)| PMID |
15850589 ( ) |
|---|---|
| Title | Low levels of ALS-linked Cu/Zn superoxide dismutase increase the production of reactive oxygen species and cause mitochondrial damage and death in motor neuron-like cells. |
| Abstract | Mutations of Cu/Zn superoxide dismutase (SOD1) are found in patients with familial amyotrophic lateral sclerosis (FALS). A cellular model of FALS was developed by stably transfecting the motor neuron-like cell line NSC-34 with human wild type (wt) or mutant (G93A) SOD1. Expression levels of G93ASOD1 were close to those seen in the human disease. The presence of G93ASOD1 did not alter cell proliferation but toxicity was evident when the cells were in the growth plateau phase. Flow cytometry analysis indicated that, in this phase, G93ASOD1 significantly lowered viability and that the level of reactive oxygen species was significantly higher in living G93ASOD1 cells compared to wt SOD1 cells. Biparametric analysis of mitochondrial membrane potential and viability of transfected cells highlighted a peculiar population of damaged cells with strong mitochondrial depolarization in the G93ASOD1 cells. Mitochondrial function seemed related to the level of the mutant protein since MTT conversion decreased when expression of G93ASOD1 doubled after treating cells with sodium butyrate. The mutant protein rendered G93ASOD1 cells more sensitive to mitochondrial dysfunction induced by stimuli that alter cellular free radical homeostasis, like serum withdrawal, depletion of glutathione by ethacrynic acid or rotenone-mediated inhibition of complex I of the mitochondrial electron transport chain. In conclusion, even a small amount of mutant SOD1 put motor neurons in a condition of oxidative stress and mitochondrial damage that causes cell vulnerability and death. Mario Negri, Via Eritrea 62, 20157 Milan, Italy. |
NOTE: Color highlight is limited to the abstract and SciMiner text-mining mode. If you see much more identified targets below from "Targets by SciMiner Summary" and "Targets by SciMiner Full list", they may have been identified from the full text.
Targets by SciMiner Summary
| HUGO ID | Symbol | Target Name | #Occur | ActualStr |
|---|---|---|---|---|
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | 75 | SOD1-associated | SOD1s | superoxide dismutase | |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | 2 | bcl2 | |
| 11180 | SOD2 | superoxide dismutase 2, mitochondrial | 1 | MnSOD | |
| 16554 | SLC25A6P1 | solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 6, pseudogene 1 | 1 | adenine nucleotide translocator | |
| 10990 | SLC25A4 | solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 4 | 1 | ANT | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | Mutations of Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 are found in patients with familial amyotrophic lateral sclerosis (FALS) |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | with human wild type (wt) wt or mutant (G93A) G93A SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | In conclusion even a small amount of mutant SOD1 put motor neurons in a condition of oxidative stress and |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | the gene encoding for Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 and over 100 missense mutations have been described |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | SOD1 is a free radical-scavenging enzyme since it converts the superoxide |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | is now generally accepted that the toxic effect of mutant SOD1 is not due to the loss of dismutase activity but |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | oxidative chemistry and/or and or misfolding and aggregation of mutant SOD1 (for for a review see Ref 1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | Apparently mutation converts SOD1 from an anti-apoptotic gene to a pro-apoptotic one 2 3 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | The presence of SOD1 not only in the cytosol but also in the mitochondrial |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | and in vitro models were generated by genetic manipulation of SOD1 expression |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | previous in vitro studies of the toxic effects of mutant SOD1 were conducted in cells which did not have a motor |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | However while mutant SOD1 is ubiquitously expressed the selectivity of damage towards motor neurons |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | that this cell type has a peculiar susceptibility to mutant SOD1 toxicity |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | Accordingly microinjected mutant SOD1 protein caused death in primary motor neurons but not in |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | review see Ref 10 and by a selective enrichment of SOD1 in motor neurons of the spinal cord and brainstem 11 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | Recently the effects of human mutant SOD1 were investigated in the NSC-34 motor neuron-like cell line 12 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | wt or mutant G93ASOD1 and investigated the toxicity of mutant SOD1 expressed at levels close to those seen in the human |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | and generation of NSC-34 cell lines stably transfected with human SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | with the vector cloned with wt or G93A mutant human SOD1 cDNAs 16 using the LipofectAMINE PLUS reagent (Invitrogen Invitrogen Life |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | clones were isolated grown and tested for expression of human SOD1 protein by Western blotting |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 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 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | SDS PAGE and Western blotting of SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | Protein bands identified by SOD1 antibody were detected using the ECL-Plus detection system (Amersham Amersham |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | The continued expression of wt and G93A human SOD1 was routinely checked in order to ensure the cell lines |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | cell lines expressed similar quantities of human wt and mutant SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1s | 2.4 | The expression of human SOD1s was measured with an anti-human SOD1 antibody which also cross-reacts |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | The expression of human SOD1s was measured with an anti-human SOD1 antibody which also cross-reacts with murine SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | with an anti-human SOD1 antibody which also cross-reacts with murine SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1s | 2.4 | In SDS-PAGE human SOD1s migrate at a slower rate than mouse SOD1 18 and |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | SDS-PAGE human SOD1s migrate at a slower rate than mouse SOD1 18 and accordingly two bands were detected with mouse SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | SOD1 18 and accordingly two bands were detected with mouse SOD1 being the band with the lower molecular weight |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | No human SOD1 expression is seen in cells transfected with empty vector |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | in this study was about 30% of the endogenous mouse SOD1 as measured by densitometry ( Fig 1 C |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | observed in NSC-34 cells transfected with the wt form of SOD1 while a shift towards a higher DCF fluorescence level was |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | level was observed in NSC-34 cells transfected with the mutant SOD1 protein ( Fig 3 A |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | quantified measuring the average DCF fluorescence of living untransfected wt SOD1 and G93ASOD1 transfected cells ( Fig 3 B |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | This suggests the two forms of SOD1 handle free radicals differently |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | of cells with depolarized mitochondria compared to untransfected or wt SOD1 transfected cell lines ( Fig 4 A |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 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 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | expressing mutant SOD1 protein more than in NSC-34 expressing wt SOD1 or untransfected cells ( Fig 5 A |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | h caused preferential toxicity towards cells transfected with the mutant SOD1 (about about 35% decrease Fig 5 C |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 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 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | human mutant G93A form of SOD1 as representative of the SOD1 mutant forms seen in about 20% of FALS patients |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | containing G93ASOD1 had a lower viability than those expressing wt SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | though it was expressed at a lower level than normal SOD1 a condition similar to FALS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1s | 2.4 | Apoptotic cell death by mutant SOD1s was shown in other cellular models but in these studies |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | was not investigated whether the expression level of the mutant SOD1 proteins was comparable to the level observed in the FALS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | The effect of mutant SOD1 on viability appeared when motor neurons were in the growth |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | event is the enhanced ROS formation in cells containing mutant SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | This effect is peculiar to G93ASOD1 and wt SOD1 might in fact afford protection since it lowered intracellular ROS |
| 10990 | SLC25A4 | solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 4 | ANT | 0.0 | particularly in MPTP components such as adenine nucleotide translocator (ANT) ANT |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | was also reduced in human neuroblastoma SH-SY5Y cells expressing mutant SOD1 in a ratio of 1 1 with the endogenous SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | SOD1 in a ratio of 1 1 with the endogenous SOD1 protein 24 and in primary motor neurons from G93A mice |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | The presence of mutant SOD1 in our cellular model caused the appearance of a population |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | Mitochondria of mutant SOD1 transgenic mice are also swollen and in addition abnormally vacuolated |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | damage with some relationship with the high content of mutant SOD1 in some of these in vivo experimental models |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | more affected in these cells than in NSC-34 expressing wt SOD1 after exposure to rotenone EA or serum withdrawal |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | Altered ETC activities were shown in FALS patients with SOD1 mutations (for for a review see Ref 9 in mutant |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | mutations (for for a review see Ref 9 in mutant SOD1 transgenic mice 31 and 32 and in a cell culture |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | motor neurons to excitotoxicity 36 and motor neurons containing mutant SOD1 were more vulnerable to glutamate 25 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | A fraction of SOD1 is located in this space with the putative function to |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | The presence of mutant SOD1 in the intermembrane space of FALS mitochondria might however be |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1-associated | 2.4 | mitochondria might however be critical in the pathogenesis of mutant SOD1-associated FALS 32 38 and 39 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | Our study shows that overexpression of wt SOD1 did indeed reduce the ROS level in viable motor neurons |
| 11180 | SOD2 | superoxide dismutase 2, mitochondrial | MnSOD | 1.9 | In agreement with this overexpression of MnSOD attenuates neuronal death in cellular models of FALS 12 and |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | disease onset and prolonged survival in transgenic mice with mutant SOD1 42 43 and 44 and rendered cells transfected with mutant |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | 42 43 and 44 and rendered cells transfected with mutant SOD1 more resistant to apoptosis 45 |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | bcl2 | 0.0 | Treatment with inhibitors of MPTP opening and overexpression of bcl2 which inhibits the opening of MPTP under stressful conditions delayed |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | scavengers reversed mitochondrial dysfunction and cell death due to mutant SOD1 in cell culture models of FALS 12 and 35 and |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | In conclusion this study found that motor neurons containing mutant SOD1 in amounts comparable to FALS patients are in a condition |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | determining the cell destiny in the presence of the mutant SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | Fig 1._amp_#xa0 Morphology and transfection of NSC-34 cells with human SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | Panels B and C show the expression of human SOD1 after transient or stable transfection of NSC-34 cells with empty |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | cells with empty vector wild type or G93A mutant human SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | upper and lower bands correspond to the human and murine SOD1 respectively |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | Fig 6._amp_#xa0 Effect of sodium butyrate on expression of human SOD1 and mitochondrial function |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.7 | shows the Western blot analysis of human wt or G93A SOD1 expression after 24 h treatment with sodium butyrate (NaB; NaB |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | nitrocellulose membranes were probed with a polyclonal sheep anti human superoxide dismutase cu/zn antibody 1:1000; calbiochem emd biosciences inc la jolla ca usa . |
| 16554 | SLC25A6P1 | solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 6, pseudogene 1 | adenine nucleotide translocator | 1.0 | failure to maintain this condition can result from several mechanisms including oxidative modifications of critical thiols in the inner mitochondrial membrane particularly in mptp components such as adenine nucleotide translocator ant . |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | bcl2 | 1.0 | treatment with inhibitors of mptp opening and overexpression of bcl2 which inhibits the opening of mptp under stressful conditions delayed the disease onset and prolonged survival in transgenic mice with mutant sod1 [42] [43] and [44] and rendered cells transfected wi |