the presence of enhancer antibody (1 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000840215821746618<>ScoreDetail__11920|FAS|0.000840215821746618__3594|FASN|0.000403033744916279__ 0 0 0 0 0 49133 17634371 61598 22562 11917 TNFRSF1B p75 p75 6 2.1 Treatment with antisense oligonucleotides to downregulate p75 expression in motor neurons was performed as described previously (Pehar 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49134 17634371 61601 22562 11917 TNFRSF1B p75 p75 10 2.1 To determine the efficiency of uptake cultures were incubated with p75 antisense oligonucleotides with a 5' 56-FAM fluorescent label 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49135 17634371 61605 22562 11917 TNFRSF1B p75 p75 5 2.1 Sequences used were as follows p75 antisense 5'-ACCTGCCCTCCTCATTGCA-3' and p75 missense 5'-CTCCCACTCGTCATTCGAC-3' (Florez-McClure Florez-McClure et al. 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49136 17634371 61605 22562 11917 TNFRSF1B p75 p75 9 2.1 Sequences used were as follows p75 antisense 5'-ACCTGCCCTCCTCATTGCA-3' and p75 missense 5'-CTCCCACTCGTCATTCGAC-3' (Florez-McClure Florez-McClure et al. 2004 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49137 17634371 61606 22562 11917 TNFRSF1B p75 p75 12 2.1 sequence has previously been shown to be effective at inhibiting p75 -induced apoptosis in motor neurons both in vivo and in 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49138 17634371 61609 14345 7782 NFE2L2 NRF2 Nrf2 9 3.1 PCR primers specific to each gene are as follows Nrf2 5'-TTCCTCTGCTGCCATTAGTCAGTC-3' and 5'-GCTCTTCCATTTCCGAGTCACTG-3' (242 242 bp glutamate-cysteine ligase modifier subunit 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49139 17634371 61609 8205 4312 GCLM GCLM GCLM 19 3.0 and 5'-GCTCTTCCATTTCCGAGTCACTG-3' (242 242 bp glutamate-cysteine ligase modifier subunit (GCLM), GCLM 5'-AATCTTGCCTCCTGCTGTGTGATG-3' and 5'-GGCTTCAATGTCAGGGATGCTTTC-3' (153 153 bp glutamate-cysteine ligase catalytic subunit 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49140 17634371 61609 8204 4311 GCLC GCLC GCLC 29 2.5 and 5'-GGCTTCAATGTCAGGGATGCTTTC-3' (153 153 bp glutamate-cysteine ligase catalytic subunit (GCLC), GCLC 5'-ATGAAAGTGGCACAGGAGCGAG-3' and 5'-AAACACGCCTTCCTTCCCATTG-3' (186 186 bp neuronal nitric oxide synthase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49141 17634371 61609 14533 7872 NOS1 nNOS nNOS 39 3.7 and 5'-AAACACGCCTTCCTTCCCATTG-3' (186 186 bp neuronal nitric oxide synthase (nNOS), nNOS 5'-CCACACCAACGGGAATCAGGAG-3' and 5'-TCCTCCAGCACCTCCACCATTG-3' (405 405 bp actin 5'-CATGAAGATCCTGACCGAGCGTG-3' and 5'-TCTGCTGGAAGGTGGACAGTGAGG-3' 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49142 17634371 61609 22562 11917 TNFRSF1B p75 p75 51 2.1 (405 405 bp actin 5'-CATGAAGATCCTGACCGAGCGTG-3' and 5'-TCTGCTGGAAGGTGGACAGTGAGG-3' (497 497 bp p75 primers were from Promega (Madison, Madison WI 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49143 17634371 61620 3628 25079 CCDC34 L15 L15 17 0.6 mito-HE for 15 min and after washing incubated in supplemented L15 (Pehar Pehar et al. 2004 without phenol red 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>25079|CCDC34|91057|No_GeneRif__5748|IGKV1D-16|28901|No_GeneRif__<>AvaiableGeneRif=0<> 0 0 0 0 0 49144 17634371 61623 14373 7808 NGF NGF NGF 10 1.2 mito-HE incubation cells were treated with 100 ng/ml ng ml NGF and then imaged every 15 min 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49145 17634371 61627 8240 4232 GDNF GDNF GDNF 9 1.2 To test monochlorobimane fluorescence emission motor neurons maintained with GDNF (1 1 ng/ml) ng ml were treated with buthionine-sulfoximine (BSO) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49146 17634371 61631 20996 11179 SOD1 SOD1 SOD1 2 1.7 Nontransgenic and SOD1 motor neuron cultures were maintained for 16 h in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49147 17634371 61631 8240 4232 GDNF GDNF GDNF 15 1.2 cultures were maintained for 16 h in the presence of GDNF (1 1 ng/ml) ng ml and then treated with NGF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49148 17634371 61631 14373 7808 NGF NGF NGF 22 1.2 GDNF (1 1 ng/ml) ng ml and then treated with NGF (100 100 ng/ml) ng ml in the presence or absence 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49149 17634371 61639 22562 11917 TNFRSF1B p75 p75 17 2.1 as a central component of the apoptotic pathway mediated by p75 in other cell types we examined its role in p75 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49150 17634371 61639 22562 11917 TNFRSF1B p75 p75 27 2.1 p75 in other cell types we examined its role in p75 -mediated motor neuron apoptosis 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49151 17634371 61640 14373 7808 NGF NGF NGF 10 1.2 Consistent with our previous results (Pehar Pehar et al. 2004 NGF reduced motor neuron survival by 40% only in the presence 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49152 17634371 61641 14373 7808 NGF NGF NGF-induced 3 1.2 The extent of NGF-induced reduction in motor neuron survival was similar to that induced 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49153 17634371 61642 14373 7808 NGF NGF NGF-induced 0 1.2 NGF-induced motor neuron death was blocked by manumycin A (10 10 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49154 17634371 61642 20486 11121 SMPD2 nSMase nSMase 22 1.9 M and GW4869 (100 100 n M specific inhibitors of nSMase (Arenz Arenz et al. 2001 Luberto et al. 2002 ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49155 17634371 61644 20486 11121 SMPD2 nSMase nSMase 9 1.9 These results indicate the involvement of ceramide production by nSMase activation in p75 -mediated motor neuron apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49156 17634371 61644 22562 11917 TNFRSF1B p75 p75 12 2.1 indicate the involvement of ceramide production by nSMase activation in p75 -mediated motor neuron apoptosis 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49157 17634371 61645 22562 11917 TNFRSF1B p75 p75 2 2.1 Reexpression of p75 under pathological conditions renders motor neurons vulnerable to NGF (Ferri 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49158 17634371 61645 14373 7808 NGF NGF NGF 11 1.2 of p75 under pathological conditions renders motor neurons vulnerable to NGF (Ferri Ferri et al. 1998 Wiese et al. 1999 Lowry 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49159 17634371 61646 14373 7808 NGF NGF NGF 8 1.2 In the present study we show that the NGF/p75 NGF p75 -mediated motor neuron apoptosis involved increased production of mitochondrial 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49160 17634371 61646 22562 11917 TNFRSF1B p75 p75 8 2.1 In the present study we show that the NGF/p75 NGF p75 -mediated motor neuron apoptosis involved increased production of mitochondrial superoxide 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49161 17634371 61647 20996 11179 SOD1 ALS ALS-linked 1 1.7 Moreover ALS-linked SOD1 overexpression increases motor neuron vulnerability to NGF-mediated apoptosis by 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00263912306447868<>ScoreDetail__5468|IGFALS|0.000345527577419773__11179|SOD1|0.00263912306447868__ 0 0 0 0 0 49162 17634371 61647 20996 11179 SOD1 SOD1 SOD1 2 1.7 Moreover ALS-linked SOD1 overexpression increases motor neuron vulnerability to NGF-mediated apoptosis by reducing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49163 17634371 61647 14373 7808 NGF NGF NGF-mediated 9 1.2 Moreover ALS-linked SOD1 overexpression increases motor neuron vulnerability to NGF-mediated apoptosis by reducing antioxidant defenses 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49164 17634371 61648 20996 11179 SOD1 SOD1 SOD1 11 1.7 effect could be explained not only by the expression of SOD1 with aberrant redox properties (Beckman Beckman et al. 2001 but 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49165 17634371 61648 14345 7782 NFE2L2 NRF2 Nrf2 25 3.1 properties (Beckman Beckman et al. 2001 but also by reduced Nrf2 expression which leads to a downregulation of the key enzymes 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49166 17634371 61649 14345 7782 NFE2L2 NRF2 Nrf2 5 3.1 In accordance pharmacological activation of Nrf2 prevented NGF/p75 NGF p75 -induced motor neuron apoptosis suggesting a 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49167 17634371 61649 14373 7808 NGF NGF NGF 7 1.2 In accordance pharmacological activation of Nrf2 prevented NGF/p75 NGF p75 -induced motor neuron apoptosis suggesting a potential target to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49168 17634371 61649 22562 11917 TNFRSF1B p75 p75 7 2.1 In accordance pharmacological activation of Nrf2 prevented NGF/p75 NGF p75 -induced motor neuron apoptosis suggesting a potential target to counteract 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49169 17634371 61649 22562 11917 TNFRSF1B p75 p75 18 2.1 -induced motor neuron apoptosis suggesting a potential target to counteract p75 -mediated motor neuron death occurring in pathological conditions 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49170 17634371 61650 22562 11917 TNFRSF1B p75 p75 0 2.1 p75 induces cell death by activating different signaling pathways depending on 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49171 17634371 61651 7333 11920 FAS FAS Fas 11 0.3 observed for other apoptotic stimuli including trophic factor deprivation and Fas (Est_amp_eacute;vez Est_amp_eacute vez et al 1998 Raoul et al. 2002 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000840215821746618<>ScoreDetail__11920|FAS|0.000840215821746618__3594|FASN|0.000403033744916279__ 0 0 0 0 0 49172 17634371 61651 22562 11917 TNFRSF1B p75 p75 24 2.1 et al 1998 Raoul et al. 2002 the mechanism of p75 -induced apoptosis in motor neurons involves downstream production of nitric 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49173 17634371 61652 22562 11917 TNFRSF1B p75 p75 8 2.1 In the present study we found that the p75 apoptotic pathway in motor neurons involved increased ceramide production and 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49174 17634371 61652 22562 11917 TNFRSF1B p75 p75 51 2.1 Hertel 1998 Brann et al. 2002 Bhakar et al. 2003 p75 -induced ceramide generation in motor neurons was mediated by activation 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49175 17634371 61653 22562 11917 TNFRSF1B p75 p75 2 2.1 A similar p75 -mediated apoptotic pathway was described previously in hippocampal neurons involving 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49176 17634371 61653 20486 11121 SMPD2 nSMase nSMase 13 1.9 -mediated apoptotic pathway was described previously in hippocampal neurons involving nSMase activation increased ceramide generation and subsequent JNK activation (Brann Brann 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49177 17634371 61653 12349 6881 MAPK8 JNK JNK 20 0.6 hippocampal neurons involving nSMase activation increased ceramide generation and subsequent JNK activation (Brann Brann et al. 2002 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49178 17634371 61654 22562 11917 TNFRSF1B p75 p75 2 2.1 However in p75 -expressing NIH-3T3 and PC12 cell lines the acid isoform of 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49179 17634371 61654 22562 11917 TNFRSF1B p75 p75 22 2.1 of SMase has been implicated in ceramide production induced by p75 signaling (Dobrowsky Dobrowsky and Carter 1998 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49180 17634371 61655 22562 11917 TNFRSF1B p75 p75 4 2.1 Thus it seems that p75 is able to activate different SMases depending on the cell 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49181 17634371 61656 20996 11179 SOD1 ALS ALS 5 1.7 Interestingly the spinal cord of ALS patients and SOD1 mice exhibit a remarkable increase in ceramides 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00263912306447868<>ScoreDetail__5468|IGFALS|0.000345527577419773__11179|SOD1|0.00263912306447868__ 0 0 0 0 0 49182 17634371 61656 20996 11179 SOD1 SOD1 SOD1 8 1.7 Interestingly the spinal cord of ALS patients and SOD1 mice exhibit a remarkable increase in ceramides and cholesterol esters 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49183 17634371 61657 14373 7808 NGF NGF NGF 1 1.2 Therefore NGF signaling through p75 and the subsequent increase in ceramide production 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49184 17634371 61657 22562 11917 TNFRSF1B p75 p75 4 2.1 Therefore NGF signaling through p75 and the subsequent increase in ceramide production may also modulate 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49185 17634371 61658 22562 11917 TNFRSF1B p75 p75 7 2.1 In motor neurons ceramide generation induced by p75 signaling increased superoxide production by mitochondria as evidenced by oxidation 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49186 17634371 61659 14373 7808 NGF NGF NGF 15 1.2 an important source of superoxide in motor neurons exposed to NGF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49187 17634371 61662 14373 7808 NGF NGF NGF 16 1.2 and peroxynitrite scavengers completely prevent motor neuron death induced by NGF through p75 (Pehar Pehar et al. 2004 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49188 17634371 61662 22562 11917 TNFRSF1B p75 p75 18 2.1 scavengers completely prevent motor neuron death induced by NGF through p75 (Pehar Pehar et al. 2004 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49189 17634371 61663 14373 7808 NGF NGF NGF-mediated 23 1.2 (mitoCP) mitoCP supports a role for mitochondrial oxidative damage in NGF-mediated apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49190 17634371 61665 14373 7808 NGF NGF NGF 31 1.2 prevent mitochondrial oxidative damage and neuronal death induced by NGF/p75 NGF p75 -signaling in vivo 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49191 17634371 61665 22562 11917 TNFRSF1B p75 p75 31 2.1 mitochondrial oxidative damage and neuronal death induced by NGF/p75 NGF p75 -signaling in vivo 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49192 17634371 61666 20996 11179 SOD1 ALS ALS-linked 8 1.7 It was previously shown that motor neurons overexpressing ALS-linked SOD1 mutations (G37R, G37R G85R or G93A display increased susceptibility 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00263912306447868<>ScoreDetail__5468|IGFALS|0.000345527577419773__11179|SOD1|0.00263912306447868__ 0 0 0 0 0 49193 17634371 61666 20996 11179 SOD1 SOD1 SOD1 9 1.7 It was previously shown that motor neurons overexpressing ALS-linked SOD1 mutations (G37R, G37R G85R or G93A display increased susceptibility to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49194 17634371 61666 7333 11920 FAS FAS Fas 21 0.3 G37R G85R or G93A display increased susceptibility to activation of Fas apoptotic pathway but not to trophic factor deprivation or excitotoxic 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000840215821746618<>ScoreDetail__11920|FAS|0.000840215821746618__3594|FASN|0.000403033744916279__ 0 0 0 0 0 49195 17634371 61667 20996 11179 SOD1 SOD1 SOD1 5 1.7 We show here that transgenic SOD1 motor neurons also show increased susceptibility to p75 -mediated apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49196 17634371 61667 22562 11917 TNFRSF1B p75 p75 13 2.1 that transgenic SOD1 motor neurons also show increased susceptibility to p75 -mediated apoptosis 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49197 17634371 61668 20996 11179 SOD1 SOD1 SOD1 6 1.7 In contrast to nontransgenic motor neurons SOD1 motor neurons are sensitive to NGF-mediated apoptosis in the absence 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49198 17634371 61668 14373 7808 NGF NGF NGF-mediated 12 1.2 to nontransgenic motor neurons SOD1 motor neurons are sensitive to NGF-mediated apoptosis in the absence of exogenous nitric oxide 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49199 17634371 61669 14373 7808 NGF NGF NGF-induced 10 1.2 Although an external source of nitric oxide is not required NGF-induced apoptosis in SOD1 transgenic motor neurons requires endogenous production of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49200 17634371 61669 20996 11179 SOD1 SOD1 SOD1 13 1.7 source of nitric oxide is not required NGF-induced apoptosis in SOD1 transgenic motor neurons requires endogenous production of nitric oxide by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49201 17634371 61669 14533 7872 NOS1 nNOS nNOS 24 3.7 transgenic motor neurons requires endogenous production of nitric oxide by nNOS because apoptosis is prevented by nNOS inhibitors 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49202 17634371 61669 14533 7872 NOS1 nNOS nNOS 30 3.7 of nitric oxide by nNOS because apoptosis is prevented by nNOS inhibitors 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49203 17634371 61670 20996 11179 SOD1 SOD1 SOD1 13 1.7 the execution of a similar apoptotic pathway in nontransgenic and SOD1 motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49204 17634371 61671 20996 11179 SOD1 SOD1 SOD1 4 1.7 The increased susceptibility of SOD1 motor neurons to NGF-induced apoptosis was not mediated by increased 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49205 17634371 61671 14373 7808 NGF NGF NGF-induced 8 1.2 The increased susceptibility of SOD1 motor neurons to NGF-induced apoptosis was not mediated by increased expression of p75 or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49206 17634371 61671 22562 11917 TNFRSF1B p75 p75 17 2.1 to NGF-induced apoptosis was not mediated by increased expression of p75 or nNOS mRNA 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49207 17634371 61671 14533 7872 NOS1 nNOS nNOS 19 3.7 apoptosis was not mediated by increased expression of p75 or nNOS mRNA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49208 17634371 61672 14533 7872 NOS1 NOS NOS 12 2.7 nitric oxide production may still result from activation of endogenous NOS enzymatic activity 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000594372057189296<>ScoreDetail__7873|NOS2A|0.000542681145488186__7872|NOS1|0.000594372057189296__ 0 0 0 0 0 49209 17634371 61673 7333 11920 FAS FAS Fas 6 0.3 Nevertheless for other apoptotic stimuli including Fas (Raoul Raoul et al. 2002 and trophic factor deprivation (Est_amp_eacute;vez 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000840215821746618<>ScoreDetail__11920|FAS|0.000840215821746618__3594|FASN|0.000403033744916279__ 0 0 0 0 0 49210 17634371 61673 14533 7872 NOS1 nNOS nNOS 21 3.7 and trophic factor deprivation (Est_amp_eacute;vez Est_amp_eacute vez et al. 1998 nNOS regulation in motor neurons occurs at the transcriptional level 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49211 17634371 61674 14373 7808 NGF NGF NGF-mediated 15 1.2 nitric oxide production was counteracted by endogenous antioxidant defenses and NGF-mediated apoptosis only proceeds in the presence of an exogenous source 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49212 17634371 61675 20996 11179 SOD1 SOD1 SOD1 4 1.7 The expression of mutant SOD1 leads to decreased antioxidant defenses thereby potentiating the detrimental stress 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49213 17634371 61676 22562 11917 TNFRSF1B p75 p75 9 2.1 Together our results suggest a critical modulation of the p75 -apoptotic pathway in motor neurons that is specifically regulated by 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49214 17634371 61677 14373 7808 NGF NGF NGF-mediated 0 1.2 NGF-mediated apoptosis will be executed only in the presence of surrounding 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49215 17634371 61679 8190 15990 GCA GCL GCL 10 0.0 GSH is synthesized by the consecutive action of the enzymes GCL and glutathione synthetase 1 JUMiner_v2.2 1 0 0 2 23843 TotalCon:3<>15990|GCA|25801|Complete__19717|GMCL1L|64396|No_GeneRif__23843|GMCL1|64395|Complete__<>AvaiableGeneRif=2<>BEST:23843|GMCL1|0.000291833863150763<>ScoreDetail__23843|GMCL1|0.000291833863150763__15990|GCA|0.000132177999706271__ 0 0 0 0 0 49216 17634371 61680 8204 4311 GCLC GCLC GCLC 14 2.5 step in GSH biosynthesis and both subunits of the enzyme GCLC and GCLM are transcriptionally regulated by Nrf2 a redox-sensitive transcription 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49217 17634371 61680 8205 4312 GCLM GCLM GCLM 16 3.0 GSH biosynthesis and both subunits of the enzyme GCLC and GCLM are transcriptionally regulated by Nrf2 a redox-sensitive transcription factor and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49218 17634371 61680 14345 7782 NFE2L2 NRF2 Nrf2 21 3.1 of the enzyme GCLC and GCLM are transcriptionally regulated by Nrf2 a redox-sensitive transcription factor and member of the Cap'n'Collar/basic-leucine Cap'n'Collar 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49219 17634371 61680 8190 15990 GCA GCL GCL 0 0.0 GCL catalyzes the rate-limiting step in GSH biosynthesis and both subunits 1 JUMiner_v2.2 1 0 0 2 23843 TotalCon:3<>15990|GCA|25801|Complete__19717|GMCL1L|64396|No_GeneRif__23843|GMCL1|64395|Complete__<>AvaiableGeneRif=2<>BEST:23843|GMCL1|0.000291833863150763<>ScoreDetail__23843|GMCL1|0.000291833863150763__15990|GCA|0.000132177999706271__ 0 0 0 0 0 49220 17634371 61681 20996 11179 SOD1 SOD1 SOD1 5 1.7 Compared with nontransgenic motor neurons SOD1 motor neurons showed reduced Nrf2 mRNA expression which correlated with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49221 17634371 61681 14345 7782 NFE2L2 NRF2 Nrf2 10 3.1 Compared with nontransgenic motor neurons SOD1 motor neurons showed reduced Nrf2 mRNA expression which correlated with a decreased transcription of GCLC 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49222 17634371 61681 8204 4311 GCLC GCLC GCLC 20 2.5 Nrf2 mRNA expression which correlated with a decreased transcription of GCLC and GCLM 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49223 17634371 61681 8205 4312 GCLM GCLM GCLM 22 3.0 expression which correlated with a decreased transcription of GCLC and GCLM 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49224 17634371 61682 14345 7782 NFE2L2 NRF2 Nrf2 4 3.1 A similar reduction in Nrf2 expression was previously observed in a motor neuron-like NSC34 cell 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49225 17634371 61682 20996 11179 SOD1 SOD1 SOD1 20 1.7 a motor neuron-like NSC34 cell line transfected with a mutant SOD1 expression vector and in motor neurons from SOD1-associated familial ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49226 17634371 61682 20996 11179 SOD1 SOD1 SOD1-associated 28 1.7 a mutant SOD1 expression vector and in motor neurons from SOD1-associated familial ALS cases (Kirby Kirby et al. 2005 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49227 17634371 61682 20996 11179 SOD1 ALS ALS 30 1.7 SOD1 expression vector and in motor neurons from SOD1-associated familial ALS cases (Kirby Kirby et al. 2005 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00263912306447868<>ScoreDetail__5468|IGFALS|0.000345527577419773__11179|SOD1|0.00263912306447868__ 0 0 0 0 0 49228 17634371 61683 14345 7782 NFE2L2 NRF2 Nrf2 3 3.1 This reduction in Nrf2 expression could explain the increased susceptibility of SOD1 motor neurons 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49229 17634371 61683 20996 11179 SOD1 SOD1 SOD1 11 1.7 reduction in Nrf2 expression could explain the increased susceptibility of SOD1 motor neurons not only to NGF but also to Fas-mediated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49230 17634371 61683 14373 7808 NGF NGF NGF 17 1.2 the increased susceptibility of SOD1 motor neurons not only to NGF but also to Fas-mediated apoptosis which also involves ROS and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49231 17634371 61683 6981 22140 FAM20C RNS RNS 28 0.6 but also to Fas-mediated apoptosis which also involves ROS and RNS production (Raoul Raoul et al. 2002 tBHQ has been established 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 49232 17634371 61683 14345 7782 NFE2L2 NRF2 Nrf2 46 3.1 has been established to strongly activate gene expression mediated by Nrf2 and to subsequently increase GSH content by induction of GCL 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49233 17634371 61683 14345 7782 NFE2L2 NRF2 Nrf2 64 3.1 induction of GCL tBHQ causes increased GCL expression only when Nrf2 is present but it does not in Nrf2 knock-out cells 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49234 17634371 61683 14345 7782 NFE2L2 NRF2 Nrf2 72 3.1 only when Nrf2 is present but it does not in Nrf2 knock-out cells (Lee Lee et al. 2003 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49235 17634371 61683 18723 10261 ROS1 ROS ROS 26 0.1 to NGF but also to Fas-mediated apoptosis which also involves ROS and RNS production (Raoul Raoul et al. 2002 tBHQ has 6 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 49236 17634371 61683 8190 15990 GCA GCL GCL 56 0.0 Nrf2 and to subsequently increase GSH content by induction of GCL tBHQ causes increased GCL expression only when Nrf2 is present 1 JUMiner_v2.2 1 0 0 2 23843 TotalCon:3<>15990|GCA|25801|Complete__19717|GMCL1L|64396|No_GeneRif__23843|GMCL1|64395|Complete__<>AvaiableGeneRif=2<>BEST:23843|GMCL1|0.000291833863150763<>ScoreDetail__23843|GMCL1|0.000291833863150763__15990|GCA|0.000132177999706271__ 0 0 0 0 0 49237 17634371 61683 8190 15990 GCA GCL GCL 60 0.0 increase GSH content by induction of GCL tBHQ causes increased GCL expression only when Nrf2 is present but it does not 1 JUMiner_v2.2 1 0 0 2 23843 TotalCon:3<>15990|GCA|25801|Complete__19717|GMCL1L|64396|No_GeneRif__23843|GMCL1|64395|Complete__<>AvaiableGeneRif=2<>BEST:23843|GMCL1|0.000291833863150763<>ScoreDetail__23843|GMCL1|0.000291833863150763__15990|GCA|0.000132177999706271__ 0 0 0 0 0 49238 17634371 61684 14345 7782 NFE2L2 NRF2 Nrf2 4 3.1 Accordingly pharmacological activation of Nrf2 by tBHQ treatment completely prevented NGF- and Fas-mediated motor neuron 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49239 17634371 61684 14373 7808 NGF NGF NGF- 10 1.2 Accordingly pharmacological activation of Nrf2 by tBHQ treatment completely prevented NGF- and Fas-mediated motor neuron apoptosis in nontransgenic and SOD1 motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49240 17634371 61684 20996 11179 SOD1 SOD1 SOD1 19 1.7 prevented NGF- and Fas-mediated motor neuron apoptosis in nontransgenic and SOD1 motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49241 17634371 61685 14345 7782 NFE2L2 NRF2 Nrf2 1 3.1 Thus Nrf2 manipulation may be a target in the prevention of motor 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49242 17634371 61685 22562 11917 TNFRSF1B p75 p75 20 2.1 of motor neuron death occurring in neuropathological conditions involving either p75 - or Fas-apoptotic signaling 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49243 17634371 61685 7333 11920 FAS FAS Fas-apoptotic 23 0.3 death occurring in neuropathological conditions involving either p75 - or Fas-apoptotic signaling 1 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000840215821746618<>ScoreDetail__11920|FAS|0.000840215821746618__3594|FASN|0.000403033744916279__ 0 0 0 0 0 49244 17634371 61687 14373 7808 NGF NGF NGF-induced 0 1.2 NGF-induced apoptosis in motor neurons involves nSMase activation and triggers cytochrome 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49245 17634371 61687 20486 11121 SMPD2 nSMase nSMase 6 1.9 NGF-induced apoptosis in motor neurons involves nSMase activation and triggers cytochrome c release from mitochondria 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49246 17634371 61688 8240 4232 GDNF GDNF GDNF 8 1.2 A Pure motor neuron cultures maintained with GDNF (1 1 ng/ml) ng ml were exposed to NGF (100 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49247 17634371 61688 14373 7808 NGF NGF NGF 14 1.2 with GDNF (1 1 ng/ml) ng ml were exposed to NGF (100 100 ng/ml) ng ml plus 10 micro M DETA-NONOate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49248 17634371 61689 14373 7808 NGF NGF NGF 7 1.2 SMase inhibitors were added 1 h before NGF and DETA-NONOate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49249 17634371 61691 8240 4232 GDNF GDNF GDNF 12 1.2 represent the SD of trophic factor deprivation (NONE; NONE without GDNF as a control for maximum cell death observed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49250 17634371 61692 8240 4232 GDNF GDNF GDNF 6 1.2 Data are expressed as percentage of GDNF (mean mean _amp_#177 SD * p _lt_ 0.05 significantly different 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49251 17634371 61692 8240 4232 GDNF GDNF GDNF 17 1.2 mean _amp_#177 SD * p _lt_ 0.05 significantly different from GDNF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49252 17634371 61693 8240 4232 GDNF GDNF GDNF 13 1.2 microphotographs showing cytochrome c immunoreactivity in motor neurons maintained with GDNF (control) control or exposed to NGF plus DETA-NONOate (NGF+NO) NGF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49253 17634371 61693 14373 7808 NGF NGF NGF 18 1.2 motor neurons maintained with GDNF (control) control or exposed to NGF plus DETA-NONOate (NGF+NO) NGF NO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49254 17634371 61693 14373 7808 NGF NGF NGF 21 1.2 GDNF (control) control or exposed to NGF plus DETA-NONOate (NGF+NO) NGF NO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49255 17634371 61694 14373 7808 NGF NGF NGF 4 1.2 In the absence of NGF motor neurons showed a punctuate (mitochondrial) mitochondrial labeling of cytochrome 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49256 17634371 61694 14373 7808 NGF NGF NGF 22 1.2 labeling of cytochrome c whereas 12 h after treatment with NGF NO motor neurons showed a diffuse cytoplasmic labeling 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49257 17634371 61695 14373 7808 NGF NGF NGF 14 1.2 100 n M GW prevented cytochrome c release induced by NGF NO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49258 17634371 61696 8240 4232 GDNF GDNF GDNF 4 1.2 Motor neurons maintained with GDNF (1 1 ng/ml) ng ml were exposed to vehicle (Ctrl), 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49259 17634371 61696 14373 7808 NGF NGF NGF 12 1.2 1 ng/ml) ng ml were exposed to vehicle (Ctrl), Ctrl NGF (100 100 ng/ml), ng ml DETA-NONOate (10 10 micro M 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49260 17634371 61696 5131 2524 CTRL CTRL Ctrl 11 0.2 (1 1 ng/ml) ng ml were exposed to vehicle (Ctrl), Ctrl NGF (100 100 ng/ml), ng ml DETA-NONOate (10 10 micro 5 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 49261 17634371 61700 14373 7808 NGF NGF NGF 0 1.2 NGF increases superoxide production by mitochondria 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49262 17634371 61702 14373 7808 NGF NGF NGF 19 1.2 0.1 micro M mito-HE and after washing were exposed to NGF (100 100 ng/ml) ng ml 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49263 17634371 61703 14373 7808 NGF NGF NGF 14 1.2 fluorescence emission of mito-HE ( exc 405 nm immediately after NGF addition ( t = 0 min and 40 min later 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49264 17634371 61704 8240 4232 GDNF GDNF GDNF 12 1.2 did not change after 40 min in cultures maintained with GDNF in the absence of NGF (data data not shown 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49265 17634371 61704 14373 7808 NGF NGF NGF 17 1.2 min in cultures maintained with GDNF in the absence of NGF (data data not shown 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49266 17634371 61705 14373 7808 NGF NGF NGF 7 1.2 The increased mito-HE fluorescence emission induced by NGF was not observed in cultures preincubated for 24 h with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49267 17634371 61705 22562 11917 TNFRSF1B p75 p75 22 2.1 cultures preincubated for 24 h with antisense oligonucleotides to downregulate p75 expression or GW4869 (100 100 n M 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49268 17634371 61706 14373 7808 NGF NGF NGF 10 1.2 Preincubation with missense oligonucleotides did not prevent the effect of NGF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49269 17634371 61707 8240 4232 GDNF GDNF GDNF 7 1.2 B Motor neuron cultures maintained with GDNF (1 1 ng/ml) ng ml were exposed to NGF (100 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49270 17634371 61707 14373 7808 NGF NGF NGF 13 1.2 with GDNF (1 1 ng/ml) ng ml were exposed to NGF (100 100 ng/ml) ng ml plus DETA-NONOate (10 10 micro 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49271 17634371 61707 14373 7808 NGF NGF NGF 22 1.2 ng/ml) ng ml plus DETA-NONOate (10 10 micro M (NGF+NO) NGF NO in the presence of vehicle (white white bar or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49272 17634371 61708 8240 4232 GDNF GDNF GDNF 7 1.2 The dashed lines represent the SD of GDNF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49273 17634371 61709 8240 4232 GDNF GDNF GDNF 6 1.2 Data are expressed as percentage of GDNF (mean mean _amp_#177 SD * p _lt_ 0.05 significantly different 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49274 17634371 61709 14373 7808 NGF NGF NGF 17 1.2 mean _amp_#177 SD * p _lt_ 0.05 significantly different from NGF NO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49275 17634371 61711 20996 11179 SOD1 SOD1 SOD1 3 1.7 Motor neurons overexpressing SOD1 show increase susceptibility to NGF-induced apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49276 17634371 61711 14373 7808 NGF NGF NGF-induced 8 1.2 Motor neurons overexpressing SOD1 show increase susceptibility to NGF-induced apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49277 17634371 61712 20996 11179 SOD1 SOD1 SOD1 6 1.7 A Motor neurons isolated from SOD1 or nontransgenic (Non-Tg) Non-Tg E15 embryos were maintained in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49278 17634371 61712 8240 4232 GDNF GDNF GDNF 18 1.2 (Non-Tg) Non-Tg E15 embryos were maintained in the presence of GDNF (1 1 ng/ml) ng ml and exposed to increasing concentrations 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49279 17634371 61712 14373 7808 NGF NGF NGF 27 1.2 1 ng/ml) ng ml and exposed to increasing concentrations of NGF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49280 17634371 61713 14373 7808 NGF NGF NGF 11 1.2 gray bars represent motor neuron survival in cultures exposed to NGF (100 100 ng/ml) ng ml in the presence of DETA-NONOate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49281 17634371 61714 8240 4232 GDNF GDNF GDNF 8 1.2 Data are expressed as percentage of its respective GDNF condition (mean mean _amp_#177 SD * p _lt_ 0.05 significantly 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49282 17634371 61714 8240 4232 GDNF GDNF GDNF 20 1.2 mean _amp_#177 SD * p _lt_ 0.05 significantly different from GDNF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49283 17634371 61715 20996 11179 SOD1 SOD1 SOD1 2 1.7 B SOD1 transgenic motor neurons were exposed to NGF in the presence 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49284 17634371 61715 14373 7808 NGF NGF NGF 9 1.2 B SOD1 transgenic motor neurons were exposed to NGF in the presence of vehicle GW4869 (100 100 n M 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49285 17634371 61716 8240 4232 GDNF GDNF GDNF 7 1.2 The dashed lines represent the SD of GDNF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49286 17634371 61717 8240 4232 GDNF GDNF GDNF 6 1.2 Data are expressed as percentage of GDNF (mean mean _amp_#177 SD * p _lt_ 0.05 significantly different 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49287 17634371 61717 14373 7808 NGF NGF NGF 17 1.2 mean _amp_#177 SD * p _lt_ 0.05 significantly different from NGF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49288 17634371 61718 20996 11179 SOD1 SOD1 SOD1 9 1.7 C Fluorescence microphotographs showing cytochrome c immunoreactivity in SOD1 motor neurons maintained with GDNF and exposed to vehicle (control) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49289 17634371 61718 8240 4232 GDNF GDNF GDNF 14 1.2 showing cytochrome c immunoreactivity in SOD1 motor neurons maintained with GDNF and exposed to vehicle (control) control or NGF (100 100 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49290 17634371 61718 14373 7808 NGF NGF NGF 21 1.2 maintained with GDNF and exposed to vehicle (control) control or NGF (100 100 ng/ml) ng ml 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49291 17634371 61719 14373 7808 NGF NGF NGF 4 1.2 In the absence of NGF motor neurons showed a punctuate labeling of cytochrome c and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49292 17634371 61719 14373 7808 NGF NGF NGF 21 1.2 labeling of cytochrome c and 12 h after treatment with NGF a diffuse labeling was observed in affected motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49293 17634371 61720 20996 11179 SOD1 SOD1 SOD1 15 1.7 the fluorescence emission of mito-HE ( exc 405 nm in SOD1 motor neurons immediately after NGF addition ( t = 0 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49294 17634371 61720 14373 7808 NGF NGF NGF 20 1.2 ( exc 405 nm in SOD1 motor neurons immediately after NGF addition ( t = 0 min and 40 min later 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49295 17634371 61722 20996 11179 SOD1 SOD1 SOD1 2 1.7 E SOD1 transgenic motor neurons were exposed to NGF in the presence 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49296 17634371 61722 14373 7808 NGF NGF NGF 9 1.2 E SOD1 transgenic motor neurons were exposed to NGF in the presence of vehicle mitoQ (10 10 p M 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49297 17634371 61722 22825 30698 TRAT1 TRIM TRIM 31 1.3 (1 1 n M NAME (1 1 m M or TRIM (10 10 micro M 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 49298 17634371 61724 8240 4232 GDNF GDNF GDNF 7 1.2 The dashed lines represent the SD of GDNF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49299 17634371 61725 8240 4232 GDNF GDNF GDNF 6 1.2 Data are expressed as percentage of GDNF (mean mean _amp_#177 SD * p _lt_ 0.05 significantly different 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49300 17634371 61725 14373 7808 NGF NGF NGF 17 1.2 mean _amp_#177 SD * p _lt_ 0.05 significantly different from NGF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49301 17634371 61726 20996 11179 SOD1 SOD1 SOD1 10 1.7 F Western blot showing the expression of human mutant SOD1 (hSOD1) hSOD1 in the spinal cord and isolated motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49302 17634371 61726 20996 11179 SOD1 SOD1 hSOD1 11 1.7 Western blot showing the expression of human mutant SOD1 (hSOD1) hSOD1 in the spinal cord and isolated motor neurons from transgenic 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49303 17634371 61726 20996 11179 SOD1 ALS ALS 22 1.7 in the spinal cord and isolated motor neurons from transgenic ALS mice embryos 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00263912306447868<>ScoreDetail__5468|IGFALS|0.000345527577419773__11179|SOD1|0.00263912306447868__ 0 0 0 0 0 49304 17634371 61727 20996 11179 SOD1 SOD1 SOD1 4 1.7 Only the endogenous rat SOD1 (rSOD1) rSOD1 was detected in either the spinal cord or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49305 17634371 61729 20996 11179 SOD1 SOD1 SOD1 4 1.7 Reduced antioxidant defenses in SOD1 motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49306 17634371 61730 20996 11179 SOD1 SOD1 SOD1 0 1.7 SOD1 and nontransgenic (Non-Tg) Non-Tg motor neuron cultures were maintained with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49307 17634371 61730 8240 4232 GDNF GDNF GDNF 10 1.2 and nontransgenic (Non-Tg) Non-Tg motor neuron cultures were maintained with GDNF (1 1 ng/ml) ng ml for 24 h and the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49308 17634371 61730 14345 7782 NFE2L2 NRF2 Nrf2 21 3.1 ng ml for 24 h and the expression level of Nrf2 GCLC and GCLM mRNA was determined by relative quantitative RT-PCR 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49309 17634371 61730 8204 4311 GCLC GCLC GCLC 22 2.5 ml for 24 h and the expression level of Nrf2 GCLC and GCLM mRNA was determined by relative quantitative RT-PCR as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49310 17634371 61730 8205 4312 GCLM GCLM GCLM 24 3.0 24 h and the expression level of Nrf2 GCLC and GCLM mRNA was determined by relative quantitative RT-PCR as described in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49311 17634371 61732 14373 7808 NGF NGF NGF-induced 3 1.2 Glutathione levels modulate NGF-induced motor neuron apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49312 17634371 61733 14373 7808 NGF NGF NGF 23 1.2 10 n M and 24 h later were exposed to NGF (100 100 ng/ml) ng ml 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49313 17634371 61734 14373 7808 NGF NGF NGF 8 1.2 Motor neuron survival was determined 48 h after NGF treatment 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49314 17634371 61735 14373 7808 NGF NGF NGF 0 1.2 NGF did not affect motor neuron survival in cultures preincubated with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49315 17634371 61738 8240 4232 GDNF GDNF GDNF 6 1.2 Data are expressed as percentage of GDNF (mean mean _amp_#177 SD *p _lt_ 0.05 significantly different from 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49316 17634371 61738 8240 4232 GDNF GDNF GDNF 16 1.2 (mean mean _amp_#177 SD *p _lt_ 0.05 significantly different from GDNF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49317 17634371 61739 8240 4232 GDNF GDNF GDNF 11 1.2 top panel shows monochlorobimane fluorescence emission from cultures maintained with GDNF (1 1 ng/ml) ng ml and treated for 24 h 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49318 17634371 61740 14373 7808 NGF NGF NGF 37 1.2 vehicle (control) control tBHQ prevented motor neuron death induced by NGF (100 100 ng/ml) ng ml plus DETA-NONOate (10 10 micro 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49319 17634371 61740 14373 7808 NGF NGF NGF 46 1.2 100 ng/ml) ng ml plus DETA-NONOate (10 10 micro M NGF NO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49320 17634371 61741 8240 4232 GDNF GDNF GDNF 6 1.2 Data are expressed as percentage of GDNF (mean mean _amp_#177 SD 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49321 17634371 61742 8240 4232 GDNF GDNF GDNF 15 1.2 SD of NONE * p _lt_ 0.05 significantly different from GDNF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49322 17634371 61744 14345 7782 NFE2L2 NRF2 Nrf2 1 3.1 Increased Nrf2 activation prevents SOD1 motor neuron death induced by NGF or 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49323 17634371 61744 20996 11179 SOD1 SOD1 SOD1 4 1.7 Increased Nrf2 activation prevents SOD1 motor neuron death induced by NGF or sFasL 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49324 17634371 61744 14373 7808 NGF NGF NGF 10 1.2 Increased Nrf2 activation prevents SOD1 motor neuron death induced by NGF or sFasL 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49325 17634371 61745 20996 11179 SOD1 SOD1 SOD1 2 1.7 A SOD1 motor neuron cultures maintained with GDNF (1 1 ng/ml) ng 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49326 17634371 61745 8240 4232 GDNF GDNF GDNF 8 1.2 A SOD1 motor neuron cultures maintained with GDNF (1 1 ng/ml) ng ml were exposed to NGF (100 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49327 17634371 61745 14373 7808 NGF NGF NGF 14 1.2 with GDNF (1 1 ng/ml) ng ml were exposed to NGF (100 100 ng/ml) ng ml in the presence of vehicle 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49328 17634371 61748 8240 4232 GDNF GDNF GDNF 6 1.2 Data are expressed as percentage of GDNF (mean mean _amp_#177 SD * p _lt_ 0.05 significantly different 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49329 17634371 61748 8240 4232 GDNF GDNF GDNF 17 1.2 mean _amp_#177 SD * p _lt_ 0.05 significantly different from GDNF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49330 17634371 61749 20996 11179 SOD1 SOD1 SOD1 2 1.7 B SOD1 or nontransgenic (Non-Tg) Non-Tg motor neuron cultures were maintained in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49331 17634371 61749 8240 4232 GDNF GDNF GDNF 15 1.2 Non-Tg motor neuron cultures were maintained in the presence of GDNF (1 1 ng/ml) ng ml and exposed to increasing concentrations 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49332 17634371 61750 8240 4232 GDNF GDNF GDNF 8 1.2 Data are expressed as percentage of its respective GDNF condition (mean mean _amp_#177 SD * p _lt_ 0.05 significantly 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49333 17634371 61750 8240 4232 GDNF GDNF GDNF 20 1.2 mean _amp_#177 SD * p _lt_ 0.05 significantly different from GDNF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49334 17634371 61751 20486 11121 SMPD2 nSMase nSMase 4 1.9 Immunofluorescence studies revealed that nSMase activation was followed by cytochrome c release from mitochondria ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49335 17634371 61752 14373 7808 NGF NGF NGF 4 1.2 In the absence of NGF motor neurons showed a punctate pattern of cytochrome c immunoreactivity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49336 17634371 61753 14373 7808 NGF NGF NGF 0 1.2 NGF (100 100 ng/ml) ng ml or DETA-NONOate (10 10 micro 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49337 17634371 61754 14373 7808 NGF NGF NGF 6 1.2 In contrast after 12 h of NGF treatment in the presence of DETA-NONOate ~27% of motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49338 17634371 61755 14373 7808 NGF NGF NGF 5 1.2 Cytochrome c release induced by NGF in the presence of nitric oxide was prevented by the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49339 17634371 61755 20486 11121 SMPD2 nSMase nSMase 19 1.9 of nitric oxide was prevented by the addition of the nSMase inhibitor GW4869 ( Fig 1 C indicating that cytochrome c 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49340 17634371 61756 18723 10261 ROS1 ROS ROS 9 0.0 It has been previously shown that ceramide may induce ROS production by mitochondria (Garcia-Ruiz Garcia-Ruiz et al. 1997 Quillet-Mary et 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49341 17634371 61756 12393 6899 MAS1 MAS Mas 24 0.0 (Garcia-Ruiz Garcia-Ruiz et al. 1997 Quillet-Mary et al. 1997 Mansat-de Mas et al. 1999 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49342 17634371 61757 14373 7808 NGF NGF NGF-mediated 12 1.2 tested for the potential involvement of mitochondrial ROS production in NGF-mediated motor neuron death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49343 17634371 61757 18723 10261 ROS1 ROS ROS 9 0.0 We therefore tested for the potential involvement of mitochondrial ROS production in NGF-mediated motor neuron death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49344 17634371 61762 14373 7808 NGF NGF NGF 0 1.2 NGF (100 100 ng/ml) ng ml treatment induced a 1.7 _amp_#177 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49345 17634371 61763 22562 11917 TNFRSF1B p75 p75 11 2.1 increase in mito-HE fluorescence emission was prevented by downregulation of p75 expression by antisense treatment or preincubation of motor neurons with 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49346 17634371 61763 20486 11121 SMPD2 nSMase nSMase 23 1.9 by antisense treatment or preincubation of motor neurons with the nSMase inhibitor GW4869 (100 100 n M ( Fig 2 A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49347 17634371 61763 22562 11917 TNFRSF1B p75 p75 42 2.1 Fig 2 A suggesting that increased production by mitochondria follows p75 and nSMase activation 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49348 17634371 61763 20486 11121 SMPD2 nSMase nSMase 44 1.9 A suggesting that increased production by mitochondria follows p75 and nSMase activation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49349 17634371 61764 14373 7808 NGF NGF NGF-induced 25 1.2 Kelso et al. 2001 Dhanasekaran et al. 2005 also blocked NGF-induced motor neuron death ( Fig 2 B strengthening the role 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49350 17634371 61764 22562 11917 TNFRSF1B p75 p75 43 2.1 B strengthening the role of ROS production by mitochondria in p75 -mediated motor neuron apoptosis 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49351 17634371 61764 18723 10261 ROS1 ROS ROS 38 0.0 neuron death ( Fig 2 B strengthening the role of ROS production by mitochondria in p75 -mediated motor neuron apoptosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49352 17634371 61765 20996 11179 SOD1 SOD1 SOD1 6 1.7 In contrast to nontransgenic motor neurons SOD1 -expressing motor neurons were sensitive to NGF-induced apoptosis in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49353 17634371 61765 14373 7808 NGF NGF NGF-induced 13 1.2 nontransgenic motor neurons SOD1 -expressing motor neurons were sensitive to NGF-induced apoptosis in the absence of the nitric oxide donor DETA-NONOate 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49354 17634371 61765 14373 7808 NGF NGF NGF 30 1.2 donor DETA-NONOate even at concentrations of 10 ng/ml ng ml NGF ( Fig 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49355 17634371 61766 20996 11179 SOD1 SOD1 SOD1 3 1.7 The expression of SOD1 in transgenic motor neurons under our culture conditions was confirmed 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49356 17634371 61766 20996 11179 SOD1 SOD1 SOD1 27 1.7 and found to be significantly higher than the endogenous rat SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49357 17634371 61767 14373 7808 NGF NGF NGF-induced 16 1.2 10 micro M which renders nontransgenic motor neurons sensitive to NGF-induced apoptosis did not further decrease the survival of SOD1 -expressing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49358 17634371 61767 20996 11179 SOD1 SOD1 SOD1 25 1.7 to NGF-induced apoptosis did not further decrease the survival of SOD1 -expressing motor neurons ( Fig 3 A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49359 17634371 61768 14373 7808 NGF NGF NGF-induced 0 1.2 NGF-induced apoptosis in SOD1 -expressing motor neurons was prevented by blocking 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49360 17634371 61768 20996 11179 SOD1 SOD1 SOD1 3 1.7 NGF-induced apoptosis in SOD1 -expressing motor neurons was prevented by blocking antibodies to p75 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49361 17634371 61768 22562 11917 TNFRSF1B p75 p75 13 2.1 SOD1 -expressing motor neurons was prevented by blocking antibodies to p75 (93 93 _amp_#177 6% of control 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49362 17634371 61769 22562 11917 TNFRSF1B p75 p75 4 2.1 The effectiveness of the p75 blocking antibodies to prevent signaling through p75 in motor neuron 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49363 17634371 61769 22562 11917 TNFRSF1B p75 p75 11 2.1 effectiveness of the p75 blocking antibodies to prevent signaling through p75 in motor neuron cultures has been previously established (Pehar Pehar 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49364 17634371 61770 22562 11917 TNFRSF1B p75 p75 1 2.1 Moreover p75 -mediated apoptosis in SOD1 motor neurons was prevented by nSMase 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49365 17634371 61770 20996 11179 SOD1 SOD1 SOD1 5 1.7 Moreover p75 -mediated apoptosis in SOD1 motor neurons was prevented by nSMase inhibitors ( Fig 3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49366 17634371 61770 20486 11121 SMPD2 nSMase nSMase 11 1.9 p75 -mediated apoptosis in SOD1 motor neurons was prevented by nSMase inhibitors ( Fig 3 B and involved mitochondrial production and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49367 17634371 61771 14373 7808 NGF NGF NGF-induced 18 1.2 p M and mitoCP (1 1 n M also prevented NGF-induced apoptosis in SOD1 motor neurons ( Fig 3 E 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49368 17634371 61771 20996 11179 SOD1 SOD1 SOD1 21 1.7 mitoCP (1 1 n M also prevented NGF-induced apoptosis in SOD1 motor neurons ( Fig 3 E 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49369 17634371 61772 14373 7808 NGF NGF NGF 11 1.2 an exogenous source of nitric oxide is not required for NGF to induce SOD1 motor neuron death N -nitro-L -arginine methyl 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49370 17634371 61772 20996 11179 SOD1 SOD1 SOD1 14 1.7 of nitric oxide is not required for NGF to induce SOD1 motor neuron death N -nitro-L -arginine methyl ester (NAME) NAME 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49371 17634371 61772 14533 7872 NOS1 NOS NOS 34 2.7 (1 1 m M a general nitric oxide synthase (NOS) NOS inhibitor and 1-(2-trifluoromethylphenyl)imidazole 1- 2-trifluoromethylphenyl imidazole (TRIM) TRIM (10 10 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000594372057189296<>ScoreDetail__7873|NOS2A|0.000542681145488186__7872|NOS1|0.000594372057189296__ 0 0 0 0 0 49372 17634371 61772 22825 30698 TRAT1 TRIM TRIM 38 1.3 synthase (NOS) NOS inhibitor and 1-(2-trifluoromethylphenyl)imidazole 1- 2-trifluoromethylphenyl imidazole (TRIM) TRIM (10 10 micro M a specific inhibitor of the neuronal 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 49373 17634371 61772 14533 7872 NOS1 NOS NOS 51 2.7 micro M a specific inhibitor of the neuronal isoform of NOS prevented NGF-induced apoptosis in SOD1 motor neurons ( Fig 3 1 JUMiner_v2.2 1 0 0 2 7872 TotalCon:2<>7872|NOS1|4842|Complete__7873|NOS2A|4843|Complete__<>AvaiableGeneRif=2<>BEST:7872|NOS1|0.000594372057189296<>ScoreDetail__7873|NOS2A|0.000542681145488186__7872|NOS1|0.000594372057189296__ 0 0 0 0 0 49374 17634371 61772 14373 7808 NGF NGF NGF-induced 53 1.2 a specific inhibitor of the neuronal isoform of NOS prevented NGF-induced apoptosis in SOD1 motor neurons ( Fig 3 E 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49375 17634371 61772 20996 11179 SOD1 SOD1 SOD1 56 1.7 of the neuronal isoform of NOS prevented NGF-induced apoptosis in SOD1 motor neurons ( Fig 3 E 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49376 17634371 61773 14373 7808 NGF NGF NGF 9 1.2 These results indicate that the apoptotic pathway induced by NGF in SOD1 motor neurons required endogenous nitric oxide production by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49377 17634371 61773 20996 11179 SOD1 SOD1 SOD1 11 1.7 results indicate that the apoptotic pathway induced by NGF in SOD1 motor neurons required endogenous nitric oxide production by nNOS activation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49378 17634371 61773 14533 7872 NOS1 nNOS nNOS 20 3.7 in SOD1 motor neurons required endogenous nitric oxide production by nNOS activation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49379 17634371 61774 20996 11179 SOD1 SOD1 SOD1 4 1.7 The increased sensitivity of SOD1 motor neurons to NGF could not be explained by differential 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49380 17634371 61774 14373 7808 NGF NGF NGF 8 1.2 The increased sensitivity of SOD1 motor neurons to NGF could not be explained by differential expression of p75 or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49381 17634371 61774 22562 11917 TNFRSF1B p75 p75 17 2.1 to NGF could not be explained by differential expression of p75 or nNOS 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49382 17634371 61774 14533 7872 NOS1 nNOS nNOS 19 3.7 could not be explained by differential expression of p75 or nNOS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49383 17634371 61775 22562 11917 TNFRSF1B p75 p75 6 2.1 No significant difference was observed in p75 and nNOS mRNA expression levels between nontransgenic and SOD1 motor 1 JUMiner_v2.2 1 0 0 2 11917 TotalCon:4<>9527|PSIP1|11168|Complete__11917|TNFRSF1B|7133|Complete__2557|CUX1|1523|Complete__10876|SIGLEC7|27036|Complete__<>AvaiableGeneRif=4<>BEST:11917|TNFRSF1B|0.000518448422006252<>ScoreDetail__9527|PSIP1|0.000404865105671193__2557|CUX1|0.000483424676559512__10876|SIGLEC7|0.000320875225376646__11917|TNFRSF1B|0.000518448422006252__ 0 0 0 0 0 49384 17634371 61775 14533 7872 NOS1 nNOS nNOS 8 3.7 No significant difference was observed in p75 and nNOS mRNA expression levels between nontransgenic and SOD1 motor neurons as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49385 17634371 61775 20996 11179 SOD1 SOD1 SOD1 15 1.7 in p75 and nNOS mRNA expression levels between nontransgenic and SOD1 motor neurons as determined by RT-PCR (data data not shown 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49386 17634371 61776 14345 7782 NFE2L2 NRF2 Nrf2 11 3.1 a ~30% decrease in the expression of the transcription factor Nrf2 was observed in SOD1 motor neurons compared with nontransgenic ones 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49387 17634371 61776 20996 11179 SOD1 SOD1 SOD1 15 1.7 the expression of the transcription factor Nrf2 was observed in SOD1 motor neurons compared with nontransgenic ones ( Fig 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49388 17634371 61777 14345 7782 NFE2L2 NRF2 Nrf2 3 3.1 The decrease in Nrf2 expression correlated with a decrease in the expression of Nrf2 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49389 17634371 61777 14345 7782 NFE2L2 NRF2 Nrf2 13 3.1 Nrf2 expression correlated with a decrease in the expression of Nrf2 regulated genes including both subunits of glutamate-cysteine ligase (GCL), GCL 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49390 17634371 61777 8204 4311 GCLC GCLC GCLC 23 2.5 regulated genes including both subunits of glutamate-cysteine ligase (GCL), GCL GCLC and GCLM the rate-limiting enzyme in reduced glutathione (GSH) GSH 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49391 17634371 61777 8205 4312 GCLM GCLM GCLM 25 3.0 including both subunits of glutamate-cysteine ligase (GCL), GCL GCLC and GCLM the rate-limiting enzyme in reduced glutathione (GSH) GSH biosynthesis ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49392 17634371 61777 8205 4312 GCLM GCL GCL 22 0.2 Nrf2 regulated genes including both subunits of glutamate-cysteine ligase (GCL), GCL GCLC and GCLM the rate-limiting enzyme in reduced glutathione (GSH) 5 JUMiner_v2.2 1 1 UserEdit 0 2 23843 TotalCon:3<>15990|GCA|25801|Complete__19717|GMCL1L|64396|No_GeneRif__23843|GMCL1|64395|Complete__<>AvaiableGeneRif=2<>BEST:23843|GMCL1|0.000291833863150763<>ScoreDetail__23843|GMCL1|0.000291833863150763__15990|GCA|0.000132177999706271__ 1 1 8190 15990 GCA 0 49393 17634371 61778 14373 7808 NGF NGF NGF 22 1.2 n M increased the sensitivity of nontransgenic motor neurons to NGF ( Fig 5 A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49394 17634371 61779 14373 7808 NGF NGF NGF-induced 10 1.2 Nontransgenic motor neurons previously exposed to BSO were sensitive to NGF-induced apoptosis even in the absence of DETA-NONOate ( Fig 5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49395 17634371 61781 14345 7782 NFE2L2 NRF2 Nrf2 7 3.1 In contrast tBHQ treatment a well known Nrf2 activator in neurons (Johnson Johnson et al. 2002 completely prevented 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49396 17634371 61781 14373 7808 NGF NGF NGF 23 1.2 et al. 2002 completely prevented motor neuron death induced by NGF in the presence of NO ( Fig 5 B 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49397 17634371 61783 14345 7782 NFE2L2 NRF2 Nrf2 0 3.1 Nrf2 activation by tBHQ also prevented NGF-induced apoptosis in SOD1 motor 2 JUMiner_v2.2 1 0 0 2 7782 TotalCon:2<>7782|NFE2L2|4780|Complete__4071|GABPA|2551|Complete__<>AvaiableGeneRif=2<>BEST:7782|NFE2L2|0.001000235349494<>ScoreDetail__7782|NFE2L2|0.001000235349494__4071|GABPA|0.000634380736421553__ 0 0 0 0 0 49398 17634371 61783 14373 7808 NGF NGF NGF-induced 6 1.2 Nrf2 activation by tBHQ also prevented NGF-induced apoptosis in SOD1 motor neurons ( Fig 6 A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49399 17634371 61783 20996 11179 SOD1 SOD1 SOD1 9 1.7 Nrf2 activation by tBHQ also prevented NGF-induced apoptosis in SOD1 motor neurons ( Fig 6 A 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49400 17634371 61784 7333 11920 FAS FAS Fas 26 0.3 we analyzed the effect of tBHQ on apoptosis induced by Fas ligand in SOD1 -expressing motor neurons 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000840215821746618<>ScoreDetail__11920|FAS|0.000840215821746618__3594|FASN|0.000403033744916279__ 0 0 0 0 0 49401 17634371 61784 20996 11179 SOD1 SOD1 SOD1 29 1.7 effect of tBHQ on apoptosis induced by Fas ligand in SOD1 -expressing motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49402 17634371 61785 20996 11179 SOD1 SOD1 SOD1 1 1.7 Rat SOD1 motor neurons also displayed increased sensitivity to Fas-mediated apoptosis ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 49403 17634371 61787 7333 11920 FAS FAS Fas 5 0.3 The soluble extracellular domain of Fas ligand (sFasL) sFasL in the presence of an enhancer antibody 2 JUMiner_v2.2 1 0 0 2 11920 TotalCon:2<>11920|FAS|355|Complete__3594|FASN|2194|Complete__<>AvaiableGeneRif=2<>BEST:11920|FAS|0.000840215821746618<>ScoreDetail__11920|FAS|0.000840215821746618__3594|FASN|0.000403033744916279__ 0 0 0 0 0 49404 17634371 61788 20996 11179 SOD1 SOD1 SOD1 13 1.7 of motor neuron survival induced by sFasL was higher in SOD1 cultures than in nontransgenic reaching a plateau at concentrations >0.5 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 51654 17678953 64372 18723 10261 ROS1 ROS ROS 14 0.0 as nitric oxide (NO) NO and reactive oxygen species (ROS), ROS can contribute to neurodegenerative diseases in part by triggering protein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 51655 17678953 64374 20996 11179 SOD1 ALS ALS 39 0.0 ranging from Parkinson's disease (PD), PD amyotrophic lateral sclerosis (ALS), ALS multiple sclerosis and Alzheimer's disease (AD) AD to stroke and 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000568982184781108<>ScoreDetail__5468|IGFALS|0.000370578326782706__11179|SOD1|0.000568982184781108__ 0 0 0 0 0 51656 17678953 64375 18723 10261 ROS1 ROS ROS 36 0.0 ion channel and subsequent free radical production including NO and ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 51657 17678953 64378 16327 14180 PDIA2 PDI PDI 8 1.5 One such molecule affected is protein disulfide isomerase (PDI), PDI an enzyme responsible for normal protein folding in the endoplasmic 1 JUMiner_v2.2 1 0 0 2 8548 TotalCon:3<>8548|P4HB|5034|Complete__18367|PADI1|29943|Complete__14180|PDIA2|64714|Complete__<>AvaiableGeneRif=3<>BEST:8548|P4HB|0.00148003894839338<>ScoreDetail__14180|PDIA2|0.000527065527065527__18367|PADI1|0.000269230769230769__8548|P4HB|0.00148003894839338__ 0 0 0 0 0 51658 17678953 64379 16327 14180 PDIA2 PDI PDI 4 1.5 We found that when PDI is S-nitrosylation (forming forming SNO-PDI the function of the enzyme 1 JUMiner_v2.2 1 0 0 2 8548 TotalCon:3<>8548|P4HB|5034|Complete__18367|PADI1|29943|Complete__14180|PDIA2|64714|Complete__<>AvaiableGeneRif=3<>BEST:8548|P4HB|0.00148003894839338<>ScoreDetail__14180|PDIA2|0.000527065527065527__18367|PADI1|0.000269230769230769__8548|P4HB|0.00148003894839338__ 0 0 0 0 0 51659 17678953 64388 1442 905 AXL UFO UFO 9 0.0 these Uncompetitive/Fast Uncompetitive Fast Off-rate therapeutics we use the term UFO drugs because like Unidentified Flying Objects they leave very quickly 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 51660 17678953 64395 16327 14180 PDIA2 PDI PDI 6 1.5 In this case in contrast to PDI or parkin S-nitrosylation proves to be neuroprotective by decreasing excessive 1 JUMiner_v2.2 1 0 0 2 8548 TotalCon:3<>8548|P4HB|5034|Complete__18367|PADI1|29943|Complete__14180|PDIA2|64714|Complete__<>AvaiableGeneRif=3<>BEST:8548|P4HB|0.00148003894839338<>ScoreDetail__14180|PDIA2|0.000527065527065527__18367|PADI1|0.000269230769230769__8548|P4HB|0.00148003894839338__ 0 0 0 0 0 51661 17678953 64396 1442 905 AXL UFO UFO 16 0.0 can be achieved by coupling NO to memantine yielding second-generation UFO drugs known as NitroMemantines 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40656 17719032 50698 20996 11179 SOD1 ALS ALS 21 1.4 may contribute to excitotoxic motor neuron (MN) MN damage in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40657 17719032 50699 18723 10261 ROS1 ROS ROS 33 0.0 mitochondrial Ca 2 overload and strong reactive oxygen species (ROS) ROS generation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40658 17719032 50701 20996 11179 SOD1 ALS ALS 36 1.4 1-naphthyl acetylspermine (NAS), NAS in G93A transgenic rat models of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40659 17719032 50702 20017 10940 SLC1A2 GLT-1 GLT-1 9 1.0 In wild-type animals immunoreactivity for the astrocytic glutamate transporter GLT-1 was particularly strong around ventral horn MNs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40660 17719032 50703 20017 10940 SLC1A2 GLT-1 GLT-1 7 1.0 However a marked loss of ventral horn GLT-1 was observed along with substantial MN damage prior to onset 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40661 17719032 50705 20017 10940 SLC1A2 GLT-1 GLT-1 25 1.0 markedly diminished the loss of both MNs and of astrocytic GLT-1 labeling 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40662 17719032 50708 20996 11179 SOD1 ALS ALS 3 1.4 Amyotrophic lateral sclerosis (ALS) ALS is an adult onset neurodegenerative disease characterized by the selective 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40663 17719032 50709 20017 10940 SLC1A2 GLT-1 GLT-1 24 1.0 resulting from a selective loss of the astrocytic glutamate transporter GLT-1 suggested an excitotoxic contribution ( Rothstein et al. 1992 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40664 17719032 50713 20996 11179 SOD1 ALS ALS 6 1.4 Currently the best animal models of ALS are provided by rodents harboring mutant forms of the enzyme 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40665 17719032 50713 20996 11179 SOD1 SOD1 SOD1 21 1.4 mutant forms of the enzyme Cu Zn superoxide dismutase (SOD1), SOD1 which are associated with familial ALS in humans 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40666 17719032 50713 20996 11179 SOD1 ALS ALS 27 1.4 Zn superoxide dismutase (SOD1), SOD1 which are associated with familial ALS in humans 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40667 17719032 50714 20996 11179 SOD1 ALS ALS 11 1.4 the role of Ca-AMPA channels in in vivo models of ALS recent studies indicate that the rate of progression of MN 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40668 17719032 50714 20996 11179 SOD1 SOD1 SOD1 24 1.4 indicate that the rate of progression of MN loss in SOD1 mutant mice varies bidirectionally with the level of expression of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40669 17719032 50715 20996 11179 SOD1 ALS ALS 16 1.4 contribute to MN loss in a distinct form of familial ALS not linked to SOD1 ( Lai et al. 2006 and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40670 17719032 50715 20996 11179 SOD1 SOD1 SOD1 20 1.4 in a distinct form of familial ALS not linked to SOD1 ( Lai et al. 2006 and a Ca-AMPA channel blocker 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40671 17719032 50717 18723 10261 ROS1 ROS ROS 39 0.0 2 is readily taken up into mitochondria resulting in strong ROS generation ( Carriedo et al. 2000 and Rao et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40672 17719032 50717 832 549 AOC2 RAO Rao 47 0.0 in strong ROS generation ( Carriedo et al. 2000 and Rao et al. 2003 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40673 17719032 50719 18723 10261 ROS1 ROS ROS 11 0.0 a possible clue recent in vitro studies indicated that the ROS produced in MNs in response to Ca-AMPA channel activation was 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40674 17719032 50719 832 549 AOC2 RAO Rao 34 0.0 inducing oxidative disruption of glutamate transporters in surrounding astrocytes ( Rao et al. 2003 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40675 17719032 50720 20996 11179 SOD1 ALS ALS 10 1.4 If such a mechanism contributed to glutamate transport disruption in ALS it could provide the basis for a feed forward cycle 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40676 17719032 50720 832 549 AOC2 RAO Rao 29 0.0 forward cycle that could be integral to disease progression ( Rao and Weiss 2004 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40677 17719032 50721 20996 11179 SOD1 ALS ALS 33 1.4 to MN degeneration in an in vivo animal model of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40678 17719032 50722 18723 10261 ROS1 ROS ROS 8 0.0 Specifically in light of culture studies suggesting that ROS produced in MNs in response to excitotoxic activation might contribute 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40679 17719032 50723 20996 11179 SOD1 SOD1 SOD1 32 1.4 Ca-AMPA channel blocker 1-naphthyl acetylspermine (NAS) NAS in G93A transgenic SOD1 rats 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40680 17719032 50724 20017 10940 SLC1A2 GLT-1 GLT-1 19 1.0 loss in these animals but also slows the loss of GLT-1 glutamate transporter in ventral horn regions near MNs consistent with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40681 17719032 50727 20996 11179 SOD1 SOD1 SOD1 2 1.4 Male hemizygous SOD1 G93A transgenic rats [Tac:N:(SD)-TgN(SOD1G93A)L26H, Tac N SD -TgN SOD1G93A L26H 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40682 17719032 50743 20017 10940 SLC1A2 GLT-1 GLT-1 32 1.0 1 8000 ip 1 2000 if Sternberger Monoclonals Berkeley CA GLT-1 1 1000 Chemicon Temecula CA 3-nitrotyrosine 10_amp_#xa0;_amp_#x3bc;g/ml, 10_amp_#xa0 _amp_#x3bc g 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40683 17719032 50743 7361 20442 FBRS FBS FBS 10 0.0 stains were carried out on floating sections blocked (10% 10% FBS 1_amp_#xa0 h and exposed to primary antibody in 10% FBS 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 40684 17719032 50743 7361 20442 FBRS FBS FBS 19 0.0 FBS 1_amp_#xa0 h and exposed to primary antibody in 10% FBS 0.3% Triton-X 100 (SMI-32, SMI-32 1 8000 ip 1 2000 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>20442|FBRS|64319|Complete__13587|FBXO8|26269|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 40685 17719032 50748 20017 10940 SLC1A2 GLT-1 GLT-1 5 1.0 For examination of NT and GLT-1 labeling staining in the neuropil surrounding ventral horn MNs care 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40686 17719032 50751 20017 10940 SLC1A2 GLT-1 GLT-1 1 1.0 For GLT-1 fluorescence was measured in 5-_amp_#x3bc m zones surrounding the MNs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40687 17719032 50752 20017 10940 SLC1A2 GLT-1 GLT-1 16 1.0 from the center of a neuron a region lacking specific GLT-1 labeling was subtracted prior to normalization of values to WT 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40688 17719032 50755 20017 10940 SLC1A2 GLT-1 GLT-1 11 1.0 were from the following sources SMI-32 Sternberger Monoclonals Berkeley CA GLT-1 Chemicon Temecula CA 3-nitrotyrosine Upstate Biotechnology Waltham MA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40689 17719032 50759 20996 11179 SOD1 SOD1 SOD1 6 1.4 NAS slows MN loss in G93A SOD1 transgenic rats 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40690 17719032 50760 20996 11179 SOD1 SOD1 SOD1 5 1.4 As previously reported hemizygous G93A SOD1 transgenic rats generally develop symptoms between 115 and 130_amp_#xa0 days 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40691 17719032 50768 11858 30830 LIN9 TGS Tg-S 21 0.0 with saline (WT), WT transgenic animals infused with saline (Tg-S), Tg-S and sibling transgenic animals infused with NAS (Tg-NAS) Tg-NAS 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40692 17719032 50773 11858 30830 LIN9 TGS Tg-S 19 0.0 (comprising comprising 2 ventral horns with 40% loss in the Tg-S condition and substantially greater MN loss in the end-stage (Tg-ES) 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40693 17719032 50775 20996 11179 SOD1 SOD1 SOD1 8 1.4 Effects of NAS on glial pathology in G93A SOD1 transgenic rats 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40694 17719032 50777 20996 11179 SOD1 SOD1 SOD1 16 1.4 astrogliosis nitrotyrosine labeling and loss of astrocytic glutamate transport in SOD1 mutant rodent models of ALS ( Alexander et al. 2000 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40695 17719032 50777 20996 11179 SOD1 ALS ALS 21 1.4 of astrocytic glutamate transport in SOD1 mutant rodent models of ALS ( Alexander et al. 2000 Ferrante et al. 1997 and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40696 17719032 50777 20017 10940 SLC1A2 GLT-1 GLT-1 44 1.0 Tu et al. 1996 and a specific decrease of the GLT-1 glutamate transporter has been reported in ventral horn of the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40697 17719032 50778 8254 4235 GFAP GFAP GFAP 15 2.5 we see a dramatic increase in astrogliosis as indicated by GFAP labeling most prominent initially in ventral horn and extending throughout 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40698 17719032 50779 8254 4235 GFAP GFAP GFAP-positive 16 2.5 increase in both numbers and intensity of labeling of large GFAP-positive astrocytes in Tg-S mild attenuation of this astrocytosis in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40699 17719032 50779 11858 30830 LIN9 TGS Tg-S 19 0.0 numbers and intensity of labeling of large GFAP-positive astrocytes in Tg-S mild attenuation of this astrocytosis in the Tg-NAS condition and 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40700 17719032 50782 18723 10261 ROS1 ROS ROS 32 0.0 sharply with distance possibly consistent with a role of MN ROS in the astrocyte damage ( Fig 2 B 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40701 17719032 50784 11858 30830 LIN9 TGS Tg-S 10 0.0 There was a modest increase in NT labeling in the Tg-S conditions which however was not decreased by NAS 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40702 17719032 50787 20017 10940 SLC1A2 GLT-1 GLT-1 9 1.0 Finally there was a marked and consistent decrease in GLT-1 staining most prominent in ventral horn 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40703 17719032 50788 20017 10940 SLC1A2 GLT-1 GLT-1 4 1.0 Notably in wild-type animals GLT-1 labeling often showed a rim of particularly strong labeling immediately 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40704 17719032 50790 20017 10940 SLC1A2 GLT-1 GLT-1 2 1.0 Quantification of GLT-1 labeling in the neuropil surrounding MNs revealed a sharp decrease 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40705 17719032 50790 20017 10940 SLC1A2 GLT-1 GLT-1 14 1.0 in the neuropil surrounding MNs revealed a sharp decrease in GLT-1 labeling surrounding MNs in sham-treated transgenic animals (Tg-S) Tg-S 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40706 17719032 50790 11858 30830 LIN9 TGS Tg-S 22 0.0 in GLT-1 labeling surrounding MNs in sham-treated transgenic animals (Tg-S) Tg-S 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40707 17719032 50791 20017 10940 SLC1A2 GLT-1 GLT-1 19 1.0 NAS on NT labeling NAS completely prevented the loss of GLT-1 labeling ( Fig 4 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40708 17719032 50794 20017 10940 SLC1A2 GLT-1 GLT-1 20 1.0 Howland et al. 2002 we observe substantial loss of the GLT-1 glutamate transporter most evident in the ventral horn in close 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40709 17719032 50796 20017 10940 SLC1A2 GLT-1 GLT-1 30 1.0 preservation not only of ventral horn MNs but also of GLT-1 labeling near ventral horn MNs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40710 17719032 50797 20017 10940 SLC1A2 GLT-1 GLT-1 52 1.0 protection by NAS of MNs themselves as well as of GLT-1 levels in the adjacent astrocytes is most consistent with the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40711 17719032 50797 18723 10261 ROS1 ROS ROS 19 0.0 has direct effects on astrocytes observations that MNs are strong ROS generators in response to Ca-AMPA channel activation taken together with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40712 17719032 50798 20996 11179 SOD1 ALS ALS 8 1.4 Clues to MN loss in G93A model of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40713 17719032 50799 20996 11179 SOD1 ALS ALS 13 1.4 in the Introduction observations of impaired astrocytic glutamate transport in ALS support an excitotoxic contribution to MN damage in the disease 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40714 17719032 50800 20017 10940 SLC1A2 GLT-1 GLT-1 6 1.0 Indeed observations that substantial loss of GLT-1 preceded much of the MN loss ( Howland et al. 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40715 17719032 50802 20996 11179 SOD1 ALS ALS 46 1.4 similar MN ROS generation might contribute to astrocyte dysfunction in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40716 17719032 50802 18723 10261 ROS1 ROS ROS 9 0.0 In our prior culture studies we found that the ROS generated in MNs in response to excitotoxic activation appeared able 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40717 17719032 50802 18723 10261 ROS1 ROS ROS 38 0.0 in adjacent astrocytes leading us to suggest that similar MN ROS generation might contribute to astrocyte dysfunction in ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40718 17719032 50803 20996 11179 SOD1 ALS ALS 10 1.4 Consistent with this possibility oxidative tissue damage is prominent in ALS and progressive nitrotyrosine labeling of astrocytes as well as MNs 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40719 17719032 50803 20996 11179 SOD1 SOD1 SOD1 29 1.4 as MNs is well documented in both sporadic human and SOD1 linked forms of the disease ( Beal et al. 1997 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40720 17719032 50804 18723 10261 ROS1 ROS ROS 34 0.0 in transgenic animals reflect tissue damage resulting in part from ROS production in MNs 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40721 17719032 50808 832 549 AOC2 RAO Rao 29 0.0 forward vicious cycle which once established could be self-propagating ( Rao and Weiss 2004 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40722 17719032 50809 20996 11179 SOD1 ALS ALS 9 1.4 Such a mechanism could help to explain features of ALS including the rapid progression of the disease after onset as 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40723 17719032 50810 20996 11179 SOD1 SOD1 SOD1 3 1.4 Of note while SOD1 mutations only account for a small percentage of human ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40724 17719032 50810 20996 11179 SOD1 ALS ALS 13 1.4 SOD1 mutations only account for a small percentage of human ALS cases these mutations cause a disease which is virtually indistinguishable 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40725 17719032 50810 20996 11179 SOD1 ALS ALS 26 1.4 mutations cause a disease which is virtually indistinguishable from sporadic ALS (which which itself likely has multiple causes with both manifesting 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40726 17719032 50811 20996 11179 SOD1 SOD1 SOD1 21 1.4 between MNs and glia which we suggest are unique to SOD1 linked forms of disease transporter loss and oxidative tissue damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40727 17719032 50812 20996 11179 SOD1 ALS ALS 6 1.4 Thus it seems likely that in ALS a spectrum of inciting insults can converge into a final 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40728 17719032 50814 20996 11179 SOD1 SOD1 SOD1 9 1.4 It has become increasingly clear that MN degeneration in SOD1 linked models of ALS is non-cell-autonomous with the genotype of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40729 17719032 50814 20996 11179 SOD1 ALS ALS 13 1.4 increasingly clear that MN degeneration in SOD1 linked models of ALS is non-cell-autonomous with the genotype of glia importantly impacting the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40730 17719032 50816 18723 10261 ROS1 ROS ROS 12 0.0 observations lend preliminary in vivo support to the idea that ROS produced in MNs in response to excitotoxic activation and mitochondrial 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40731 17719032 50819 20996 11179 SOD1 ALS ALS 29 1.4 disease our best chance for effective treatment of most sporadic ALS may be to target the mechanisms underlying disease propagation and 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40732 17719032 50821 20996 11179 SOD1 ALS ALS 10 1.4 However if we can further characterize late stage events in ALS particularly those that are components of positive feedback cycles between 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00106544267306096<>ScoreDetail__5468|IGFALS|0.000318658447934197__11179|SOD1|0.00106544267306096__ 0 0 0 0 0 40733 17719032 50824 11858 30830 LIN9 TGS Tg-S 19 0.0 WT condition in transgenic animals treated with saline infusion (Tg-S), Tg-S there is moderate MN injury characterized variably by cell shrinkage 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40734 17719032 50828 11858 30830 LIN9 TGS Tg-S 36 0.0 each condition # Indicates difference from WT indicates difference from Tg-S by two-tailed t test ( p _amp_#x3c 0.01 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40735 17719032 50830 8254 4235 GFAP GFAP GFAP 22 2.5 transgenic rats and stained for glial fibrillary acidic protein (GFAP, GFAP green and SMI-32 (red, red A 3-nitrotyrosine (B), B or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40736 17719032 50830 20017 10940 SLC1A2 GLT-1 GLT-1 35 1.0 red A 3-nitrotyrosine (B), B or the astrocytic glutamate transporter GLT-1 (green) green along with SMI-32 (red, red C 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40737 17719032 50831 8254 4235 GFAP GFAP GFAP 13 2.5 number of reactive astrocytes near transgenic MNs indicated by strong GFAP labeling 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40738 17719032 50832 18723 10261 ROS1 ROS ROS 20 0.0 with the possibility that the labeling is the result of ROS produced within MNs (the the image is shown in pseudocolor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40739 17719032 50833 20017 10940 SLC1A2 GLT-1 GLT-1 6 1.0 Finally note the rim of strong GLT-1 labeling surrounding MNs in wild-type animals and the distinct loss 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40740 17719032 50835 8254 4235 GFAP GFAP GFAP 31 2.5 30-day intrathecal infusions stained for glial fibrillary acidic protein (GFAP; GFAP 400_amp_#xd7 or for 3-nitrotyrosine (NT; NT 400_amp_#xd7 inserts 40_amp_#xd7 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40741 17719032 50836 8254 4235 GFAP GFAP GFAP-positive 7 2.5 Note the marked increase in numbers of GFAP-positive reactive astrocytes in transgenic animals (Tg-S), Tg-S the modest attenuation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40742 17719032 50836 11858 30830 LIN9 TGS Tg-S 13 0.0 in numbers of GFAP-positive reactive astrocytes in transgenic animals (Tg-S), Tg-S the modest attenuation of this astrogliosis in the presence of 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40743 17719032 50838 11858 30830 LIN9 TGS Tg-S 11 0.0 marked increase in NT labeling in the transgenic animals (Tg-S), Tg-S initially most prominent within and surrounding ventral horn MNs with 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40744 17719032 50841 8254 4235 GFAP GFAP GFAP 8 2.5 (B) B Quantification of labeling graphs show quantification of GFAP and NT labeling 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40745 17719032 50842 8254 4235 GFAP GFAP GFAP 0 2.5 GFAP labeling was quantified as the number of distinct GFAP-positive astrocytes 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40746 17719032 50842 8254 4235 GFAP GFAP GFAP-positive 9 2.5 GFAP labeling was quantified as the number of distinct GFAP-positive astrocytes per high power (400_amp_#xd7;) 400_amp_#xd7 field whereas NT staining 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40747 17719032 50842 8254 4235 GFAP GFAP GFAP 32 2.5 labeling intensity in 25-_amp_#x3bc m zones surrounding each MN (GFAP GFAP counts based upon 6 independent experiments _amp_#x3e 20 fields for 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40748 17719032 50842 11858 30830 LIN9 TGS Tg-S 44 0.0 based upon 6 independent experiments _amp_#x3e 20 fields for WT Tg-S and Tg-NAS conditions 3 experiments 12 fields for Tg-ES NT 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40749 17719032 50842 11858 30830 LIN9 TGS Tg-S 71 0.0 3 independent experiments _amp_#x3e 70 surround regions for WT and Tg-S conditions 3 animals _amp_#x3e 70 regions for Tg-ES condition # 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40750 17719032 50842 11858 30830 LIN9 TGS Tg-S 89 0.0 Tg-ES condition # indicates difference from WT indicates difference from Tg-S by two-tailed t test ( p _amp_#x3c 0.01 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40751 17719032 50843 20017 10940 SLC1A2 GLT-1 GLT-1 3 1.0 Fig 4._amp_#xa0 Loss of GLT-1 in ventral horn astrocytes of G93A rats and preservation by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40752 17719032 50844 20017 10940 SLC1A2 GLT-1 GLT-1 1 1.0 (A) A GLT-1 immunofluorescence photomicrographs show the ventral horn region of lumbar spinal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40753 17719032 50844 20017 10940 SLC1A2 GLT-1 GLT-1 29 1.0 (upon upon termination of the 30-day intrathecal infusions stained for GLT-1 (40, 40 400_amp_#xd7 and for SMI-32 (right, right 400_amp_#xd7 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40754 17719032 50845 20017 10940 SLC1A2 GLT-1 GLT-1 3 1.0 Note the strong GLT-1 labeling surrounding MNs and throughout ventral horn MN clusters in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40755 17719032 50845 11858 30830 LIN9 TGS Tg-S 36 0.0 with preservation of dorsal horn labeling in transgenic animals (Tg-S) Tg-S 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40756 17719032 50847 20017 10940 SLC1A2 GLT-1 GLT-1 11 1.0 show clusters of ventral horn motor neurons with strong astrocytic GLT-1 labeling arrowhead shows persistent strong GLT-1 labeling in dorsal horn 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40757 17719032 50847 20017 10940 SLC1A2 GLT-1 GLT-1 17 1.0 neurons with strong astrocytic GLT-1 labeling arrowhead shows persistent strong GLT-1 labeling in dorsal horn of untreated transgenic animals 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40758 17719032 50849 20017 10940 SLC1A2 GLT-1 GLT-1 8 1.0 (B) B Quantification of labeling graph shown quantification of GLT-1 labeling in 5-_amp_#x3bc m zones surrounding each MN (compiled compiled 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40759 17719032 50849 11858 30830 LIN9 TGS Tg-S 27 0.0 from 4 independent experiments _amp_#x3e 100 surround regions for WT Tg-S and Tg-NAS conditions 3 animals _amp_#x3e 60 regions for Tg-ES 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 40760 17719032 50849 11858 30830 LIN9 TGS Tg-S 47 0.0 Tg-ES condition # Indicates difference from WT indicates difference from Tg-S by two-tailed t test ( p _amp_#x3c 0.01 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 36239 17937892 44757 19981 14929 SIRT1 SIRT1 SIRT1 0 1.0 [SIRT1/PGC-1: SIRT1 PGC-1 a neuroprotective axis 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 36240 17937892 44757 17035 9237 PPARGC1A PGC1 PGC-1 0 2.1 [SIRT1/PGC-1: SIRT1 PGC-1 a neuroprotective axis 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 36241 17937892 44760 19981 14929 SIRT1 SIRT1 SIRT1 10 1.0 it has been recently demonstrated that activation of the SIRT1/PGC-1 SIRT1 PGC-1 pathway in a metabolic context promotes mitochondrial function we 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 36242 17937892 44760 17035 9237 PPARGC1A PGC1 PGC-1 10 2.1 has been recently demonstrated that activation of the SIRT1/PGC-1 SIRT1 PGC-1 pathway in a metabolic context promotes mitochondrial function we performed 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 36243 17937892 44761 17035 9237 PPARGC1A PGC1 PGC-1 5 2.1 Interestingly transgenic mice with impaired PGC-1 expression have neurodegenerative lesions and show behavioural abnormalities 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 36244 17937892 44762 19981 14929 SIRT1 SIRT1 SIRT1 6 1.0 As evidenced from independent investigations enhanced SIRT1 activity has been demonstrated to protect against axonal degeneration and 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 36245 17937892 44762 926 620 APP amyloid amyloid 22 1.3 protect against axonal degeneration and to decrease the accumulation of amyloid beta peptides the hallmark of Alzheimer disease in cultured murine 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 36246 17937892 44763 19981 14929 SIRT1 SIRT1 SIRT1 11 1.0 addition several studies suggest that resveratrol a specific activator of SIRT1 could have protective effects in animal models of neurodegenerative diseases 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 36247 17937892 44764 19981 14929 SIRT1 SIRT1 SIRT1 11 1.0 these results strongly suggest that the modulation of the SIRT1/PGC-1 SIRT1 PGC-1 pathway which has not been well documented in the 3 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 36248 17937892 44764 17035 9237 PPARGC1A PGC1 PGC-1 11 2.1 results strongly suggest that the modulation of the SIRT1/PGC-1 SIRT1 PGC-1 pathway which has not been well documented in the central 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37289 17956327 46598 12120 6720 LTF LTF LTF 8 0.0 For example AIH (acute acute intermittent hypoxia induces respiratory LTF (long-term long-term facilitation a form of respiratory plasticity arising largely 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37290 17956327 46599 12120 6720 LTF LTF LTF 0 0.0 LTF is a progressive augmentation of ventilation and/or and or respiratory 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37291 17956327 46600 12120 6720 LTF LTF LTF 0 0.0 LTF is observed in multiple respiratory motor outputs including phrenic inspiratory 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37292 17956327 46601 12120 6720 LTF LTF LTF 3 0.0 The magnitude of LTF depends on age gender and genetics 7-9 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37293 17956327 46602 12120 6720 LTF LTF LTF 5 0.0 A fundamental property of respiratory LTF is that it is pattern-sensitive and is elicited by intermittent 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37294 17956327 46603 12120 6720 LTF LTF LTF 19 0.0 long-term potentiation and 5-HT (5-hydroxytryptamine)-dependent 5-hydroxytryptamine -dependent intermediate-term facilitation or LTF in Aplysia 12 13 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37295 17956327 46604 12120 6720 LTF LTF LTF 5 0.0 Although the functional significance of LTF remains uncertain postulated roles include the stabilization of breathing during 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37296 17956327 46605 12120 6720 LTF LTF LTF 9 0.0 Regardless of its physiological relevance the capacity to express LTF may be harnessed as a therapeutic approach to multiple clinical 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37297 17956327 46606 12120 6720 LTF LTF LTF 10 0.0 A detailed understanding of the cellular and synaptic mechanisms of LTF may provide the rationale for new pharmacological approaches in the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37298 17956327 46607 12120 6720 LTF LTF LTF 21 0.0 the cellular/synaptic cellular synaptic mechanisms that underlie pattern-sensitivity of respiratory LTF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37299 17956327 46608 12120 6720 LTF LTF LTF 23 0.0 yield valuable insights concerning the mechanisms giving rise to respiratory LTF and these concepts may pertain to other forms of pattern-sensitive 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37300 17956327 46609 12120 6720 LTF LTF LTF 5 0.0 Cellular/synaptic Cellular synaptic mechanisms of pLTF (phrenic phrenic LTF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37301 17956327 46610 12120 6720 LTF LTF LTF 7 0.0 Our understanding of the cellular/synaptic cellular synaptic mechanisms of LTF has increased dramatically in recent years particularly for LTF in 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37302 17956327 46610 12120 6720 LTF LTF LTF 16 0.0 of LTF has increased dramatically in recent years particularly for LTF in phrenic motor output (pLTF) pLTF pLTF requires 5-HT 6 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37303 17956327 46612 12120 6720 LTF LTF LTF 15 0.0 5-HT receptor antagonists attenuate pLTF without any effect on hypoglossal LTF suggesting that the relevant 5-HT receptors for pLTF are located 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37304 17956327 46614 12120 6720 LTF LTF LTF 8 0.0 Similar localized mechanisms may give rise to hypoglossal LTF since 5-HT 2A receptors are localized to hypoglossal motor neurons 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37305 17956327 46614 12120 6720 LTF LTF LTF 30 0.0 neurons 20 5-HT 2A receptor activation is necessary for hypoglossal LTF 15 and episodic 5-HT 2 receptor activation elicits hypoglossal LTF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37306 17956327 46614 12120 6720 LTF LTF LTF 42 0.0 LTF 15 and episodic 5-HT 2 receptor activation elicits hypoglossal LTF in in vitro brainstem slice preparations via post-synaptic mechanisms 11 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37307 17956327 46615 1624 1033 BDNF BDNF BDNF 5 4.2 New synthesis and release of BDNF (brain-derived brain-derived neurotrophic factor is necessary and sufficient for pLTF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37308 17956327 46616 1624 1033 BDNF BDNF BDNF 2 4.2 AIH increases BDNF protein levels near phrenic motor neurons and this increase correlates 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37309 17956327 46617 1624 1033 BDNF BDNF BDNF 4 4.2 The 5-HT-dependent increase in BDNF synthesis following AIH is necessary for pLTF expression since translational 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37310 17956327 46617 1624 1033 BDNF BDNF BDNF 17 4.2 AIH is necessary for pLTF expression since translational inhibition of BDNF mRNA with siRNAs (small small interfering RNAs blocks both increased 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37311 17956327 46617 1624 1033 BDNF BDNF BDNF 27 4.2 mRNA with siRNAs (small small interfering RNAs blocks both increased BDNF protein levels and pLTF receptor tyrosine kinase inhibitors also block 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37312 17956327 46618 1624 1033 BDNF BDNF BDNF 0 4.2 BDNF is sufficient to elicit pLTF since localized application of BDNF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37313 17956327 46618 1624 1033 BDNF BDNF BDNF 10 4.2 BDNF is sufficient to elicit pLTF since localized application of BDNF protein near phrenic motor neurons elicits long-lasting phrenic motor facilitation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37314 17956327 46620 1624 1033 BDNF BDNF BDNF 10 4.2 (protein protein kinase C activation stimulating new protein synthesis including BDNF 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37315 17956327 46621 1624 1033 BDNF BDNF BDNF 1 4.2 Released BDNF then activates its high-affinity receptor TrkB (tropomyosin tropomyosin receptor kinase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37316 17956327 46621 14739 8032 NTRK2 TRKB TrkB 7 1.9 Released BDNF then activates its high-affinity receptor TrkB (tropomyosin tropomyosin receptor kinase B resulting in the phosphorylation of 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37317 17956327 46621 12337 6871 MAPK1 ERK ERK 17 0.9 (tropomyosin tropomyosin receptor kinase B resulting in the phosphorylation of ERK (extracellular-signal-regulated extracellular-signal-regulated kinase MAPKs (mitogen-activated mitogen-activated protein kinases and Akt 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.000960571983559348<>ScoreDetail__3393|EPHB2|0.000539444221768835__6871|MAPK1|0.000960571983559348__ 0 0 0 0 0 37318 17956327 46621 12337 6871 MAPK1 MAPK MAPKs 20 0.9 B resulting in the phosphorylation of ERK (extracellular-signal-regulated extracellular-signal-regulated kinase MAPKs (mitogen-activated mitogen-activated protein kinases and Akt also called PKB (protein 13 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37319 17956327 46621 543 391 AKT1 AKT Akt 25 0.8 ERK (extracellular-signal-regulated extracellular-signal-regulated kinase MAPKs (mitogen-activated mitogen-activated protein kinases and Akt also called PKB (protein protein kinase B 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37320 17956327 46621 543 391 AKT1 PKB PKB 28 0.8 kinase MAPKs (mitogen-activated mitogen-activated protein kinases and Akt also called PKB (protein protein kinase B 1 JUMiner_v2.2 1 0 0 2 9612 TotalCon:2<>391|AKT1|207|Complete__9612|PTK2B|2185|Complete__<>AvaiableGeneRif=2<>BEST:9612|PTK2B|0.000805308234644594<>ScoreDetail__391|AKT1|0.00079879496229174__9612|PTK2B|0.000805308234644594__ 0 0 0 0 0 37321 17956327 46625 18723 10261 ROS1 ROS ROS 0 0.9 ROS (reactive reactive oxygen species are also necessary for pLTF following 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37322 17956327 46626 18723 10261 ROS1 ROS ROS 1 0.9 Since ROS inhibit many protein phosphatases we hypothesize that ROS generated during 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37323 17956327 46626 18723 10261 ROS1 ROS ROS 9 0.9 Since ROS inhibit many protein phosphatases we hypothesize that ROS generated during AIH inhibit okadaic acid-sensitive protein phosphatases thereby relieving 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37324 17956327 46627 18723 10261 ROS1 ROS ROS 15 0.9 single sustained hypoxic exposure does not generate similar amounts of ROS and that the subsequent lack of phosphatase inhibition disenables pLTF 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37325 17956327 46628 18723 10261 ROS1 ROS ROS-phosphatase 1 0.0 Thus ROS-phosphatase interactions may be a major determinant of pattern-sensitivity in respiratory 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37326 17956327 46628 12120 6720 LTF LTF LTF 12 0.0 interactions may be a major determinant of pattern-sensitivity in respiratory LTF and quite possibly other important models of synaptic plasticity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37327 17956327 46634 12120 6720 LTF LTF LTF 6 0.0 For example 5-HT-induced intermediate-term facilitation and LTF in Aplysia which are normally elicited only by three to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37328 17956327 46641 12337 6871 MAPK1 ERK ERK 17 0.9 phosphatases that may play a role in neural plasticity including ERK and the serine/threonine serine threonine protein phosphatases 1 2A and 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.000960571983559348<>ScoreDetail__3393|EPHB2|0.000539444221768835__6871|MAPK1|0.000960571983559348__ 0 0 0 0 0 37329 17956327 46643 12337 6871 MAPK1 ERK ERK 22 0.9 is necessary for pLTF 42 and activated forms of both ERK and PKB (Akt) Akt are increased in the ventral cervical 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.000960571983559348<>ScoreDetail__3393|EPHB2|0.000539444221768835__6871|MAPK1|0.000960571983559348__ 0 0 0 0 0 37330 17956327 46643 543 391 AKT1 PKB PKB 24 0.8 for pLTF 42 and activated forms of both ERK and PKB (Akt) Akt are increased in the ventral cervical spinal cord 1 JUMiner_v2.2 1 0 0 2 9612 TotalCon:2<>391|AKT1|207|Complete__9612|PTK2B|2185|Complete__<>AvaiableGeneRif=2<>BEST:9612|PTK2B|0.000805308234644594<>ScoreDetail__391|AKT1|0.00079879496229174__9612|PTK2B|0.000805308234644594__ 0 0 0 0 0 37331 17956327 46643 543 391 AKT1 AKT Akt 25 0.8 42 and activated forms of both ERK and PKB (Akt) Akt are increased in the ventral cervical spinal cord following intermittent 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37332 17956327 46648 18723 10261 ROS1 ROS ROS 14 0.9 the pattern-sensitivity of pLTF to hypoxia is differential formation of ROS which may lead to differential inhibition of okadaic acid-sensitive protein 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37333 17956327 46649 18723 10261 ROS1 ROS ROS 2 0.9 Role of ROS in pLTF 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37334 17956327 46650 18723 10261 ROS1 ROS ROS 0 0.9 ROS such as superoxide anion H 2 O 2 and hydroxyl 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37335 17956327 46651 18723 10261 ROS1 ROS ROS 0 0.9 ROS are continuously generated in cells through enzymatic (e.g e.g NADPH 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37336 17956327 46652 18723 10261 ROS1 ROS ROS 16 0.9 utilize a variety of mechanisms to regulate intracellular and extracellular ROS levels 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37337 17956327 46654 20996 11179 SOD1 SOD SOD 0 0.9 SOD (superoxide superoxide dismutase prevent excessive ROS accumulation 46 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37338 17956327 46654 18723 10261 ROS1 ROS ROS 5 0.9 SOD (superoxide superoxide dismutase prevent excessive ROS accumulation 46 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37339 17956327 46655 18723 10261 ROS1 ROS ROS 6 0.9 Oxidation of protein amino acids by ROS (e.g e.g cysteine and tyrosine alters their function in a 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37340 17956327 46656 18723 10261 ROS1 ROS ROS 1 0.9 Although ROS are often thought of as detrimental to cellular processes recent 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37341 17956327 46656 18723 10261 ROS1 ROS ROS 17 0.9 detrimental to cellular processes recent developments have made clear that ROS play critical roles in important cell signalling events and are 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37342 17956327 46657 18723 10261 ROS1 ROS ROS 2 0.9 For example ROS are necessary for hippocampal long-term potentiation 48 and sensory facilitation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37343 17956327 46658 18723 10261 ROS1 ROS ROS 4 0.9 AIH-induced pLTF also requires ROS since pre-treatment with a SOD mimetic abolishes pLTF 23 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37344 17956327 46658 20996 11179 SOD1 SOD SOD 9 0.9 AIH-induced pLTF also requires ROS since pre-treatment with a SOD mimetic abolishes pLTF 23 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37345 17956327 46659 20996 11179 SOD1 SOD SOD 16 0.9 following AIH although changes in superoxide anion levels (e.g e.g SOD mimetic can disrupt levels of other ROS species such as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37346 17956327 46659 18723 10261 ROS1 ROS ROS 23 0.9 levels (e.g e.g SOD mimetic can disrupt levels of other ROS species such as H 2 O 2 and hydroxyl radical 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37347 17956327 46659 12120 6720 LTF LTF LTF 6 0.0 Thus superoxide anions are necessary for LTF following AIH although changes in superoxide anion levels (e.g e.g 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37348 17956327 46660 18723 10261 ROS1 ROS ROS 5 0.9 NADPH oxidase may generate the ROS necessary for pLTF since apocynin an NADPH oxidase (and and 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37349 17956327 46661 18723 10261 ROS1 ROS ROS 4 0.9 Given their short half-life ROS are most likely to be generated locally within close proximity 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37350 17956327 46663 18723 10261 ROS1 ROS ROS 0 0.9 ROS may regulate neural plasticity by altering protein kinase and phosphatase 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37351 17956327 46664 18723 10261 ROS1 ROS ROS 13 0.9 including PKC which is necessary for pLTF are activated by ROS 42 46 49 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37352 17956327 46665 18723 10261 ROS1 ROS ROS 7 0.9 Protein kinase activation is enhanced indirectly by ROS inhibition of protein phosphatase activity including those sensitive to okadaic 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37353 17956327 46667 18723 10261 ROS1 ROS ROS 9 0.9 Growth factor receptors which are receptor tyrosine kinases generate ROS when activated by their endogenous ligand 46 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37354 17956327 46668 18723 10261 ROS1 ROS ROS 2 0.9 The resulting ROS inhibit protein tyrosine phosphatases enabling their receptor tyrosine kinase activity 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37355 17956327 46670 18723 10261 ROS1 ROS ROS 17 0.9 hypothesis that the pattern of hypoxia has differential effects on ROS formation 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37356 17956327 46674 18723 10261 ROS1 ROS ROS 7 0.9 One observation supporting the hypothesis that increased ROS production is critical for pLTF is that spinal phosphatase inhibition 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37357 17956327 46674 20996 11179 SOD1 SOD SOD 28 0.9 with okadaic acid restores pLTF in animals pre-treated with a SOD mimetic (P.M P.M MacFarlane and G.S Mitchell unpublished work but 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37358 17956327 46675 18723 10261 ROS1 ROS ROS 5 0.9 Collectively our observations suggest that ROS generation during or following AIH is necessary for pLTF via 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37359 17956327 46677 12120 6720 LTF LTF LTF 12 0.0 being made towards understanding cellular/synaptic cellular synaptic mechanisms of respiratory LTF considerable work remains before we will have a full comprehension 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37360 17956327 46680 18723 10261 ROS1 ROS ROS 9 0.9 The work described in the present review implicates differential ROS formation between intermittent and sustained hypoxia as a major factor 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37361 17956327 46681 18723 10261 ROS1 ROS ROS 3 0.9 The most likely ROS targets are okadaic acid-sensitive protein phosphatases in or near phrenic 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37362 17956327 46685 1624 1033 BDNF BDNF BDNF 5 4.2 Key words brain-derived neurotrophic factor (BDNF), BDNF 5-hydroxytryptamine (5-HT), 5-HT long-term facilitation pattern-sensitivity phosphorylation plasticity 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37363 17956327 46686 1624 1033 BDNF BDNF BDNF 6 4.2 Abbreviations used AIH acute intermittent hypoxia BDNF brain-derived neurotrophic factor ERK extracellular-signal-regulated kinase 5-HT 5-hydroxytryptamine LTF long-term 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37364 17956327 46686 12337 6871 MAPK1 ERK ERK 10 0.9 Abbreviations used AIH acute intermittent hypoxia BDNF brain-derived neurotrophic factor ERK extracellular-signal-regulated kinase 5-HT 5-hydroxytryptamine LTF long-term facilitation pLTF phrenic LTF 1 JUMiner_v2.2 1 0 0 2 6871 TotalCon:2<>3393|EPHB2|2048|Complete__6871|MAPK1|5594|Complete__<>AvaiableGeneRif=2<>BEST:6871|MAPK1|0.000960571983559348<>ScoreDetail__3393|EPHB2|0.000539444221768835__6871|MAPK1|0.000960571983559348__ 0 0 0 0 0 37365 17956327 46686 543 391 AKT1 PKB PKB 25 0.8 LTF long-term facilitation pLTF phrenic LTF PKA protein kinase A PKB protein kinase B PKC protein kinase C ROS reactive oxygen 1 JUMiner_v2.2 1 0 0 2 9612 TotalCon:2<>391|AKT1|207|Complete__9612|PTK2B|2185|Complete__<>AvaiableGeneRif=2<>BEST:9612|PTK2B|0.000805308234644594<>ScoreDetail__391|AKT1|0.00079879496229174__9612|PTK2B|0.000805308234644594__ 0 0 0 0 0 37366 17956327 46686 18723 10261 ROS1 ROS ROS 33 0.9 kinase A PKB protein kinase B PKC protein kinase C ROS reactive oxygen species SOD superoxide dismutase TrkB tropomyosin receptor kinase 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 37367 17956327 46686 20996 11179 SOD1 SOD SOD 37 0.9 kinase B PKC protein kinase C ROS reactive oxygen species SOD superoxide dismutase TrkB tropomyosin receptor kinase B 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37368 17956327 46686 14739 8032 NTRK2 TRKB TrkB 40 1.9 protein kinase C ROS reactive oxygen species SOD superoxide dismutase TrkB tropomyosin receptor kinase B 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37369 17956327 46686 12120 6720 LTF LTF LTF 15 0.0 hypoxia BDNF brain-derived neurotrophic factor ERK extracellular-signal-regulated kinase 5-HT 5-hydroxytryptamine LTF long-term facilitation pLTF phrenic LTF PKA protein kinase A PKB 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 37370 17956327 46686 12120 6720 LTF LTF LTF 20 0.0 ERK extracellular-signal-regulated kinase 5-HT 5-hydroxytryptamine LTF long-term facilitation pLTF phrenic LTF PKA protein kinase A PKB protein kinase B PKC protein 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 39544 17987632 49319 20996 11179 SOD1 SOD1 SOD1 7 1.9 In AD and PD patients superoxide dismutase (SOD1) SOD1 was also indicated as a major target of oxidative damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 39545 17987632 49320 20996 11179 SOD1 SOD1 SOD1 9 1.9 In particular in brain tissue of these patients different SOD1 isoforms have been identified although their functional role still remains 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 39546 17987632 49321 20996 11179 SOD1 SOD1 SOD1 8 1.9 In the light of the possibility that different SOD1 entities could be expressed also in other neurodegenerative disorders as 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 39547 17987632 49321 20996 11179 SOD1 ALS ALS 34 1.4 AD and PD we have investigated amyotrophic lateral sclerosis (ALS) ALS using human neuroblastoma SH-SY5Y cells with mutated SOD1 gene H46R 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00240429827503436<>ScoreDetail__5468|IGFALS|0.000411753696425229__11179|SOD1|0.00240429827503436__ 0 0 0 0 0 39548 17987632 49321 20996 11179 SOD1 SOD1 SOD1 42 1.9 sclerosis (ALS) ALS using human neuroblastoma SH-SY5Y cells with mutated SOD1 gene H46R as cellular model 2-DE using a narrow-range IPG 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 39549 17987632 49321 20996 11179 SOD1 SOD1 SOD1 70 1.9 linear 15% SDS-PAGE in the second allowed to separate different SOD1 spots 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 39550 17987632 49323 20996 11179 SOD1 SOD1 SOD1 10 1.9 This is the first report in which the presence of SOD1 (iso) iso forms in a cellular model of ALS has 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 39551 17987632 49323 20996 11179 SOD1 ALS ALS 18 1.4 of SOD1 (iso) iso forms in a cellular model of ALS has been evidenced 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00240429827503436<>ScoreDetail__5468|IGFALS|0.000411753696425229__11179|SOD1|0.00240429827503436__ 0 0 0 0 0 22656 18210200 26921 9038 4827 HBB hemoglobin hemoglobin 13 1.0 also been used to produce nanotubes with glucose oxidase and hemoglobin (Hou Hou et al 2005b 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 22657 18210200 26962 18723 10261 ROS1 ROS ROS 47 0.0 nanomaterials having antioxidant properties to eliminate reactive oxygen species (ROS) ROS in the brain (Blass Blass 2003 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 22658 18210200 26963 18723 10261 ROS1 ROS ROS 25 0.0 O 3 can act as direct antioxidants and inhibit the ROS production pathway 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 22659 18210200 26980 6256 21317 DYM SMC SMC 19 0.0 decrease their toxicity with respect to smooth muscle cells (SMC), SMC as measured by SMC growth inhibition (Raja Raja et al 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 22660 18210200 26980 6256 21317 DYM SMC SMC 23 0.0 respect to smooth muscle cells (SMC), SMC as measured by SMC growth inhibition (Raja Raja et al 2007 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 22661 18210200 27007 21257 9361 SRGN PPG PPG 11 0.0 of hydrophobic polymer blocks e.g. poly(propylene poly propylene glycol (PPG), PPG poly( poly d l -lactide poly(caprolactone), poly caprolactone etc. and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 22662 18210200 27014 21257 9361 SRGN PPG PPG 10 0.0 Pluronic block copolymers contain two hydrophilic PEG and one hydrophobic PPG blocks (PEG-PPG-PEG) PEG-PPG-PEG 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 22663 18210200 27015 16478 8909 PGP Pgp Pgp 22 0.0 and to inhibit a drug efflux transport protein P-glycoprotein (Pgp) Pgp that severely restricts transport of many drugs to the brain 1 JUMiner_v2.2 1 0 0 2 8909 TotalCon:2<>8909|PGP|5240|Complete__13568|PGPEP1|54858|Complete__<>AvaiableGeneRif=2<>BEST:8909|PGP|0.000363669424493136<>ScoreDetail__13568|PGPEP1|0.000158522569650854__8909|PGP|0.000363669424493136__ 0 0 0 0 0 22664 18210200 27015 16478 8909 PGP Pgp Pgp-dependent 45 0.0 Batrakova et al 1998 2001 As a result of formulating Pgp-dependent drugs with Pluronic the bioavailability of such drugs to the 1 JUMiner_v2.2 1 0 0 2 8909 TotalCon:2<>8909|PGP|5240|Complete__13568|PGPEP1|54858|Complete__<>AvaiableGeneRif=2<>BEST:8909|PGP|0.000363669424493136<>ScoreDetail__13568|PGPEP1|0.000158522569650854__8909|PGP|0.000363669424493136__ 0 0 0 0 0 22665 18210200 27051 122 80 ABP1 KAO Kao 39 0.0 Wang et al 2005 Tsai et al 2006 Yang and Kao 2006 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 22666 18210200 27077 3865 1678 CD4 CD4 CD4 30 0.6 plasma lymph nodes spleen liver and lung as well as CD4 T-cell protection 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 22667 18210200 27081 18723 10261 ROS1 ROS ROS 19 0.0 of catalase nanozyme to the brain to mitigate production of ROS and induce neuroprotection (Batrakova Batrakova et al 2007 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 22668 18210200 27095 24109 19667 WDR20 DMR DMR 27 0.0 NS051335 RO1 CA89225 and RO1 CA116591 the National Science Foundation DMR 0513699 and the US Department of Defense USAMRMC 06108004 (all 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23638 18219386 28331 20996 11179 SOD1 SOD1 SOD1 5 2.5 Abstract Mutation in superoxide dismutase_amp_#x02013 1 (SOD1) SOD1 causes the inherited degenerative neurological disease familial amyotrophic lateral sclerosis 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23639 18219386 28331 20996 11179 SOD1 ALS ALS 16 1.7 the inherited degenerative neurological disease familial amyotrophic lateral sclerosis (ALS), ALS a non_amp_#x02013 cell-autonomous disease mutant SOD1 synthesis in motor neurons 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23640 18219386 28331 20996 11179 SOD1 SOD1 SOD1 21 2.5 amyotrophic lateral sclerosis (ALS), ALS a non_amp_#x02013 cell-autonomous disease mutant SOD1 synthesis in motor neurons and microglia drives disease onset and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23641 18219386 28332 20996 11179 SOD1 SOD1 SOD1 12 2.5 this issue of the JCI Harraz and colleagues demonstrate that SOD1 mutants expressed in human cell lines directly stimulate NADPH oxidase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23642 18219386 28332 17864 9801 RAC1 RAC1 Rac1 27 1.0 lines directly stimulate NADPH oxidase (Nox) Nox by binding to Rac1 resulting in overproduction of damaging ROS (see see the related 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23643 18219386 28332 18723 10261 ROS1 ROS ROS 33 0.0 Nox by binding to Rac1 resulting in overproduction of damaging ROS (see see the related article beginning on page 659 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23644 18219386 28333 20996 11179 SOD1 ALS ALS 18 1.7 inhibitor apocynin or by elimination of Nox extends survival in ALS mice reviving the proposal that ROS mediate ALS pathogenesis but 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23645 18219386 28333 20996 11179 SOD1 ALS ALS 26 1.7 survival in ALS mice reviving the proposal that ROS mediate ALS pathogenesis but with a new twist it_amp_#x02019 s ROS produced 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23646 18219386 28333 18723 10261 ROS1 ROS ROS 1 0.0 Diminishing ROS by treatment with the microglial Nox inhibitor apocynin or by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23647 18219386 28333 18723 10261 ROS1 ROS ROS 24 0.1 Nox extends survival in ALS mice reviving the proposal that ROS mediate ALS pathogenesis but with a new twist it_amp_#x02019 s 6 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 23648 18219386 28333 18723 10261 ROS1 ROS ROS 34 0.0 mediate ALS pathogenesis but with a new twist it_amp_#x02019 s ROS produced by microglia 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23649 18219386 28334 20996 11179 SOD1 ALS ALS 4 1.7 Footnotes Nonstandard abbreviations used ALS amyotrophic lateral sclerosis Nox NADPH oxidase O 2 _amp_#x02022 _amp_#x02013 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23650 18219386 28334 20996 11179 SOD1 SOD1 SOD1 16 2.5 lateral sclerosis Nox NADPH oxidase O 2 _amp_#x02022 _amp_#x02013 superoxide SOD1 superoxide dismutase_amp_#x02013 1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23651 18219386 28339 5281 2578 CYBB NOX2 Nox2 7 3.5 Figure 1 Production of ROS by microglial Nox2 during inflammation is amplified by mutant SOD1 binding to Rac1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23652 18219386 28339 20996 11179 SOD1 SOD1 SOD1 14 2.5 ROS by microglial Nox2 during inflammation is amplified by mutant SOD1 binding to Rac1 in ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23653 18219386 28339 17864 9801 RAC1 RAC1 Rac1 17 1.0 Nox2 during inflammation is amplified by mutant SOD1 binding to Rac1 in ALS 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23654 18219386 28339 20996 11179 SOD1 ALS ALS 19 1.7 inflammation is amplified by mutant SOD1 binding to Rac1 in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23655 18219386 28339 18723 10261 ROS1 ROS ROS 4 0.0 Figure 1 Production of ROS by microglial Nox2 during inflammation is amplified by mutant SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23656 18219386 28340 20996 11179 SOD1 ALS ALS 3 1.7 Amyotrophic lateral sclerosis (ALS) ALS is the most common adult-onset motor neuron disease 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23657 18219386 28342 20996 11179 SOD1 ALS ALS 3 1.7 The majority of ALS cases are sporadic but among the familial cases of disease 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23658 18219386 28342 20996 11179 SOD1 SOD1 SOD1 20 2.5 cases of disease mutations in the superoxide dismutase_amp_#x02013 1 ( SOD1 gene are the most frequently identified 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23659 18219386 28343 20996 11179 SOD1 SOD1 SOD1 0 2.5 SOD1 catalyzes the conversion of superoxide (O2 O2 _amp_#x02022 _amp_#x02013 to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23660 18219386 28344 20996 11179 SOD1 SOD1 SOD1 1 2.5 Indeed SOD1 mimetics have been reported to slow disease progression when administered 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23661 18219386 28344 20996 11179 SOD1 ALS ALS 16 1.7 to slow disease progression when administered at disease onset in ALS mice ( 1 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23662 18219386 28346 20996 11179 SOD1 ALS ALS-like 24 1.7 in which expression of a mutant SOD1_amp_#x02013 encoding transgene recapitulates ALS-like disease including muscle denervation and atrophy glial activation and motor 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23663 18219386 28348 20996 11179 SOD1 ALS ALS 17 1.7 environment astrocytes have been linked to motor neuron degeneration in ALS because of their reduced capacity for reuptake at synapses of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23664 18219386 28351 20996 11179 SOD1 ALS ALS 13 1.7 antibiotic also capable of downregulating microglial activation increased survival in ALS mice ( 8 9 while the proinflammatory molecule LPS exacerbated 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23665 18219386 28351 24053 12728 VWS LPS LPS 24 0.0 in ALS mice ( 8 9 while the proinflammatory molecule LPS exacerbated disease ( 10 1 JUMiner_v2.2 1 0 1 1 0 TotalCon:2<>12728|VWS||No_GeneRif__6121|IRF6|3664|Complete__<>AvaiableGeneRif=1<> 0 0 0 0 0 23666 18219386 28352 20996 11179 SOD1 SOD1 SOD1 11 2.5 more compelling are data obtained by selective silencing of mutant SOD1 synthesis by microglia ( 11 or replacement of the mutant 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23667 18219386 28353 20996 11179 SOD1 SOD1 SOD1 5 2.5 Both approaches demonstrate that mutant SOD1 synthesis in inflammatory cells of the CNS directly accelerates the 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23668 18219386 28356 20996 11179 SOD1 SOD1 SOD1 5 2.5 By crossing mice expressing the SOD1 G93A mutant with mice lacking a catalytic subunit of Nox 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23669 18219386 28356 14551 7889 NOX1 NOX1 Nox1 23 1.2 of Nox (through through deletion of the gene encoding either Nox1 or Nox2 an increase in survival was seen with Nox2 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23670 18219386 28356 5281 2578 CYBB NOX2 Nox2 25 3.5 (through through deletion of the gene encoding either Nox1 or Nox2 an increase in survival was seen with Nox2 deletion proving 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23671 18219386 28356 5281 2578 CYBB NOX2 Nox2 33 3.5 Nox1 or Nox2 an increase in survival was seen with Nox2 deletion proving to be of greater benefit than Nox1 deletion 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23672 18219386 28356 14551 7889 NOX1 NOX1 Nox1 42 1.2 with Nox2 deletion proving to be of greater benefit than Nox1 deletion ( 14 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23673 18219386 28357 5281 2578 CYBB NOX2 Nox2 7 3.5 Consistent with progressive microglial activation during disease Nox2 expression was upregulated in SOD1 G93A mice ( 13 14 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23674 18219386 28357 20996 11179 SOD1 SOD1 SOD1 12 2.5 progressive microglial activation during disease Nox2 expression was upregulated in SOD1 G93A mice ( 13 14 and sporadic ALS patients ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23675 18219386 28357 20996 11179 SOD1 ALS ALS 22 1.7 upregulated in SOD1 G93A mice ( 13 14 and sporadic ALS patients ( 13 with the former leading to increased O 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23676 18219386 28360 14554 14874 NOX5 NOX5 Nox5 8 0.9 The Nox family is composed of 7 members Nox1_amp_#x02013 Nox5 Duox1 and Duox2 are distributed in a variety of tissues 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23677 18219386 28360 6192 3062 DUOX1 DUOX1 Duox1 9 0.3 The Nox family is composed of 7 members Nox1_amp_#x02013 Nox5 Duox1 and Duox2 are distributed in a variety of tissues 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23678 18219386 28360 6193 13273 DUOX2 DUOX2 DUOX2 9 0.3 The Nox family is composed of 7 members Nox1_amp_#x02013 Nox5 Duox1 and Duox2 are distributed in a variety of tissues 15 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23679 18219386 28360 6193 13273 DUOX2 DUOX2 Duox2 11 0.3 family is composed of 7 members Nox1_amp_#x02013 Nox5 Duox1 and Duox2 are distributed in a variety of tissues 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23680 18219386 28361 5281 2578 CYBB NOX2 Nox2 3 3.5 The Nox prototype Nox2 is the phagocytic Nox (also also known as gp91 phox 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23681 18219386 28362 5281 2578 CYBB NOX2 Nox2 0 3.5 Nox2 contains an NADPH-binding site a FAD-binding site and 4 heme-binding 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23682 18219386 28362 17461 9508 PSEN1 FAD FAD-binding 6 0.3 Nox2 contains an NADPH-binding site a FAD-binding site and 4 heme-binding histidines 11 JUMiner_v2.2 1 2 nadph 0 2 9508 TotalCon:3<>1101|BRCA2|675|Complete__3585|FANCD2|2177|Complete__9508|PSEN1|5663|Complete__<>AvaiableGeneRif=3<>BEST:9508|PSEN1|0.000778601243717523<>ScoreDetail__1101|BRCA2|0.000377789506977283__9508|PSEN1|0.000778601243717523__3585|FANCD2|0.000470549640936794__ 0 0 0 0 0 23683 18219386 28363 5281 2578 CYBB NOX2 Nox2 0 3.5 Nox2 is constitutively associated with the transmembrane Nox stabilizing protein p22 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23684 18219386 28363 5279 2577 CYBA p22 p22 10 0.8 Nox2 is constitutively associated with the transmembrane Nox stabilizing protein p22 phox and recruitment of the activating cytosolic components p47 phox 3 JUMiner_v2.2 1 1 UserEdit 0 2 30306 TotalCon:2<>2961|DYNC1H1|1778|Complete__30306|PHB2|11331|Complete__<>AvaiableGeneRif=2<>BEST:30306|PHB2|0.000494580658739346<>ScoreDetail__2961|DYNC1H1|0.000100178890876565__30306|PHB2|0.000494580658739346__ 1 1 6257 2961 DYNC1H1 0 23685 18219386 28363 14167 7660 NCF1 p47 p47 20 0.6 protein p22 phox and recruitment of the activating cytosolic components p47 phox p67 phox and p40 phox are needed for function 1 JUMiner_v2.2 1 1 UserEdit 0 2 9070 TotalCon:4<>10576|CLEC11A|6320|Complete__9070|PLEK|5341|Complete__15912|NSFL1C|55968|No_GeneRif__6062|ING1|3621|Complete__<>AvaiableGeneRif=3<>BEST:9070|PLEK|0.000773036487322202<>ScoreDetail__6062|ING1|0.000355697834689431__10576|CLEC11A|0.000377928949357521__9070|PLEK|0.000773036487322202__ 1 1 14167 7660 NCF1 1 UserEdit 23686 18219386 28363 14170 7661 NCF2 p67 p67 23 0.3 phox and recruitment of the activating cytosolic components p47 phox p67 phox and p40 phox are needed for function (Figure Figure 1 JUMiner_v2.2 1 1 UserEdit 0 2 16672 TotalCon:2<>1659|CD33|945|Complete__16672|METAP2|10988|Complete__<>AvaiableGeneRif=2<>BEST:16672|METAP2|0.000921097704868116<>ScoreDetail__1659|CD33|0.000843144596524802__16672|METAP2|0.000921097704868116__ 1 1 3884 1659 CD33 0 23687 18219386 28363 14171 7662 NCF4 p40 p40 27 0.6 of the activating cytosolic components p47 phox p67 phox and p40 phox are needed for function (Figure Figure 1 1 JUMiner_v2.2 1 1 UserEdit 0 2 6871 TotalCon:9<>682|ARHGEF2|9181|Complete__15531|EBNA1BP2|10969|Complete__9565|PSMD7|5713|Complete__6029|IL9|3578|Complete__6508|LANCL1|10314|No_GeneRif__6502|RPSA|3921|Complete__6871|MAPK1|5594|Complete__16896|RABEPK|10244|Complete__15979|TP63|8626|Complete__<>AvaiableGeneRif=8<>BEST:6871|MAPK1|0.000924400182496915<>ScoreDetail__15979|TP63|0.000530775128270656__16896|RABEPK|8.94454382826476e-05__6502|RPSA|0.000463233217211185__15531|EBNA1BP2|0.000825650199532132__682|ARHGEF2|0.000879294139049756__9565|PSMD7|0.000238521168753727__6029|IL9|0.000680307640076779__6871|MAPK1|0.000924400182496915__ 1 1 1013 682 ARHGEF2 0 23688 18219386 28364 14167 7660 NCF1 p47 p47 3 0.6 Upon cell activation p47 phox is phosphorylated thereby initiating translocation of the p47 phox 1 JUMiner_v2.2 1 1 UserEdit 0 2 9070 TotalCon:4<>10576|CLEC11A|6320|Complete__9070|PLEK|5341|Complete__15912|NSFL1C|55968|No_GeneRif__6062|ING1|3621|Complete__<>AvaiableGeneRif=3<>BEST:9070|PLEK|0.000773036487322202<>ScoreDetail__6062|ING1|0.000355697834689431__10576|CLEC11A|0.000377928949357521__9070|PLEK|0.000773036487322202__ 1 1 10577 6062 ING1 0 23689 18219386 28364 14167 7660 NCF1 p47 p47 12 0.6 activation p47 phox is phosphorylated thereby initiating translocation of the p47 phox /p67 p67 phox /p40 p40 phox complex to the 1 JUMiner_v2.2 1 1 UserEdit 0 2 9070 TotalCon:4<>10576|CLEC11A|6320|Complete__9070|PLEK|5341|Complete__15912|NSFL1C|55968|No_GeneRif__6062|ING1|3621|Complete__<>AvaiableGeneRif=3<>BEST:9070|PLEK|0.000773036487322202<>ScoreDetail__6062|ING1|0.000355697834689431__10576|CLEC11A|0.000377928949357521__9070|PLEK|0.000773036487322202__ 1 1 10577 6062 ING1 0 23690 18219386 28364 14170 7661 NCF2 p67 p67 14 0.3 is phosphorylated thereby initiating translocation of the p47 phox /p67 p67 phox /p40 p40 phox complex to the membrane where phosphorylated 1 JUMiner_v2.2 1 1 UserEdit 0 2 16672 TotalCon:2<>1659|CD33|945|Complete__16672|METAP2|10988|Complete__<>AvaiableGeneRif=2<>BEST:16672|METAP2|0.000921097704868116<>ScoreDetail__1659|CD33|0.000843144596524802__16672|METAP2|0.000921097704868116__ 1 1 3884 1659 CD33 0 23691 18219386 28364 14171 7662 NCF4 p40 p40 16 0.6 initiating translocation of the p47 phox /p67 p67 phox /p40 p40 phox complex to the membrane where phosphorylated p47 phox binds 1 JUMiner_v2.2 1 1 UserEdit 0 2 6871 TotalCon:9<>682|ARHGEF2|9181|Complete__15531|EBNA1BP2|10969|Complete__9565|PSMD7|5713|Complete__6029|IL9|3578|Complete__6508|LANCL1|10314|No_GeneRif__6502|RPSA|3921|Complete__6871|MAPK1|5594|Complete__16896|RABEPK|10244|Complete__15979|TP63|8626|Complete__<>AvaiableGeneRif=8<>BEST:6871|MAPK1|0.000924400182496915<>ScoreDetail__15979|TP63|0.000530775128270656__16896|RABEPK|8.94454382826476e-05__6502|RPSA|0.000463233217211185__15531|EBNA1BP2|0.000825650199532132__682|ARHGEF2|0.000879294139049756__9565|PSMD7|0.000238521168753727__6029|IL9|0.000680307640076779__6871|MAPK1|0.000924400182496915__ 1 1 1013 682 ARHGEF2 0 23692 18219386 28364 14167 7660 NCF1 p47 p47 24 0.6 phox /p40 p40 phox complex to the membrane where phosphorylated p47 phox binds to p22 phox 1 JUMiner_v2.2 1 1 UserEdit 0 2 9070 TotalCon:4<>10576|CLEC11A|6320|Complete__9070|PLEK|5341|Complete__15912|NSFL1C|55968|No_GeneRif__6062|ING1|3621|Complete__<>AvaiableGeneRif=3<>BEST:9070|PLEK|0.000773036487322202<>ScoreDetail__6062|ING1|0.000355697834689431__10576|CLEC11A|0.000377928949357521__9070|PLEK|0.000773036487322202__ 1 1 10577 6062 ING1 0 23693 18219386 28364 5279 2577 CYBA p22 p22 28 0.8 complex to the membrane where phosphorylated p47 phox binds to p22 phox 3 JUMiner_v2.2 1 1 UserEdit 0 2 30306 TotalCon:2<>2961|DYNC1H1|1778|Complete__30306|PHB2|11331|Complete__<>AvaiableGeneRif=2<>BEST:30306|PHB2|0.000494580658739346<>ScoreDetail__2961|DYNC1H1|0.000100178890876565__30306|PHB2|0.000494580658739346__ 1 1 6257 2961 DYNC1H1 0 23694 18219386 28365 18312 670 RHOD Rho Rho 9 0.3 Another level of regulation comes from members of the Rho family of small GTPases including the Rac family 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23695 18219386 28365 543 391 AKT1 RAC Rac 16 0.0 members of the Rho family of small GTPases including the Rac family 2 JUMiner_v2.2 1 1 rac; 0 0 0 0 0 0 0 0 23696 18219386 28366 543 391 AKT1 RAC Rac 3 0.0 Members of the Rac family are not strictly NADPH subunits as they regulate other 2 JUMiner_v2.2 1 1 rac; 0 0 0 0 0 0 0 0 23697 18219386 28367 14167 7660 NCF1 p47 p47 8 0.6 Rac acts to coordinate the translocation of the p47 phox /p67 p67 phox /p40 p40 phox complex and is 1 JUMiner_v2.2 1 1 UserEdit 0 2 9070 TotalCon:4<>10576|CLEC11A|6320|Complete__9070|PLEK|5341|Complete__15912|NSFL1C|55968|No_GeneRif__6062|ING1|3621|Complete__<>AvaiableGeneRif=3<>BEST:9070|PLEK|0.000773036487322202<>ScoreDetail__6062|ING1|0.000355697834689431__10576|CLEC11A|0.000377928949357521__9070|PLEK|0.000773036487322202__ 1 1 10577 6062 ING1 0 23698 18219386 28367 14170 7661 NCF2 p67 p67 10 0.3 acts to coordinate the translocation of the p47 phox /p67 p67 phox /p40 p40 phox complex and is active only when 1 JUMiner_v2.2 1 1 UserEdit 0 2 16672 TotalCon:2<>1659|CD33|945|Complete__16672|METAP2|10988|Complete__<>AvaiableGeneRif=2<>BEST:16672|METAP2|0.000921097704868116<>ScoreDetail__1659|CD33|0.000843144596524802__16672|METAP2|0.000921097704868116__ 1 1 3884 1659 CD33 0 23699 18219386 28367 14171 7662 NCF4 p40 p40 12 0.6 the translocation of the p47 phox /p67 p67 phox /p40 p40 phox complex and is active only when bound to GTP 1 JUMiner_v2.2 1 1 UserEdit 0 2 6871 TotalCon:9<>682|ARHGEF2|9181|Complete__15531|EBNA1BP2|10969|Complete__9565|PSMD7|5713|Complete__6029|IL9|3578|Complete__6508|LANCL1|10314|No_GeneRif__6502|RPSA|3921|Complete__6871|MAPK1|5594|Complete__16896|RABEPK|10244|Complete__15979|TP63|8626|Complete__<>AvaiableGeneRif=8<>BEST:6871|MAPK1|0.000924400182496915<>ScoreDetail__15979|TP63|0.000530775128270656__16896|RABEPK|8.94454382826476e-05__6502|RPSA|0.000463233217211185__15531|EBNA1BP2|0.000825650199532132__682|ARHGEF2|0.000879294139049756__9565|PSMD7|0.000238521168753727__6029|IL9|0.000680307640076779__6871|MAPK1|0.000924400182496915__ 1 1 1013 682 ARHGEF2 0 23700 18219386 28367 13812 32159 MTG1 GTP GTP 22 0.3 p40 phox complex and is active only when bound to GTP not when bound to GDP 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 23701 18219386 28367 543 391 AKT1 RAC Rac 0 0.0 Rac acts to coordinate the translocation of the p47 phox /p67 2 JUMiner_v2.2 1 1 rac; 0 0 0 0 0 0 0 0 23702 18219386 28368 13812 32159 MTG1 GTP GTP 10 0.3 The release of GDP to enable a new round of GTP loading is catalyzed by guanine nucleotide exchange factors 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 23703 18219386 28369 13812 32159 MTG1 GTP GTP 17 0.3 proteins which stimulate the intrinsic ability of Rac to hydrolyze GTP to GDP 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 23704 18219386 28369 543 391 AKT1 RAC Rac 2 0.0 Inactivation of Rac is mediated via GTPase-activating proteins which stimulate the intrinsic ability 2 JUMiner_v2.2 1 1 rac; 0 0 0 0 0 0 0 0 23705 18219386 28369 543 391 AKT1 RAC Rac 14 0.0 mediated via GTPase-activating proteins which stimulate the intrinsic ability of Rac to hydrolyze GTP to GDP 2 JUMiner_v2.2 1 1 rac; 0 0 0 0 0 0 0 0 23706 18219386 28370 14551 7889 NOX1 NOX1 Nox1 11 1.2 all Nox family members require the same interacting partners but Nox1 and Nox2 are both p47 phox and Rac dependent ( 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23707 18219386 28370 5281 2578 CYBB NOX2 NOX2 11 3.5 all Nox family members require the same interacting partners but Nox1 and Nox2 are both p47 phox and Rac dependent ( 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23708 18219386 28370 5281 2578 CYBB NOX2 Nox2 13 3.5 family members require the same interacting partners but Nox1 and Nox2 are both p47 phox and Rac dependent ( 15 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23709 18219386 28370 14167 7660 NCF1 p47 p47 16 0.6 the same interacting partners but Nox1 and Nox2 are both p47 phox and Rac dependent ( 15 1 JUMiner_v2.2 1 1 UserEdit 0 2 9070 TotalCon:4<>10576|CLEC11A|6320|Complete__9070|PLEK|5341|Complete__15912|NSFL1C|55968|No_GeneRif__6062|ING1|3621|Complete__<>AvaiableGeneRif=3<>BEST:9070|PLEK|0.000773036487322202<>ScoreDetail__6062|ING1|0.000355697834689431__10576|CLEC11A|0.000377928949357521__9070|PLEK|0.000773036487322202__ 1 1 10577 6062 ING1 0 23710 18219386 28370 543 391 AKT1 RAC Rac 19 0.0 partners but Nox1 and Nox2 are both p47 phox and Rac dependent ( 15 2 JUMiner_v2.2 1 1 rac; 0 0 0 0 0 0 0 0 23711 18219386 28373 20996 11179 SOD1 ALS ALS 8 1.7 How does Nox participate in the pathogenesis of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23712 18219386 28374 20996 11179 SOD1 ALS ALS 24 1.7 the simplest view of a potential role for Nox in ALS would be that activation of Nox consequent to microglial cell 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23713 18219386 28376 5281 2578 CYBB NOX2 Nox2 8 3.5 This scenario is consistent with protection observed by Nox2 deletion in other models of neurodegeneration in which inflammation has 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23714 18219386 28377 5281 2578 CYBB NOX2 Nox2 10 3.5 In addition dopaminergic neurons cocultured with microglial cells lacking the Nox2 gene are more resistant to rotenone-induced neuronal death ( 18 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23715 18219386 28377 926 620 APP amyloid amyloid 25 1.0 to rotenone-induced neuronal death ( 18 and Alzheimer disease_amp_#x02013 linked amyloid peptides (derived derived from neurons activate microglial cells to produce 1 JUMiner_v2.2 1 1 UserEdit 0 0 0 1 1 888 598 APLP2 0 23716 18219386 28377 18723 10261 ROS1 ROS ROS 36 0.0 (derived derived from neurons activate microglial cells to produce more ROS ( 19 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23717 18219386 28378 20996 11179 SOD1 ALS ALS 5 1.7 However in the case of ALS associated with SOD1 mutations the new data reported by Harraz 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23718 18219386 28378 20996 11179 SOD1 SOD1 SOD1 8 2.5 However in the case of ALS associated with SOD1 mutations the new data reported by Harraz Engelhardt and colleagues 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23719 18219386 28378 20996 11179 SOD1 SOD1 SOD1 36 2.5 ( 20 provide a direct link between the disease-causing mutant SOD1 and Nox-mediated ROS production by microglial cells through SOD1 binding 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23720 18219386 28378 20996 11179 SOD1 SOD1 SOD1 45 2.5 mutant SOD1 and Nox-mediated ROS production by microglial cells through SOD1 binding to the Nox activator Rac1 thereby influencing the non_amp_#x02013 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23721 18219386 28378 17864 9801 RAC1 RAC1 Rac1 51 1.0 by microglial cells through SOD1 binding to the Nox activator Rac1 thereby influencing the non_amp_#x02013 cell autonomous killing of motor neurons 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23722 18219386 28378 18723 10261 ROS1 ROS ROS 39 0.0 a direct link between the disease-causing mutant SOD1 and Nox-mediated ROS production by microglial cells through SOD1 binding to the Nox 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23723 18219386 28379 20996 11179 SOD1 SOD1 SOD1 1 2.5 Mutant SOD1 stimulates Rac1-GTP activation of Nox and production of ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23724 18219386 28379 18723 10261 ROS1 ROS ROS 10 0.0 Mutant SOD1 stimulates Rac1-GTP activation of Nox and production of ROS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23725 18219386 28380 17864 9801 RAC1 RAC1 Rac1 6 1.0 Using an approach involving immunoprecipitation of Rac1 from different mouse tissues Harraz and colleagues proposed that SOD1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23726 18219386 28380 20996 11179 SOD1 SOD1 SOD1 16 2.5 Rac1 from different mouse tissues Harraz and colleagues proposed that SOD1 interacts directly with Rac1 but not with the other Nox2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23727 18219386 28380 17864 9801 RAC1 RAC1 Rac1 20 1.0 tissues Harraz and colleagues proposed that SOD1 interacts directly with Rac1 but not with the other Nox2 cytosolic regulators ( 20 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23728 18219386 28380 5281 2578 CYBB NOX2 Nox2 26 3.5 SOD1 interacts directly with Rac1 but not with the other Nox2 cytosolic regulators ( 20 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23729 18219386 28381 20996 11179 SOD1 SOD1 SOD1-interacting 8 2.2 It is puzzling why multiple earlier screens for SOD1-interacting proteins including yeast 2-hybrid approaches did not identify Rac1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23730 18219386 28381 17864 9801 RAC1 RAC1 Rac1 17 1.0 for SOD1-interacting proteins including yeast 2-hybrid approaches did not identify Rac1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23731 18219386 28382 20996 11179 SOD1 SOD1 SOD1 16 2.5 _amp_#x02013 that is converted to H 2 O 2 by SOD1 it was further tested whether the enzymatic activity of SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23732 18219386 28382 20996 11179 SOD1 SOD1 SOD1 26 2.5 SOD1 it was further tested whether the enzymatic activity of SOD1 was important for this interaction of SOD1 with Rac1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23733 18219386 28382 20996 11179 SOD1 SOD1 SOD1 33 2.5 enzymatic activity of SOD1 was important for this interaction of SOD1 with Rac1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23734 18219386 28382 17864 9801 RAC1 RAC1 Rac1 35 1.0 of SOD1 was important for this interaction of SOD1 with Rac1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23735 18219386 28383 20996 11179 SOD1 SOD1 SOD1 6 2.5 Only the metalated (native) native form of SOD1 bound to Rac1 while the demetalated (enzymatically enzymatically inactive SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23736 18219386 28383 17864 9801 RAC1 RAC1 Rac1 9 1.0 Only the metalated (native) native form of SOD1 bound to Rac1 while the demetalated (enzymatically enzymatically inactive SOD1 did not 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23737 18219386 28383 20996 11179 SOD1 SOD1 SOD1 15 2.5 SOD1 bound to Rac1 while the demetalated (enzymatically enzymatically inactive SOD1 did not 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23738 18219386 28384 20996 11179 SOD1 SOD1 SOD1 5 2.5 In addition the binding of SOD1 to Rac1 was redox sensitive and could be cycled between 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23739 18219386 28384 17864 9801 RAC1 RAC1 Rac1 7 1.0 In addition the binding of SOD1 to Rac1 was redox sensitive and could be cycled between bound and 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23740 18219386 28384 17864 9801 RAC1 RAC1 Rac1 26 1.0 bound and unbound states depending on the redox state of Rac1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23741 18219386 28385 20996 11179 SOD1 SOD1 SOD1 3 2.5 Under reducing conditions SOD1 efficiently bound Rac1-GTP the form of Rac1 that is recruited 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23742 18219386 28385 17864 9801 RAC1 RAC1 Rac1 10 1.0 Under reducing conditions SOD1 efficiently bound Rac1-GTP the form of Rac1 that is recruited to Nox2 upon activation 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23743 18219386 28385 5281 2578 CYBB NOX2 Nox2 15 3.5 bound Rac1-GTP the form of Rac1 that is recruited to Nox2 upon activation 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23744 18219386 28386 20996 11179 SOD1 SOD1 SOD1 3 2.5 The binding of SOD1 to Rac1-GTP inhibited the intrinsic and/or and or GAP-facilitated GTPase 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23745 18219386 28386 17864 9801 RAC1 RAC1 Rac1 14 1.0 inhibited the intrinsic and/or and or GAP-facilitated GTPase activity of Rac1 (Figure Figure 1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23746 18219386 28386 17966 9871 RASA1 GAP GAP-facilitated 10 0.0 of SOD1 to Rac1-GTP inhibited the intrinsic and/or and or GAP-facilitated GTPase activity of Rac1 (Figure Figure 1 11 JUMiner_v2.2 1 0 0 2 9871 TotalCon:2<>9871|RASA1|5921|Complete__10002|RGS6|9628|Complete__<>AvaiableGeneRif=2<>BEST:9871|RASA1|0.000694789081885856<>ScoreDetail__9871|RASA1|0.000694789081885856__10002|RGS6|0.00031374707582221__ 0 0 0 0 0 23747 18219386 28387 20996 11179 SOD1 ALS ALS-linked 6 1.7 It is now widely accepted that ALS-linked mutations in SOD1 provoke disease due to the acquisition of 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23748 18219386 28387 20996 11179 SOD1 SOD1 SOD1 9 2.5 It is now widely accepted that ALS-linked mutations in SOD1 provoke disease due to the acquisition of one or more 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23749 18219386 28387 20996 11179 SOD1 SOD1 SOD1 24 2.5 the acquisition of one or more toxic properties of mutant SOD1 ( 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23750 18219386 28388 20996 11179 SOD1 ALS ALS-linked 24 1.7 was enhanced in tissues from mice expressing the catalytically active ALS-linked mutant SOD1 G93A but not in tissues from mice expressing 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23751 18219386 28388 20996 11179 SOD1 SOD1 SOD1 26 2.5 in tissues from mice expressing the catalytically active ALS-linked mutant SOD1 G93A but not in tissues from mice expressing comparably high 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23752 18219386 28388 20996 11179 SOD1 SOD1 SOD1 40 2.5 not in tissues from mice expressing comparably high levels of SOD1 WT (Figure Figure 1 and ref 20 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23753 18219386 28389 20996 11179 SOD1 SOD1 SOD1 36 2.5 also seen in glial and neuronal cell lines expressing mutant SOD1 G93A and SOD1 L8Q but not SOD1 WT and was 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23754 18219386 28389 20996 11179 SOD1 SOD1 SOD1 39 2.5 glial and neuronal cell lines expressing mutant SOD1 G93A and SOD1 L8Q but not SOD1 WT and was accompanied by increased 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23755 18219386 28389 20996 11179 SOD1 SOD1 SOD1 44 2.5 lines expressing mutant SOD1 G93A and SOD1 L8Q but not SOD1 WT and was accompanied by increased cell death 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23756 18219386 28390 20996 11179 SOD1 SOD1 SOD1 5 2.5 In addition liver tissues from SOD1 G93A mice _amp_#x02014 in which no altered pathology is normally 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23757 18219386 28390 20996 11179 SOD1 ALS ALS 18 1.7 _amp_#x02014 in which no altered pathology is normally observed in ALS _amp_#x02014 also displayed increased production of O 2 _amp_#x02022 _amp_#x02013 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23758 18219386 28390 20996 11179 SOD1 SOD1 SOD1 37 2.5 _amp_#x02022 _amp_#x02013 in agreement with a direct effect of mutant SOD1 on Nox activation rather than a consequence of increased inflammation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23759 18219386 28391 20996 11179 SOD1 SOD1 SOD1 12 2.5 direct effect of increased ROS as a result of mutant SOD1 within microglial cells obviously could influence the survival of motor 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23760 18219386 28391 20996 11179 SOD1 SOD1 SOD1 38 2.5 demonstrations of slowed disease progression after reducing or eliminating mutant SOD1 synthesis within the myeloid lineage ( 11 12 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23761 18219386 28391 18723 10261 ROS1 ROS ROS 6 0.0 Such a direct effect of increased ROS as a result of mutant SOD1 within microglial cells obviously 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23762 18219386 28392 20996 11179 SOD1 SOD1 SOD1 11 2.5 between increased production of O 2 _amp_#x02022 _amp_#x02013 by mutant SOD1 and elevated Rac1-GTP levels was seen not just for SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23763 18219386 28392 20996 11179 SOD1 SOD1 SOD1 21 2.5 SOD1 and elevated Rac1-GTP levels was seen not just for SOD1 G93A but also for 2 additional ALS-linked SOD1 mutants SOD1 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23764 18219386 28392 20996 11179 SOD1 ALS ALS-linked 29 1.7 not just for SOD1 G93A but also for 2 additional ALS-linked SOD1 mutants SOD1 L8Q and SOD1 G10V ( 20 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23765 18219386 28392 20996 11179 SOD1 SOD1 SOD1 30 2.5 just for SOD1 G93A but also for 2 additional ALS-linked SOD1 mutants SOD1 L8Q and SOD1 G10V ( 20 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23766 18219386 28392 20996 11179 SOD1 SOD1 SOD1 32 2.5 SOD1 G93A but also for 2 additional ALS-linked SOD1 mutants SOD1 L8Q and SOD1 G10V ( 20 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23767 18219386 28392 20996 11179 SOD1 SOD1 SOD1 35 2.5 also for 2 additional ALS-linked SOD1 mutants SOD1 L8Q and SOD1 G10V ( 20 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23768 18219386 28393 20996 11179 SOD1 SOD1 SOD1 58 2.5 property of the more than 115 different mutations in the SOD1 gene known to cause ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23769 18219386 28393 20996 11179 SOD1 ALS ALS 63 1.7 115 different mutations in the SOD1 gene known to cause ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23770 18219386 28394 20996 11179 SOD1 SOD1 SOD1 17 2.5 is independent of dismutase activity with multiple mutants (including including SOD1 G85R SOD1 H46R and SOD1 G127X shown to be causative 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23771 18219386 28394 20996 11179 SOD1 SOD1 SOD1 20 2.5 of dismutase activity with multiple mutants (including including SOD1 G85R SOD1 H46R and SOD1 G127X shown to be causative for disease 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23772 18219386 28394 20996 11179 SOD1 SOD1 SOD1 24 2.5 with multiple mutants (including including SOD1 G85R SOD1 H46R and SOD1 G127X shown to be causative for disease in humans and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23773 18219386 28396 20996 11179 SOD1 SOD1 SOD1 5 2.5 Similarly the failure of demetalated SOD1 WT to bind and activate Rac1-GTP would predict that removal 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23774 18219386 28396 20996 11179 SOD1 SOD1 SOD1 21 2.5 Rac1-GTP would predict that removal of the copper chaperone for SOD1 (CCS) CCS would substantially slow disease but this was not 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23775 18219386 28396 3838 1613 CCS CCS CCS 22 1.2 predict that removal of the copper chaperone for SOD1 (CCS) CCS would substantially slow disease but this was not the case 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23776 18219386 28397 20996 11179 SOD1 SOD1 SOD1 3 2.5 Thus only if SOD1 mutants increase Nox2 activity independently of their metalated state could 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23777 18219386 28397 5281 2578 CYBB NOX2 Nox2 6 3.5 Thus only if SOD1 mutants increase Nox2 activity independently of their metalated state could mutant SOD1_amp_#x02013 enhanced 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23778 18219386 28397 17864 9801 RAC1 RAC1 Rac1 16 1.0 activity independently of their metalated state could mutant SOD1_amp_#x02013 enhanced Rac1 activation and Nox-dependent O 2 _amp_#x02022 _amp_#x02013 production be a 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23779 18219386 28397 20996 11179 SOD1 ALS ALS-linked 33 1.7 production be a feature common to the broader set of ALS-linked SOD1 mutants 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23780 18219386 28397 20996 11179 SOD1 SOD1 SOD1 34 2.5 be a feature common to the broader set of ALS-linked SOD1 mutants 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23781 18219386 28399 20996 11179 SOD1 ALS ALS 7 1.7 The Nox inhibitor apocynin increases survival in ALS mice 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23782 18219386 28400 5281 2578 CYBB NOX2 Nox2 5 3.5 Decreasing ROS production by deleting Nox2 has already proven efficacious in ALS mice ( 13 14 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23783 18219386 28400 20996 11179 SOD1 ALS ALS 11 1.7 ROS production by deleting Nox2 has already proven efficacious in ALS mice ( 13 14 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23784 18219386 28400 18723 10261 ROS1 ROS ROS 1 0.0 Decreasing ROS production by deleting Nox2 has already proven efficacious in ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23785 18219386 28402 20996 11179 SOD1 SOD1 SOD1 9 2.5 The addition of apocynin to the drinking water of SOD1 G93A ALS mice beginning at 2 weeks of age increased 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23786 18219386 28402 20996 11179 SOD1 ALS ALS 11 1.7 addition of apocynin to the drinking water of SOD1 G93A ALS mice beginning at 2 weeks of age increased the animals_amp_#x02019 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23787 18219386 28403 5281 2578 CYBB NOX2 Nox2 17 3.5 and in fact greater than _amp_#x02014 the deletion of the Nox2 gene in SOD1 G93A mice previously reported by the same 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23788 18219386 28403 20996 11179 SOD1 SOD1 SOD1 20 2.5 greater than _amp_#x02014 the deletion of the Nox2 gene in SOD1 G93A mice previously reported by the same group ( 14 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23789 18219386 28404 14167 7660 NCF1 p47 p47 8 0.6 Apocynin is believed to block the translocation of p47 phox /p67 p67 phox to Nox ( 23 and would 1 JUMiner_v2.2 1 1 UserEdit 0 2 9070 TotalCon:4<>10576|CLEC11A|6320|Complete__9070|PLEK|5341|Complete__15912|NSFL1C|55968|No_GeneRif__6062|ING1|3621|Complete__<>AvaiableGeneRif=3<>BEST:9070|PLEK|0.000773036487322202<>ScoreDetail__6062|ING1|0.000355697834689431__10576|CLEC11A|0.000377928949357521__9070|PLEK|0.000773036487322202__ 1 1 10577 6062 ING1 0 23790 18219386 28404 14170 7661 NCF2 p67 p67 10 0.3 is believed to block the translocation of p47 phox /p67 p67 phox to Nox ( 23 and would therefore inhibit only 1 JUMiner_v2.2 1 1 UserEdit 0 2 16672 TotalCon:2<>1659|CD33|945|Complete__16672|METAP2|10988|Complete__<>AvaiableGeneRif=2<>BEST:16672|METAP2|0.000921097704868116<>ScoreDetail__1659|CD33|0.000843144596524802__16672|METAP2|0.000921097704868116__ 1 1 3884 1659 CD33 0 23791 18219386 28404 14551 7889 NOX1 NOX1 Nox1 31 1.2 only the Nox proteins requiring these cytosolic activators which include Nox1 and Nox2 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23792 18219386 28404 5281 2578 CYBB NOX2 NOX2 31 3.5 only the Nox proteins requiring these cytosolic activators which include Nox1 and Nox2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23793 18219386 28404 5281 2578 CYBB NOX2 Nox2 33 3.5 Nox proteins requiring these cytosolic activators which include Nox1 and Nox2 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23794 18219386 28405 20996 11179 SOD1 SOD1 SOD1 29 2.5 a neuronal cell line when cells were transfected with mutant SOD1 ( 20 providing support that apocynin effectiveness may be acting 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23795 18219386 28406 5281 2578 CYBB NOX2 Nox2 3 3.5 Although expression of Nox2 by neurons astrocytes and endothelial cells has been reported ( 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23796 18219386 28406 5281 2578 CYBB NOX2 Nox2 18 3.5 and endothelial cells has been reported ( 15 staining for Nox2 in ALS mice only revealed accumulation in microglial cells ( 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23797 18219386 28406 20996 11179 SOD1 ALS ALS 20 1.7 cells has been reported ( 15 staining for Nox2 in ALS mice only revealed accumulation in microglial cells ( 13 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23798 18219386 28407 14551 7889 NOX1 NOX1 Nox1 10 1.2 However other Nox proteins are expressed in the CNS including Nox1 in neurons and endothelial cells Nox4 in astrocytes neurons and 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23799 18219386 28407 14553 7891 NOX4 NOX4 Nox4 16 0.9 in the CNS including Nox1 in neurons and endothelial cells Nox4 in astrocytes neurons and endothelial cells and Nox5 in endothelial 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23800 18219386 28407 14554 14874 NOX5 NOX5 Nox5 24 0.9 endothelial cells Nox4 in astrocytes neurons and endothelial cells and Nox5 in endothelial cells moreover high doses of apocynin have been 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23801 18219386 28407 14553 7891 NOX4 NOX4 Nox4 38 0.9 moreover high doses of apocynin have been reported to inhibit Nox4 and Nox5 ( 15 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23802 18219386 28407 14554 14874 NOX5 NOX5 NOX5 38 0.9 moreover high doses of apocynin have been reported to inhibit Nox4 and Nox5 ( 15 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23803 18219386 28407 14554 14874 NOX5 NOX5 Nox5 40 0.9 doses of apocynin have been reported to inhibit Nox4 and Nox5 ( 15 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23804 18219386 28409 5281 2578 CYBB NOX2 Nox2 4 3.5 Of relevance for patients Nox2 upregulation has been reported in spinal cords of sporadic ALS 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23805 18219386 28409 20996 11179 SOD1 ALS ALS 14 1.7 Nox2 upregulation has been reported in spinal cords of sporadic ALS cases ( 13 but it is still unknown whether patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23806 18219386 28409 20996 11179 SOD1 SOD1 SOD1 27 2.5 ( 13 but it is still unknown whether patients with SOD1 mutations generate similar or greater increases in Nox2 activity or 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23807 18219386 28409 5281 2578 CYBB NOX2 Nox2 35 3.5 patients with SOD1 mutations generate similar or greater increases in Nox2 activity or expression 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23808 18219386 28411 20996 11179 SOD1 ALS ALS 4 1.7 Two reported studies of ALS mice with a Nox2 deletion reached divergent conclusions one group 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23809 18219386 28411 5281 2578 CYBB NOX2 Nox2 8 3.5 Two reported studies of ALS mice with a Nox2 deletion reached divergent conclusions one group described downregulation of microglial 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23810 18219386 28412 20996 11179 SOD1 SOD1 SOD1 22 2.5 in the progression of disease and whether apocynin affects mutant SOD1 expression 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23811 18219386 28415 5281 2578 CYBB NOX2 Nox2 5 3.5 Mutations altering the activity of Nox2 (or or other subunits of Nox are known to cause 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23812 18219386 28415 5281 2578 CYBB CGD CGD 18 2.5 of Nox are known to cause chronic granulomatous disease (CGD) CGD ( 15 which is characterized by severe and chronic infections 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23813 18219386 28416 5281 2578 CYBB CGD CGD 0 2.5 CGD patients are usually chronically administered antibiotics and IFN-_amp_#x003b3 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23814 18219386 28416 9905 5438 IFNG IFN IFN-G 8 0.0 CGD patients are usually chronically administered antibiotics and IFN-_amp_#x003b3 11 JUMiner_v2.2 1 0 0 2 5417 TotalCon:2<>5438|IFNG|3458|Complete__5417|IFNA1|3439|Complete__<>AvaiableGeneRif=2<>BEST:5417|IFNA1|0.000644085702671974<>ScoreDetail__5438|IFNG|0.000531194392064397__5417|IFNA1|0.000644085702671974__ 0 0 0 0 0 23815 18219386 28417 20996 11179 SOD1 ALS ALS 13 1.7 both studies from the Engelhardt group ( 14 20 their ALS animals with lowered Nox activity developed eye infections that if 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23816 18219386 28418 20996 11179 SOD1 SOD1 SOD1 18 2.5 disease and might therefore be a direct consequence of mutant SOD1 expression in the infected tissues deprived of Nox activity rather 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23817 18219386 28420 20996 11179 SOD1 ALS ALS 10 1.7 In the current study ( 20 apocynin treatment of ALS mice at 80 days of age (45 45 days before 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23818 18219386 28423 20996 11179 SOD1 ALS ALS 25 1.7 when administered early also implies that inflammation at least in ALS mice must happen earlier than commonly thought (before before obvious 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 23819 18219386 28424 20996 11179 SOD1 SOD1 SOD1 8 2.5 With this new finding that interaction of metalated SOD1 with Rac1 serves to activate Nox2 and that mutant forms 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23820 18219386 28424 17864 9801 RAC1 RAC1 Rac1 10 1.0 With this new finding that interaction of metalated SOD1 with Rac1 serves to activate Nox2 and that mutant forms of SOD1 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23821 18219386 28424 5281 2578 CYBB NOX2 Nox2 14 3.5 that interaction of metalated SOD1 with Rac1 serves to activate Nox2 and that mutant forms of SOD1 amplify production of ROS 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23822 18219386 28424 20996 11179 SOD1 SOD1 SOD1 20 2.5 Rac1 serves to activate Nox2 and that mutant forms of SOD1 amplify production of ROS by locking Nox2 in its activated 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23823 18219386 28424 5281 2578 CYBB NOX2 Nox2 27 3.5 mutant forms of SOD1 amplify production of ROS by locking Nox2 in its activated state Harraz and colleagues have advanced a 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23824 18219386 28424 20996 11179 SOD1 SOD1 SOD1 48 2.5 new hypothesis for the gain of toxic function of mutant SOD1 ( 20 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23825 18219386 28424 18723 10261 ROS1 ROS ROS 24 0.0 Nox2 and that mutant forms of SOD1 amplify production of ROS by locking Nox2 in its activated state Harraz and colleagues 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23826 18219386 28425 20996 11179 SOD1 SOD1 SOD1 2 2.5 Indeed normal SOD1 function typically defined only by its dismutase activity is now 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23827 18219386 28426 20996 11179 SOD1 SOD1 SOD1 13 2.5 of these additional properties could be induced by mutations in SOD1 as one of the toxic contributors in ALS 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 23828 18219386 28426 20996 11179 SOD1 ALS ALS 21 1.7 mutations in SOD1 as one of the toxic contributors in ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00179324454093775<>ScoreDetail__5468|IGFALS|0.00052622644712273__11179|SOD1|0.00179324454093775__ 0 0 0 0 0 26429 18270519 31299 18723 10261 ROS1 ROS ROS 3 0.0 Reactive oxygen species (ROS) ROS and compromised antioxidant defense may contribute to brain disorders such 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 26430 18270519 31301 3892 6953 CD46 MCP MC-P 9 0.0 barrier (BBB)-permeable BBB -permeable nitroxide methoxycarbonyl-2 2 5 5-tetramethylpyrrolidine-1-oxyl (MC-P), MC-P as a magnetic resonance-imaging (MRI) MRI contrast agent for brain 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26431 18270519 31302 3892 6953 CD46 MCP MC-P 0 0.0 MC-P relaxation in rodent brain was quantified by MRI using a 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26432 18270519 31303 3892 6953 CD46 MCP MC-P 15 0.0 thalamus the MRI signal intensity increased up to 50% after MC-P injection but increased only by 2.7% when a BBB-impermeable nitroxide 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26433 18270519 31304 3892 6953 CD46 MCP MC-P 10 0.0 The maximum concentrations in the thalamus and cerebral cortex after MC-P injection were calculated to be 1.9 0.35 and 3.0 0.50 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26434 18270519 31306 3892 6953 CD46 MCP MC-P 4 0.0 Also reduction rates of MC-P were significantly decreased after reperfusion following transient MCAO (middle middle 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26435 18270519 31307 18723 10261 ROS1 ROS ROS 19 0.0 MRI contrast agents and antioxidants to evaluate the role of ROS in neurologic diseases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 26436 18270519 31310 18723 10261 ROS1 ROS ROS 4 0.0 Increased reactive oxygen species (ROS) ROS and decreased antioxidant defense may contribute to numerous brain disorders 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 26437 18270519 31311 18723 10261 ROS1 ROS ROS 13 0.0 oxidative stress is therefore useful to monitor the role of ROS in brain disorders 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 26438 18270519 31312 18723 10261 ROS1 ROS ROS 4 0.0 For image studies of ROS in vivo nitroxide compounds have been used as redox-sensitive contrast 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 26439 18270519 31323 3892 6953 CD46 MCP MC-P 5 0.0 One of the nitroxides methoxycarbonyl-2 2 5 5-tetramethylpyrrolidine-1-oxyl (MC-P; MC-P Figure 1 has been used as a contrast agent for 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26440 18270519 31324 3892 6953 CD46 MCP MC-P 8 0.0 Anzai et al (2003) 2003 confirmed that the nitroxide MC-P after intravenous injection accumulated in the brain tissue as evidenced 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26441 18270519 31325 3892 6953 CD46 MCP MC-P 4 0.0 These findings suggest that MC-P can pass through the blood-brain barrier (BBB) BBB and give 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26442 18270519 31327 3892 6953 CD46 MCP MC-P 1 0.0 Therefore MC-P can be used as a BBB-permeable MRI contrast agent that 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26443 18270519 31329 18723 10261 ROS1 ROS ROS 13 0.0 ischemia on reperfusion with oxygenated buffer solutions a burst of ROS has been shown to be generated with a propensity to 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 26444 18270519 31330 3892 6953 CD46 MCP MC-P 6 0.0 To show the possibility of using MC-P in brain redox imaging in neurologic disease model rat transient 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26445 18270519 31334 3892 6953 CD46 MCP MC-P 12 0.0 LL sequence we used MRI to study the pharmacokinetics of MC-P concentration in the brain by monitoring T 1 changes before 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26446 18270519 31334 3892 6953 CD46 MCP MC-P 25 0.0 the brain by monitoring T 1 changes before and after MC-P injection 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26447 18270519 31335 3892 6953 CD46 MCP MC-P 14 0.0 readily detected throughout the brain at a well-tolerated dose of MC-P 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26448 18270519 31338 3892 6953 CD46 MCP MC-P 5 0.0 Estimation of the concentration of MC-P using in vitro relaxivities agreed with EPR results from extracted 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26449 18270519 31339 3892 6953 CD46 MCP MC-P 4 0.0 The results indicate that MC-P goes into the brain and causes reduction of T 1 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26450 18270519 31340 3892 6953 CD46 MCP MC-P 6 0.0 In addition the reduction rate of MC-P was significantly decreased in the infarct region of brain after 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26451 18270519 31343 3892 6953 CD46 MCP MC-P 1 0.0 Chemicals MC-P was purchased from Columbia Advanced Science LC (Baltimore, Baltimore MD 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26452 18270519 31355 8363 23217 GKN1 FOV FOV 21 0.0 256 256 (0.125 0.125 mm resolution field of view (FOV)=3.2 FOV =3.2 3.2 cm slice thickness=2.0 mm and 0.2 mm gap 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 26453 18270519 31358 22050 11760 TFPI EPI EPI 21 0.3 0 compensation multislice LL data were acquired by segmented gradient-echo EPI (echo echo planar imaging with TR=10 secs TE 6.7 ms 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 26454 18270519 31361 3892 6953 CD46 MCP MC-P 19 0.0 mm inner diameter containing 0 to 50 mmol/L mmol L MC-P in phosphate-buffered saline (PBS) PBS as shown in Figure 2A 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26455 18270519 31367 3892 6953 CD46 MCP MC-P 9 0.0 The tail vein was cannulated for the injection of MC-P or 3CxP 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26456 18270519 31372 3892 6953 CD46 MCP MC-P 5 0.0 Before making the measurements with MC-P or 3CxP images of the rat were taken with the 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26457 18270519 31374 3892 6953 CD46 MCP MC-P 3 0.0 A solution of MC-P or CxP (1.5 1.5 mol/g mol g body weight was 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26458 18270519 31375 3892 6953 CD46 MCP MC-P 21 0.0 mequiv mL was injected 40 secs after the administration of MC-P and then continuously measured by SPGR till 13 mins 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26459 18270519 31381 7357 3604 FBN2 CCA CCA 2 0.0 The right CCA (common common carotid artery ECA (extra extra carotid artery and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 26460 18270519 31382 7357 3604 FBN2 CCA CCA 1 0.0 The CCA and ECA were ligated and a suture was placed at 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 26461 18270519 31384 7357 3604 FBN2 CCA CCA 2 0.0 The left CCA was ligated with a suture to complete the MCAO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 26462 18270519 31385 7357 3604 FBN2 CCA CCA 26 0.0 withdrawing the suture tip and the suture of the left CCA region 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 26463 18270519 31394 3892 6953 CD46 MCP MC-P 3 0.0 The concentration of MC-P was estimated by the LL T 1 maps using the 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26464 18270519 31395 3892 6953 CD46 MCP MC-P 0 0.0 [MC-P]=( MC-P = R 1 -R 10 )/Relaxivity Relaxivity 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26465 18270519 31396 21414 11362 STAT1 STAT Stat 8 0.3 Statistical analysis was performed using the StatView software Stat View 5.0 (SAS SAS Institute Inc. Cary NC USA 2 JUMiner_v2.2 1 2 stat view 0 0 0 0 0 0 0 0 26466 18270519 31396 23261 10539 TSPAN31 SAS SAS 11 0.0 was performed using the StatView software Stat View 5.0 (SAS SAS Institute Inc. Cary NC USA 1 JUMiner_v2.2 1 0 0 2 19237 TotalCon:2<>10539|TSPAN31|6302|Complete__19237|NANS|54187|Complete__<>AvaiableGeneRif=2<>BEST:19237|NANS|0.000624417520969245<>ScoreDetail__10539|TSPAN31|0__19237|NANS|0.000624417520969245__ 0 0 0 0 0 26467 18270519 31398 3892 6953 CD46 MCP MC-P 2 0.0 Quantification of MC-P in Brain and Blood by EPR Spectroscopy MC-P dissolved in 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26468 18270519 31398 3892 6953 CD46 MCP MC-P 10 0.0 Quantification of MC-P in Brain and Blood by EPR Spectroscopy MC-P dissolved in saline was injected in the tail vein of 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26469 18270519 31401 3892 6953 CD46 MCP MC-P 12 0.0 was extracted 2 5 and 8 mins after injection of MC-P and wet weight was determined 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26470 18270519 31407 3892 6953 CD46 MCP MC-P 15 0.0 mmol/L mmol L between concentration and EPR signal height of MC-P (data data not shown EPR signal heights of homogenate mixtures 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26471 18270519 31408 3892 6953 CD46 MCP MC-P 1 0.0 Finally MC-P concentrations in the brain tissue and blood were calculated based 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26472 18270519 31410 3892 6953 CD46 MCP MC-P 15 0.0 T 1 -weighted images of phantom with various concentrations of MC-P acquired using the SPGR sequence 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26473 18270519 31411 3892 6953 CD46 MCP MC-P 8 0.0 The MR signal intensity increased with concentration of MC-P up to 50 mmol/L mmol L ( Figure 2B with 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26474 18270519 31412 3892 6953 CD46 MCP MC-P 8 0.0 intensity change (%) % in the 5 mmol/L mmol L MC-P tube was about 100% compared with PBS (center center tube 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26475 18270519 31414 3892 6953 CD46 MCP MC-P 8 0.0 The T 1 values decreased depending on the MC-P concentration from 2 246 ms (0.5 0.5 mmol/L) mmol L 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26476 18270519 31415 3892 6953 CD46 MCP MC-P 3 0.0 The relaxivity of MC-P in PBS solution was measured to be 0.16 sec -1 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26477 18270519 31418 3892 6953 CD46 MCP MC-P 4 0.0 After the injection of MC-P solution the intensity in the rat head region immediately increased 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26478 18270519 31420 3892 6953 CD46 MCP MC-P 14 0.0 the signal intensity in the brain tissue after injection of MC-P was about 50% compared with the pre-injection image ( Figure 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26479 18270519 31421 3892 6953 CD46 MCP MC-P 5 0.0 The signal intensity derived from MC-P (oxidized oxidized form MRI visible reached a maximum at 30 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26480 18270519 31422 3892 6953 CD46 MCP MC-P 30 0.0 relaxivity (0.17 0.17 sec -1 mmol/L mmol L -1 as MC-P ( Figure 3B 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26481 18270519 31424 3892 6953 CD46 MCP MC-P 6 0.0 To check if blood flow affected MC-P reduction blood flow was stopped by KCl injection 40 secs 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26482 18270519 31424 3892 6953 CD46 MCP MC-P 20 0.0 was stopped by KCl injection 40 secs after administration of MC-P 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26483 18270519 31426 3892 6953 CD46 MCP MC-P 10 0.0 The MR signal intensity in brain decreased after enhancement by MC-P in a manner similar to that found for brain but 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26484 18270519 31427 3892 6953 CD46 MCP MC-P 1 0.0 The MC-P reduction rate ( k =0.30 0.066 min -1 in brain 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26485 18270519 31432 3892 6953 CD46 MCP MC-P 4 0.0 The reduction rate of MC-P in the right hemisphere was significantly decreased compared with the 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26486 18270519 31433 3892 6953 CD46 MCP MC-P 16 0.0 of quantitative T 1 maps before and after injection of MC-P 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26487 18270519 31437 3892 6953 CD46 MCP MC-P 11 0.0 T 1 of these regions rapidly decreased after injection of MC-P and the minimum T 1 (secs) secs of the cerebral 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26488 18270519 31439 3892 6953 CD46 MCP MC-P 8 0.0 From T 1 and in vitro relaxivity of MC-P (0.16 0.16 mmol/L mmol L -1 s -1 the concentration 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26489 18270519 31439 3892 6953 CD46 MCP MC-P 18 0.0 0.16 mmol/L mmol L -1 s -1 the concentration of MC-P at all time points in the ROI was calculated ( 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26490 18270519 31443 3892 6953 CD46 MCP MC-P 6 0.0 To confirm whether the concentration of MC-P determined by the MRI technique is reliable an ex vivo 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26491 18270519 31443 3892 6953 CD46 MCP MC-P 29 0.0 X-band EPR was carried out on the brain tissue for MC-P levels ( Figure 6 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26492 18270519 31444 3892 6953 CD46 MCP MC-P 4 0.0 The oxidized and total MC-P (oxidized+reduced oxidized reduced form levels were determined with and without 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26493 18270519 31445 3892 6953 CD46 MCP MC-P 3 0.0 The brain tissue MC-P level was 0.84 0.035 mmol/L mmol L at 2 mins 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26494 18270519 31445 3892 6953 CD46 MCP MC-P 13 0.0 was 0.84 0.035 mmol/L mmol L at 2 mins after MC-P injection ( Figure 6A 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26495 18270519 31447 3892 6953 CD46 MCP MC-P 5 0.0 On the other hand total MC-P level (oxidized+reduced oxidized reduced form was 1.57 0.199 mmol/L, mmol 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26496 18270519 31447 3892 6953 CD46 MCP MC-P 18 0.0 1.57 0.199 mmol/L, mmol L suggesting that approximately half of MC-P was in the reduced form in the brain at this 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26497 18270519 31448 3892 6953 CD46 MCP MC-P 5 0.0 At 8 mins most of MC-P was reduced (0.24 0.24 0.107 mmol/L); mmol L however total 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26498 18270519 31448 3892 6953 CD46 MCP MC-P 13 0.0 was reduced (0.24 0.24 0.107 mmol/L); mmol L however total MC-P (reduced+oxidized) reduced oxidized still remained (0.92 0.92 0.092 mmol/L) mmol 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26499 18270519 31449 3892 6953 CD46 MCP MC-P 4 0.0 The blood concentrations of MC-P at different time points in six rats are shown in 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26500 18270519 31450 3892 6953 CD46 MCP MC-P 4 0.0 The oxidized form of MC-P followed similar kinetics as the brain peaking at similar concentration 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26501 18270519 31451 3892 6953 CD46 MCP MC-P 1 0.0 Total MC-P levels slowly decreased but MC-P was still present at 30 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26502 18270519 31451 3892 6953 CD46 MCP MC-P 6 0.0 Total MC-P levels slowly decreased but MC-P was still present at 30 mins (level level of oxidized 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26503 18270519 31451 3892 6953 CD46 MCP MC-P 16 0.0 was still present at 30 mins (level level of oxidized MC-P 0.33 0.084 mmol/L, mmol L level of total MC-P 1.04 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26504 18270519 31451 3892 6953 CD46 MCP MC-P 23 0.0 oxidized MC-P 0.33 0.084 mmol/L, mmol L level of total MC-P 1.04 0.07 mmol/L), mmol L suggesting that the clearance of 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26505 18270519 31451 3892 6953 CD46 MCP MC-P 32 0.0 1.04 0.07 mmol/L), mmol L suggesting that the clearance of MC-P from the blood was much slower than the reduction detected 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26506 18270519 31453 3892 6953 CD46 MCP MC-P 15 0.0 show that the cell-permeable and low-molecular-weight BBB-permeable MRI contrast agent MC-P is useful for enhancing MRI intensity in the brain 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26507 18270519 31454 3892 6953 CD46 MCP MC-P 22 0.0 T 1 maps from the brain region before and after MC-P injection 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26508 18270519 31455 3892 6953 CD46 MCP MC-P 5 0.0 This enabled determination of the MC-P concentration in brain regions assuming the in vivo relaxivity of 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26509 18270519 31455 3892 6953 CD46 MCP MC-P 16 0.0 concentration in brain regions assuming the in vivo relaxivity of MC-P as the same in vivo 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26510 18270519 31457 3892 6953 CD46 MCP MC-P 9 0.0 In this study the cell-permeable and highly lipophilic nitroxide MC-P was tested in the brain as an imaging probe 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26511 18270519 31458 3892 6953 CD46 MCP MC-P 8 0.0 The T 1 -weighted MR signal intensity of MC-P showed linearity up to 5 mmol/L mmol L ( Figure 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26512 18270519 31460 3892 6953 CD46 MCP MC-P 2 0.0 Because the MC-P concentration in the thalamus region went up to approximately 3 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26513 18270519 31462 3892 6953 CD46 MCP MC-P 18 0.0 brain regions clearly increased up to 50% after injection of MC-P although there was no enhancement ( 3% in the case 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26514 18270519 31463 3892 6953 CD46 MCP MC-P 24 0.0 similar (0.16 0.16 mmol/L mmol L -1 sec -1 for MC-P 0.17 mmol/L mmol L -1 sec -1 for 3CxP 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26515 18270519 31464 3892 6953 CD46 MCP MC-P 12 0.0 difference detected is most likely because of the distribution of MC-P in the brain 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26516 18270519 31465 3892 6953 CD46 MCP MC-P 0 0.0 MC-P is a highly lipophilic substance with an octanol-water partition coefficient 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26517 18270519 31467 3892 6953 CD46 MCP MC-P 10 0.0 Therefore SPGR signal intensity in the brain region increased after MC-P injection ( Figure 3A 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26518 18270519 31470 3892 6953 CD46 MCP MC-P 7 0.0 The ratio of maximum intensity change between MC-P and 3CxP was 18.5 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26519 18270519 31473 3892 6953 CD46 MCP MC-P 4 0.0 These data suggest that MC-P got distributed in the whole-brain tissue region after passing through 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26520 18270519 31477 3892 6953 CD46 MCP MC-P 1 0.0 Therefore MC-P reduction rate without blood flow was tested ( Figure 3E 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26521 18270519 31478 3892 6953 CD46 MCP MC-P 10 0.0 Even though blood flow was stopped after injecting KCl solution MC-P reduced in the brain 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26522 18270519 31479 3892 6953 CD46 MCP MC-P 4 0.0 The reduction rate of MC-P without blood flow was 60% compared with blood flow suggesting 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26523 18270519 31479 3892 6953 CD46 MCP MC-P 16 0.0 blood flow was 60% compared with blood flow suggesting that MC-P reduction represents reaction with intracellular reductants such as GSH (glutathione), 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26524 18270519 31480 3892 6953 CD46 MCP MC-P 24 0.0 brain changed in a manner that showed the reduction of MC-P 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26525 18270519 31481 3892 6953 CD46 MCP MC-P 10 0.0 of T 1 (secs) secs before and after injection of MC-P using LL sequence allowed the calculation of MC-P concentration in 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26526 18270519 31481 3892 6953 CD46 MCP MC-P 18 0.0 injection of MC-P using LL sequence allowed the calculation of MC-P concentration in the brain ( Figure 5 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26527 18270519 31483 3892 6953 CD46 MCP MC-P 10 0.0 The T 1 values in the ROI were converted to MC-P concentration ( Figure 5C 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26528 18270519 31484 3892 6953 CD46 MCP MC-P 24 0.0 tissues and the blood concentration of the oxidized form of MC-P as determined ex vivo from EPR ( Figure 6 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26529 18270519 31485 3892 6953 CD46 MCP MC-P 11 0.0 about 0.5 mmol/L mmol L of the oxidized form of MC-P at 10 mins after injection the total MC-P levels (nitroxide+hydroxylamine) 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26530 18270519 31485 3892 6953 CD46 MCP MC-P 19 0.0 form of MC-P at 10 mins after injection the total MC-P levels (nitroxide+hydroxylamine) nitroxide hydroxylamine were still around 1.2 mmol/L, mmol 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26531 18270519 31485 3892 6953 CD46 MCP MC-P 32 0.0 around 1.2 mmol/L, mmol L suggesting that the reduction from MC-P (oxidized, oxidized paramagnetic to hydroxylamine (reduced, reduced diamagnetic was predominant 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26532 18270519 31489 18723 10261 ROS1 ROS ROS 8 0.0 Under normal physiologic conditions neurologic damages mediated by ROS can be prevented by the cellular antioxidant network 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 26533 18270519 31495 3892 6953 CD46 MCP MC-P 7 0.0 These data suggest that the effect of MC-P on MRI signal intensity might enable monitoring of brain damage 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26534 18270519 31496 3892 6953 CD46 MCP MC-P 6 0.0 As a consequence the BBB-permeable nitroxide MC-P may be useful as an MRI contrast agent to indicate 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26535 18270519 31497 3892 6953 CD46 MCP MC-P 1 0.0 Furthermore MC-P might provide protection of brain because of tissue antioxidant properties 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26536 18270519 31499 3892 6953 CD46 MCP MC-P 2 0.0 The BBB-permeable MC-P is a potent redox-sensitive MRI contrast agent in brain 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26537 18270519 31500 3892 6953 CD46 MCP MC-P 11 0.0 MRI intensity in brain was clearly enhanced after injection of MC-P 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26538 18270519 31501 3892 6953 CD46 MCP MC-P 14 0.0 1 mapping by LL sequence allowed accurate monitoring of pharmacokinetic MC-P concentration changes with whole-brain coverage 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26539 18270519 31504 3892 6953 CD46 MCP MC-P 11 0.0 reduction oxidation showing the interconversion and the molecular structure of MC-P 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26540 18270519 31505 3892 6953 CD46 MCP MC-P 10 0.0 The structure on the left is the radical form of MC-P 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26541 18270519 31506 3892 6953 CD46 MCP MC-P 11 0.0 on the right is the reduced form (hydroxylamine) hydroxylamine of MC-P 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26542 18270519 31509 3892 6953 CD46 MCP MC-P 3 0.0 MR images of MC-P phantom by SPGR and LL sequences 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26543 18270519 31510 3892 6953 CD46 MCP MC-P 6 0.0 ( A Schematics of the MC-P phantom (left left column T 1 -weighted SPGR images (middle 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26544 18270519 31512 3892 6953 CD46 MCP MC-P 0 0.0 MC-P was dissolved in saline 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26545 18270519 31513 3892 6953 CD46 MCP MC-P 10 0.0 ( B Change in the MR signal intensity of MC-P phantom as a function of concentration from 0.2 mmol/L mmol 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26546 18270519 31515 3892 6953 CD46 MCP MC-P 10 0.0 ( C Relaxation rate (1/ 1 T 1 of MC-P as a function of concentration 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26547 18270519 31519 3892 6953 CD46 MCP MC-P 14 0.0 images of rat head region after injection of ( A MC-P (cell-permeable) cell-permeable and ( B 3CxP (cell-impermeable) cell-impermeable 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26548 18270519 31526 3892 6953 CD46 MCP MC-P 10 0.0 The time courses of intensity change of ( C MC-P and ( D 3CxP in the ROI of cerebral cortex 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26549 18270519 31527 3892 6953 CD46 MCP MC-P 6 0.0 ( E Intensity change of MC-P without blood flow is shown 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26550 18270519 31528 3892 6953 CD46 MCP MC-P 8 0.0 KCl (2 2 mL was injected 40 secs after MC-P injection and rats died within 20 secs 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26551 18270519 31532 3892 6953 CD46 MCP MC-P 21 0.0 -weighted MR image of sham and IR treated rats after MC-P injection 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26552 18270519 31533 3892 6953 CD46 MCP MC-P 16 0.0 right hemisphere in the T 1 -weighted MR images after MC-P injection 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26553 18270519 31539 3892 6953 CD46 MCP MC-P 9 0.0 Dynamic T 1 maps of rat head region after MC-P injection acquired by LL sequence 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26554 18270519 31540 3892 6953 CD46 MCP MC-P 12 0.0 A Time-course T 1 maps of rat head region after MC-P injection 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26555 18270519 31541 22050 11760 TFPI EPI EPI 10 0.3 Multislice LL data were acquired every 20 secs by segmented EPI with TR=10 secs TE 6.7 ms FA=20degree acquisition interval=400 ms 1 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 26556 18270519 31543 3892 6953 CD46 MCP MC-P 12 0.0 The changes in ( B T 1 and ( C MC-P concentration in the cerebral cortex and thalamus regions were shown 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26557 18270519 31544 3892 6953 CD46 MCP MC-P 1 0.0 The MC-P concentration was calculated from T 1 using the equation described 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26558 18270519 31546 3892 6953 CD46 MCP MC-P 16 0.0 * P _lt_0.01 the significant difference of maximum concentration of MC-P between cerebral cortex and thalamus by t -test 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26559 18270519 31549 3892 6953 CD46 MCP MC-P 7 0.0 The quantification of oxidized and total (oxidized+reduced) oxidized reduced MC-P in brain tissue and blood using X-band EPR 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26560 18270519 31550 3892 6953 CD46 MCP MC-P 14 0.0 in oxidized (white white bar and total (black black bar MC-P in brain tissue ( N =4 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 26561 18270519 31551 3892 6953 CD46 MCP MC-P 16 0.0 concentration of oxidized Hillered et al (1988) 1988 and total MC-P (brown) brown in the blood 11 JUMiner_v2.2 1 0 0 2 1474 TotalCon:3<>6953|CD46|4179|Complete__1474|CAPG|822|Complete__32018|C1orf132|388732|No_GeneRif__<>AvaiableGeneRif=2<>BEST:1474|CAPG|0.000424732250622584<>ScoreDetail__6953|CD46|0.000329903940451608__1474|CAPG|0.000424732250622584__ 0 0 0 0 0 15717 18308427 18543 20996 11179 SOD1 SOD SOD 5 1.7 Antioxidant defense enzymes superoxide dismutase (SOD), SOD catalase (CAT), CAT glutathione peroxidase (GSHPx), GSHPx glutathione reductase (GR) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15718 18308427 18543 3544 1516 CAT CAT CAT 7 1.0 Antioxidant defense enzymes superoxide dismutase (SOD), SOD catalase (CAT), CAT glutathione peroxidase (GSHPx), GSHPx glutathione reductase (GR) GR and glucose-6-phosphate 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>1516|CAT|847|Complete__13734|GLYAT|10249|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 15719 18308427 18544 20996 11179 SOD1 ALS ALS 24 1.7 in the erythrocytes of 20 sporadic amyotrophic lateral sclerosis (ALS) ALS patients and 20 controls 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15720 18308427 18544 11960 6678 LPO LPO LPO 9 0.0 In the present study the extent of lipid peroxidation (LPO) LPO and antioxidant defenses were evaluated in the erythrocytes of 20 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15721 18308427 18547 20996 11179 SOD1 ALS ALS 18 1.7 glutathione levels were also found to be significantly reduced in ALS patients compared to healthy subjects (P P _amp_#x3c 0.001 P 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15722 18308427 18552 20996 11179 SOD1 ALS ALS 3 1.7 Amyotrophic lateral sclerosis (ALS), ALS a progressive disorder that usually runs a fatal course within 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15723 18308427 18555 20996 11179 SOD1 ALS ALS 9 1.7 Plaitakis (1990) 1990 proposed the hypothesis of glutamatergic dysfunction in ALS i.e imbalance between brain and blood glutamate levels 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15724 18308427 18557 20996 11179 SOD1 ALS ALS 11 1.7 also observed that blood glutamate levels were significantly higher in ALS patients ( Babu et al. 1998 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15725 18308427 18558 20996 11179 SOD1 ALS ALS 14 1.7 hallmark of neurodegenerative disorders such as motor neuron degeneration/ALS, degeneration ALS progressive bulbar palsy (PBP) PBP 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15726 18308427 18558 12527 9234 MED1 PBP PBP 18 0.3 as motor neuron degeneration/ALS, degeneration ALS progressive bulbar palsy (PBP) PBP 1 JUMiner_v2.2 1 2 UserEdit 0 2 8630 TotalCon:5<>8630|PEBP1|5037|Complete__2989|DOCK3|1795|Complete__9234|MED1|5469|Complete__9008|PKD1|5310|Complete__9240|PPBP|5473|Complete__<>AvaiableGeneRif=5<>BEST:8630|PEBP1|0.000447008008444681<>ScoreDetail__9234|MED1|0.000431204810269883__9008|PKD1|0.000294857549651991__8630|PEBP1|0.000447008008444681__2989|DOCK3|0.000131274942239025__9240|PPBP|0.000379687525245181__ 1 1 0 0 0 15727 18308427 18561 20996 11179 SOD1 SOD SOD 5 1.7 These enzymes include superoxide dismutase (SOD) SOD (E.C E.C No 1.15.1.1 that remove O 2_amp_#x2212 by catalyzing 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15728 18308427 18562 3544 1516 CAT CAT CAT 1 1.0 Catalase (CAT) CAT (E.C E.C No 1.11.1.6 catalyzes the conversion of hydrogen peroxide 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>1516|CAT|847|Complete__13734|GLYAT|10249|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 15729 18308427 18569 3544 1516 CAT CAT CAT 30 1.0 other sulfydryl groups of a cell and the antioxidant enzyme CAT in its active form ( Kletzien et al. 1994 and 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>1516|CAT|847|Complete__13734|GLYAT|10249|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 15730 18308427 18570 20996 11179 SOD1 ALS ALS 16 1.7 determine the oxidant/antioxidant oxidant antioxidant status in the erythrocytes of ALS patients and to evaluate the correlation if any between the 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15731 18308427 18570 20996 11179 SOD1 SOD SOD 30 1.7 the correlation if any between the lipid peroxidation (LPO), LPO SOD CAT GSH GSHPx GR and G-6-PDH levels and the progression 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15732 18308427 18570 3544 1516 CAT CAT CAT 31 1.0 correlation if any between the lipid peroxidation (LPO), LPO SOD CAT GSH GSHPx GR and G-6-PDH levels and the progression of 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>1516|CAT|847|Complete__13734|GLYAT|10249|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 15733 18308427 18570 11960 6678 LPO LPO LPO 29 0.3 evaluate the correlation if any between the lipid peroxidation (LPO), LPO SOD CAT GSH GSHPx GR and G-6-PDH levels and the 6 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 15734 18308427 18571 20996 11179 SOD1 ALS ALS 22 1.7 oxidative stress and antioxidant defense parameters in the patients of ALS and may help in evaluating their role in the pathogenesis 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15735 18308427 18575 20996 11179 SOD1 ALS ALS 0 1.7 ALS patients and control subjects 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15736 18308427 18576 20996 11179 SOD1 ALS ALS 0 1.7 ALS patients were selected using the World Federation Of Neurology (WFN) 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15737 18308427 18578 20996 11179 SOD1 ALS ALS 3 1.7 The diagnosis of ALS required the presence of both upper and lower motor neurones 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15738 18308427 18579 20996 11179 SOD1 ALS ALS 3 1.7 Patients diagnosed with ALS also met an extensive list of exclusionary criteria including sensory 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15739 18308427 18579 20996 11179 SOD1 ALS ALS 28 1.7 bladder changes and metabolic or toxic disorder that could mimic ALS e.g myelopathy lead intoxication endocrine abnormalities or peripheral neuropathy 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15740 18308427 18580 20996 11179 SOD1 ALS ALS 7 1.7 Twenty patients were diagnosed as having sporadic ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15741 18308427 18583 12527 9234 MED1 PBP PBP 8 0.3 Six of these patients were diagnosed as having PBP which results from exclusive lower motor neuron involvement in bulbar 1 JUMiner_v2.2 1 2 UserEdit 0 2 8630 TotalCon:5<>8630|PEBP1|5037|Complete__2989|DOCK3|1795|Complete__9234|MED1|5469|Complete__9008|PKD1|5310|Complete__9240|PPBP|5473|Complete__<>AvaiableGeneRif=5<>BEST:8630|PEBP1|0.000447008008444681<>ScoreDetail__9234|MED1|0.000431204810269883__9008|PKD1|0.000294857549651991__8630|PEBP1|0.000447008008444681__2989|DOCK3|0.000131274942239025__9240|PPBP|0.000379687525245181__ 1 1 0 0 0 15742 18308427 18584 12527 9234 MED1 PBP PBP 1 0.3 These PBP patients were having tongue fasciculations and swallowing difficulty but their 1 JUMiner_v2.2 1 2 UserEdit 0 2 8630 TotalCon:5<>8630|PEBP1|5037|Complete__2989|DOCK3|1795|Complete__9234|MED1|5469|Complete__9008|PKD1|5310|Complete__9240|PPBP|5473|Complete__<>AvaiableGeneRif=5<>BEST:8630|PEBP1|0.000447008008444681<>ScoreDetail__9234|MED1|0.000431204810269883__9008|PKD1|0.000294857549651991__8630|PEBP1|0.000447008008444681__2989|DOCK3|0.000131274942239025__9240|PPBP|0.000379687525245181__ 1 1 0 0 0 15743 18308427 18610 20996 11179 SOD1 SOD SOD 0 1.7 SOD activity was estimated by the method of Nishikimi et al 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15744 18308427 18612 17238 9337 PRB1 PMS PMS 16 0.0 10 mM NBT 45 _amp_#x3bc M NADH 23.5 _amp_#x3bc M PMS 12.4 nM 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15745 18308427 18618 3544 1516 CAT CAT CAT 0 1.0 CAT was estimated by the method of Aebi (1984) 1984 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>1516|CAT|847|Complete__13734|GLYAT|10249|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 15746 18308427 18634 6181 3058 DTNB DTNB DTNB-containing 23 0.0 modifications 200 _amp_#x3bc l of 0.01N HCl was mixed with DTNB-containing buffer (110 110 mM Na 2 HPO 4 40 mM 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15747 18308427 18634 8255 4236 GFER HPO HPO 29 0.0 was mixed with DTNB-containing buffer (110 110 mM Na 2 HPO 4 40 mM NaH 2 PO 4 15 mM EDTA 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15748 18308427 18634 6181 3058 DTNB DTNB DTNB 51 0.0 w v bovine serum albumin (BSA)) BSA and 0.3 mM DTNB 11 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15749 18308427 18654 20996 11179 SOD1 ALS ALS 35 1.7 (ADEs) ADEs in erythrocytes between control subjects and patients with ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15750 18308427 18659 20996 11179 SOD1 ALS ALS 8 1.7 The rate of LPO in the erythrocytes of ALS patients was significantly increased with respect to control subjects ( 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15751 18308427 18659 20996 11179 SOD1 ALS ALS 33 1.7 ( Fig 1 whereas catalase activity in the RBC of ALS patients was significantly lower than the controls ( P _amp_#x3c 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15752 18308427 18659 11960 6678 LPO LPO LPO 3 0.0 The rate of LPO in the erythrocytes of ALS patients was significantly increased with 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15753 18308427 18661 20996 11179 SOD1 SOD SOD 4 1.7 However the activities of SOD and GSHPx were found to be insignificantly changed in comparison 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15754 18308427 18662 20996 11179 SOD1 ALS ALS 1 1.7 In ALS patients it was found that LPO ( Fig 6 started 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15755 18308427 18662 3544 1516 CAT CAT CAT 16 1.0 found that LPO ( Fig 6 started to increase and CAT GSH GR and G-6-PDH levels ( Fig 7 Fig 8 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>1516|CAT|847|Complete__13734|GLYAT|10249|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 15756 18308427 18662 11960 6678 LPO LPO LPO 7 0.0 In ALS patients it was found that LPO ( Fig 6 started to increase and CAT GSH GR 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15757 18308427 18664 20996 11179 SOD1 ALS ALS 16 1.7 above parameters showed significant correlation with the time course of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15758 18308427 18671 20996 11179 SOD1 ALS ALS 6 1.7 The greater enhancement of LPO in ALS patients may be due to the fact that erythrocytes are 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15759 18308427 18671 11960 6678 LPO LPO LPO 4 0.1 The greater enhancement of LPO in ALS patients may be due to the fact that 6 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 15760 18308427 18672 11960 6678 LPO LPO LPO 27 0.0 leading to release of iron to promote Fenton chemistry and LPO 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15761 18308427 18673 3544 1516 CAT CAT CAT 4 1.0 In the present study CAT was found to exhibit significantly reduced activity when compared to 1 JUMiner_v2.2 1 0 0 1 0 TotalCon:2<>1516|CAT|847|Complete__13734|GLYAT|10249|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 15762 18308427 18674 3544 1516 CAT CAT CAT 3 1.0 A decrease in CAT activity is indicative of a situation in which there remains 1 JUMiner_v2.2 1 2 35 0 1 0 TotalCon:2<>1516|CAT|847|Complete__13734|GLYAT|10249|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 15763 18308427 18674 18723 10261 ROS1 ROS ROS 55 0.0 to hydroxyl radical ( OH the most dreaded of the ROS ( Chattopadhyay et al. 2000 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15764 18308427 18678 20996 11179 SOD1 ALS ALS 13 1.7 stress and antioxidant parameters in erythrocytes plasma and CSF of ALS patients 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15765 18308427 18678 11629 6493 LAMC2 CSF CSF 11 0.1 measured oxidative stress and antioxidant parameters in erythrocytes plasma and CSF of ALS patients 6 JUMiner_v2.2 1 2 UserEdit 0 0 0 1 1 0 0 0 15766 18308427 18681 20996 11179 SOD1 ALS ALS 14 1.7 of glutathione in in vivo and in vitro models of ALS promotes multiple apoptotic pathways contributing at least partially to motor 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15767 18308427 18682 20996 11179 SOD1 SOD SOD 13 1.7 elevated blood free radical levels did not induce the erythrocyte SOD and GSHPx enzyme activities in sporadic amyotrophic lateral sclerosis patients 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 15768 18308427 18683 3544 1516 CAT CAT CAT 8 1.0 On the other hand GSH levels GR and CAT activities were found to be significantly lower in ALS patients 1 JUMiner_v2.2 1 2 35 0 1 0 TotalCon:2<>1516|CAT|847|Complete__13734|GLYAT|10249|No_GeneRif__<>AvaiableGeneRif=1<> 0 0 0 0 0 15769 18308427 18683 20996 11179 SOD1 ALS ALS 17 1.7 and CAT activities were found to be significantly lower in ALS patients which represents imbalance in the oxidant_amp_#x2013 antioxidant system 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15770 18308427 18684 20996 11179 SOD1 ALS ALS 19 1.7 metabolic events nevertheless it is significant that all the five ALS patients in whom erythrocyte GSH levels were extremely low at 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15771 18308427 18686 20996 11179 SOD1 ALS ALS 15 1.7 need to develop surrogate markers to monitor the progress of ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15772 18308427 18687 20996 11179 SOD1 ALS ALS 17 1.7 imbalance could be a contributing factor in the progression of ALS in an ideal situation these systemic effects should have taken 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15773 18308427 18688 20996 11179 SOD1 ALS ALS 28 1.7 the patients due to significant morbidity and mortality associated with ALS 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15774 18308427 18689 20996 11179 SOD1 ALS ALS 10 1.7 Lipid peroxidation (mean mean _amp_#xb1 S.E.M. in the erythrocytes of ALS patients *** p _amp_#x3c 0.001 vs control 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15775 18308427 18691 20996 11179 SOD1 ALS ALS 10 1.7 Catalase activity (mean mean _amp_#xb1 S.E.M. in the erythrocytes of ALS patients ** p _amp_#x3c 0.01 vs control 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15776 18308427 18693 20996 11179 SOD1 ALS ALS 9 1.7 3._amp_#xa0 Glutathione (mean mean _amp_#xb1 S.E.M. in the erythrocytes of ALS patients ** p _amp_#x3c 0.01 vs control 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15777 18308427 18695 20996 11179 SOD1 ALS ALS 11 1.7 reductase activity (mean mean _amp_#xb1 S.E.M. in the erythrocytes of ALS patients ** p _amp_#x3c 0.01 vs control 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15778 18308427 18697 20996 11179 SOD1 ALS ALS 11 1.7 dehydrogenase activity (mean mean _amp_#xb1 S.E.M. in the erythrocytes of ALS patients *** p _amp_#x3c 0.001 vs control 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15779 18308427 18699 20996 11179 SOD1 ALS ALS 12 1.7 polynomial regression plot showing lipid peroxidation in the erythrocytes of ALS patients vs duration of illness ( N = 10 at 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15780 18308427 18701 20996 11179 SOD1 ALS ALS 14 1.7 plot showing the activity of catalase in the erythrocytes of ALS vs duration of illness ( N = 10 at 6 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15781 18308427 18703 20996 11179 SOD1 ALS ALS 16 1.7 glutathione levels vs duration of illness in the erythrocytes of ALS patients ( N = 10 at 6 months 5 at 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15782 18308427 18705 20996 11179 SOD1 ALS ALS 21 1.7 vs duration of illness in the erythrocytes of patients with ALS ( N = 10 at 6 months 5 at 12 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 15783 18308427 18707 20996 11179 SOD1 ALS ALS 19 1.7 glucose-6-phosphate dehydrogenase vs duration of illness in the erythrocytes of ALS patients ( N = 10 at 6 months 5 at 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 5468 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:5468|IGFALS|0.000884320703977269<>ScoreDetail__5468|IGFALS|0.000884320703977269__11179|SOD1|0.000578917569320476__ 0 0 0 0 0 18493 18349520 21375 20996 11179 SOD1 ALS ALS 13 0.0 that an early therapeutic intervention in amyotrophic lateral sclerosis (ALS) ALS would lead to better results in terms of disease progression 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00115848913889263<>ScoreDetail__5468|IGFALS|0.000866015093405914__11179|SOD1|0.00115848913889263__ 0 0 0 0 0 18494 18349520 21376 20996 11179 SOD1 ALS ALS 26 0.0 biological parameters reflecting for example oxidative stress alterations associated with ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00115848913889263<>ScoreDetail__5468|IGFALS|0.000866015093405914__11179|SOD1|0.00115848913889263__ 0 0 0 0 0 18495 18349520 21379 20996 11179 SOD1 ALS ALS 10 0.0 Objective In this study primary fibroblasts obtained from 10 sporadic ALS (SALS) SALS patients and 10 healthy matched controls were used 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.00115848913889263<>ScoreDetail__5468|IGFALS|0.000866015093405914__11179|SOD1|0.00115848913889263__ 0 0 0 0 0 9656 18414597 11013 22551 11892 TNF TNF-alpha TNF-alpha 2 1.5 Pro-inflammatory cytokines (TNF-alpha TNF-alpha and IL-1 secretory phospholipase A(2) A 2 IIA and lipoprotein-PLA(2) 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9657 18414597 11013 10437 5992 IL1B IL-1 IL-1 4 1.0 Pro-inflammatory cytokines (TNF-alpha TNF-alpha and IL-1 secretory phospholipase A(2) A 2 IIA and lipoprotein-PLA(2) lipoprotein-PLA 2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9658 18414597 11015 22551 11892 TNF TNF-alpha TNF-alpha 0 1.5 TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9659 18414597 11015 10437 5992 IL1B IL-1 IL-1 2 1.0 TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids ceramide and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9660 18414597 11020 14569 7897 NPC1 NPC1 NPC1 26 0.9 Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes resulting in defective cholesterol transport and cholesterol 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9661 18414597 11020 14571 14537 NPC2 NPC2 NPC2 28 1.4 C is due to mutations in either the NPC1 or NPC2 genes resulting in defective cholesterol transport and cholesterol accumulation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9751 18422522 11247 14538 7876 NOS3 eNOS eNOS 25 2.2 contrast the biological significance of endothelial nitric oxide synthase (eNOS) eNOS overexpression that occurs in several pathological conditions has not yet 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9752 18422522 11248 622 443 ALS2 ALS2 ALS2 34 1.5 a protein causing an early-onset type of amyotrophic lateral sclerosis ALS2 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9753 18422522 11249 14538 7876 NOS3 eNOS eNOS 3 2.2 We found that eNOS which is endogenously expressed by these cells was activated by 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9754 18422522 11249 22551 11892 TNF TNF-alpha TNF-alpha 17 1.8 by these cells was activated by tumour necrosis factor-alpha (TNF-alpha), TNF-alpha a proinflammatory cytokine that plays important roles in ALS2 and 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9755 18422522 11249 622 443 ALS2 ALS2 ALS2 26 1.5 (TNF-alpha), TNF-alpha a proinflammatory cytokine that plays important roles in ALS2 and several neurodegenerative diseases 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9756 18422522 11250 22551 11892 TNF TNF-alpha TNF-alpha-dependent 1 1.8 The TNF-alpha-dependent eNOS activation occurred through generation by sphingosine-kinase-1 of sphingosine-1-phosphate stimulation 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9757 18422522 11250 14538 7876 NOS3 eNOS eNOS 2 2.2 The TNF-alpha-dependent eNOS activation occurred through generation by sphingosine-kinase-1 of sphingosine-1-phosphate stimulation of 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9758 18422522 11250 14538 7876 NOS3 eNOS eNOS 36 2.2 and dominant negative constructs specific for the enzymes and receptors eNOS activation by TNF-alpha conferred cytoprotection from excitotoxicity and neurotoxic cues 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9759 18422522 11250 22551 11892 TNF TNF-alpha TNF-alpha 39 1.8 constructs specific for the enzymes and receptors eNOS activation by TNF-alpha conferred cytoprotection from excitotoxicity and neurotoxic cues such as reactive 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 9760 18422522 11250 543 391 AKT1 AKT Akt 19 0.0 of sphingosine-1-phosphate stimulation of its membrane receptors and activation of Akt as determined using small interference RNA and dominant negative constructs 2 JUMiner_v2.2 1 1 akt; 0 0 0 0 0 0 0 0 9761 18422522 11251 14538 7876 NOS3 eNOS eNOS 6 2.2 Our results suggest that overexpression of eNOS by neurones is a broad-range protective mechanism activated during damage 1 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 6787 18574762 7989 20996 11179 SOD1 ALS ALS 5 0.0 Oxidative stress biomarkers in sporadic ALS 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000547064613005482<>ScoreDetail__5468|IGFALS|0.000467440940635001__11179|SOD1|0.000547064613005482__ 0 0 0 0 0 6788 18574762 7990 20996 11179 SOD1 ALS ALS 17 0.0 in a cross-sectional pilot study of 50 participants with sporadic ALS (SALS) SALS compared to 46 control subjects 1 JUMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000547064613005482<>ScoreDetail__5468|IGFALS|0.000467440940635001__11179|SOD1|0.000547064613005482__ 0 0 0 0 0 7729 18588875 8925 13708 7377 MSRA MSRA MsrA 11 1.5 function and redox control in the aging eye Role of MsrA and other repair systems in cataract and macular degenerations 14 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 7730 18588875 8927 20996 11179 SOD1 ALS ALS 18 0.3 disorders including Alzheimer's disease Parkinson's disease amyotrophic lateral sclerosis (ALS), ALS Huntington's disease and the aging process itself 1 JUMiner_v2.2 1 2 amyotrophic lateral sclerosis 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000661633789414603<>ScoreDetail__5468|IGFALS|0.000211573045593991__11179|SOD1|0.000661633789414603__ 0 0 0 0 0 7731 18588875 8930 18723 10261 ROS1 ROS ROS 13 0.3 reactions that form potentially more dangerous reactive oxygen species (ROS) ROS species such as the hydroxyl radical (OH), OH hydrogen peroxide 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 7732 18588875 8931 18723 10261 ROS1 ROS ROS 4 0.3 The major source of ROS in the mitochondria and in the cell overall is leakage 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 7733 18588875 8932 18723 10261 ROS1 ROS ROS 14 0.3 0.2-2% of oxygen taken up by cells is converted to ROS through mitochondrial superoxide generation by the mitochondria 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 7734 18588875 8934 18723 10261 ROS1 ROS ROS 4 0.3 While exogenous sources of ROS such as UV light visible light ionizing radiation chemotherapeutics and 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 7735 18588875 8934 18723 10261 ROS1 ROS ROS 31 0.3 oxidative milieu mitochondria are perhaps the most significant contribution to ROS production affecting the aging process 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 7736 18588875 8935 18723 10261 ROS1 ROS ROS 4 0.3 In addition to producing ROS mitochondria are also a target for ROS which in turn 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 7737 18588875 8935 18723 10261 ROS1 ROS ROS 11 0.3 addition to producing ROS mitochondria are also a target for ROS which in turn reduces mitochondrial efficiency and leads to the 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 7738 18588875 8935 18723 10261 ROS1 ROS ROS 25 0.3 reduces mitochondrial efficiency and leads to the generation of more ROS in a vicious self-destructive cycle 3 JUMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 7739 18588875 8938 13859 7473 MTRR MSR Msr 24 0.3 eye diseases and detail how the methionine sulfoxide reductase (Msr) Msr protein repair system and other redox systems play key roles 2 JUMiner_v2.2 1 0 0 0 0 0 0 0 0 0 1888 18715147 2783 18723 10261 ROS1 ROS ROS 6 0.3 The generation of reactive oxygen species (ROS) ROS and reactive nitrogen species (RNS) RNS leads to oxidative and/or 3 SciMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 1889 18715147 2783 6981 22140 FAM20C RNS RNS 11 0.0 reactive oxygen species (ROS) ROS and reactive nitrogen species (RNS) RNS leads to oxidative and/or and or nitrosative damage to cellular 1 SciMiner_v2.2 1 0 0 0 0 0 0 0 0 0 1890 18715147 2784 18723 10261 ROS1 ROS ROS 11 0.3 oxidative stress increases due to an aberrant generation of ROS/RNS ROS RNS and a gradual decline in cellular antioxidant defense mechanisms 3 SciMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 1891 18715147 2784 6981 22140 FAM20C RNS RNS 11 0.3 stress increases due to an aberrant generation of ROS/RNS ROS RNS and a gradual decline in cellular antioxidant defense mechanisms 4 SciMiner_v2.2 1 2 reactive nitrogen species 0 0 0 0 0 0 0 0 1892 18715147 2788 18723 10261 ROS1 ROS ROS 5 0.3 However additional intracellular sources of ROS and RNS exist as well as extracellular sources such as 3 SciMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 1893 18715147 2788 6981 22140 FAM20C RNS RNS 7 0.1 However additional intracellular sources of ROS and RNS exist as well as extracellular sources such as those resulting 6 SciMiner_v2.2 1 2 reactive nitrogen species 0 0 0 0 0 0 0 0 1894 18715147 2789 18723 10261 ROS1 ROS ROS 7 0.3 A significant body of literature indicates that ROS and/or and or RNS resulting from mitochondrial dysfunction neuroinflammation or 3 SciMiner_v2.2 1 2 ros 0 0 0 0 0 0 0 0 1895 18715147 2789 6981 22140 FAM20C RNS RNS 9 0.1 significant body of literature indicates that ROS and/or and or RNS resulting from mitochondrial dysfunction neuroinflammation or toxicants are major factors 6 SciMiner_v2.2 1 2 reactive nitrogen species 0 0 0 0 0 0 0 0 1896 18715147 2789 20996 11179 SOD1 ALS ALS 44 0.0 (AD), AD Huntingtons disease (HD), HD amyotrophic lateral sclerosis (ALS), ALS and many others (1, 1 8 9 16 18 1 SciMiner_v2.2 1 0 0 2 11179 TotalCon:2<>11179|SOD1|6647|Complete__5468|IGFALS|3483|Complete__<>AvaiableGeneRif=2<>BEST:11179|SOD1|0.000707286291639221<>ScoreDetail__5468|IGFALS|6.43107495417859e-05__11179|SOD1|0.000707286291639221__ 0 0 0 0 0 2042 18751914 3073 10437 5992 IL1B IL-1 IL-1 4 1.0 Pro-inflammatory cytokines (TNF-_amp_#945; TNF-_amp_#945 and IL-1 secretory phospholipase A 2 IIA and lipoprotein-PLA 2 are implicated 1 SciMiner_v2.2 1 0 0 0 0 0 0 0 0 0 2043 18751914 3073 22551 11892 TNF TNF TNF-_amp_#945 2 0.1 Pro-inflammatory cytokines (TNF-_amp_#945; TNF-_amp_#945 and IL-1 secretory phospholipase A 2 IIA and lipoprotein-PLA 2 6 SciMiner_v2.2 1 0 0 0 0 0 0 0 0 0 2044 18751914 3071 10437 5992 IL1B IL-1 IL-1 2 1.0 TNF-_amp_#945 and IL-1 alter lipid metabolism and stimulate production of eicosanoids ceramide and 1 SciMiner_v2.2 1 0 0 0 0 0 0 0 0 0 2045 18751914 3071 22551 11892 TNF TNF TNF-_amp_#945 0 0.1 TNF-_amp_#945 and IL-1 alter lipid metabolism and stimulate production of eicosanoids 6 SciMiner_v2.2 1 0 0 0 0 0 0 0 0 0 2046 18751914 3066 14569 7897 NPC1 NPC1 NPC1 26 0.9 Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes resulting in defective cholesterol transport and cholesterol 1 SciMiner_v2.2 1 0 0 0 0 0 0 0 0 0 2047 18751914 3066 14571 14537 NPC2 NPC2 NPC2 28 1.4 C is due to mutations in either the NPC1 or NPC2 genes resulting in defective cholesterol transport and cholesterol accumulation 1 SciMiner_v2.2 1 0 0 0 0 0 0 0 0 0