HUGO ID Detailed Result 11179

HUGO ID 11179
Symbol SOD1
Name superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))
#Occurrence 1372
#Paper 62

 

PMID Match String Actual String Score Flanking text Edited by Edit
10525172SODSOD1.4with O 2 _amp_#x2212 three-fold faster than superoxide dismutase (SOD) SOD ( k =2.3_amp_#xd7 10 9 M _amp_#x2212 1 s _amp_#x2212 
10525172SODSOD1.4NO is the only known biomolecule capable of out competing SOD for available O 2 _amp_#x2212 
10525172SODSOD1.4Because the concentrations of SOD and O 2 _amp_#x2212 in a given tissue are relatively 
10525172SODSOD1.4be unlikely since Okabe et al 65 recently shown that SOD the enzyme which scavengers O 2 _amp_#x2212 colocalizes with NOS 
10525172SODSOD1.41993 Beckman et al 8 pointed out that mutations in SOD associated with the autosomal dominant inheritance of familial ALS could 
10525172SODSOD1.4the steady state concentration of O 2 _amp_#x2212 by decreasing SOD activity by 50% and increase nitration of critical cellular targets 
10525172SODSOD1.4peroxynitrite to copper a strong tyrosyl nitration catalysis in the SOD active site 
10525172SODSOD1.4by the demonstration that the zinc affinity of four ALS-associated SOD mutants was decreased up to 30-fold compared with wild-type SOD 
10525172SODSOD1.4SOD mutants was decreased up to 30-fold compared with wild-type SOD 
10525172SODSOD1.4zinc atoms with sufficient affinity to potentially remove zinc from SOD and that the loss of zinc from wild-type SOD almost 
10525172SODSOD1.4from SOD and that the loss of zinc from wild-type SOD almost doubled the efficiency of this enzyme for catalyzing for 
10525172SODSOD1.4promoted by NO produced by Type-I NOS and reversed by SOD suggesting that formation of peroxynitrite initiates apoptosis 
11220737SOD1mSOD11.4Mutations in the copper/zinc copper zinc superoxide dismutase (mSOD1) mSOD1 gene are associated with a familial form of amyotrophic lateral 
11220737SOD1mSOD11.4In both early symptomatic and end-stage transgenic mSOD1 mice neurons and to a lesser extent glial cells in 
11220737SOD1mSOD11.4also significantly increased in the spinal cord of the transgenic mSOD1 mice 
11220737SOD1mSOD11.4Cox-2 upregulation parallels that of motor neuronal loss in transgenic mSOD1 mice 
11796754SOD1SOD12.2inflammation- and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis 
11796754SOD1SOD12.2sclerosis (FALS)-linked FALS -linked mutations in copper-zinc superoxide dismutase (SOD1) SOD1 cause motor neuron death through one or more acquired toxic 
11796754SOD1SOD12.2motor neuron degeneration in the transgenic mouse model expressing the SOD1 gene with G93A mutation 
12060810SOD1SOD12.2all cases and mutations of the superoxide dismutase 1 ( SOD1 gene have been identified in about 20_amp_#37 of the familial 
12060810SOD1SOD12.2Transgenic mice over-expressing the human SOD1 gene with a mutation identified in ALS patients develop an 
12060810SOD1SOD12.2Transgenic mice with the G93A human SOD1 mutation TgN(SOD1-G93A)G1H, TgN SOD1-G93A G1H were obtained from The Jackson 
12124437SOD1SOD11.4often caused by gain-of-function mutations in Cu Zn-superoxide dismutase (SOD1) SOD1 
12124437SOD1SOD11.4genes in spinal cords of mice that ubiquitously express human SOD1 bearing a glycine (r) r alanine substitution at residue 93 
12194501SODSOD1.7expression/activity expression activity of its endogenous scavenger superoxide dismutase (SOD), SOD as a common denominator 
12194501SODSOD1.7This review summarizes the function of SOD under normal physiological conditions as well as its role in 
12194501SODSOD1.7knockouts in antioxidant enzyme/protein enzyme protein levels and the genetic SOD mutations observed in some familial cases of ALS are also 
12270689SOD1SOD11.7anti-inflammatory properties in mice expressing a mutant superoxide dismutase (SOD1(G37R)) SOD1 G37R linked to human ALS 
12270689SOD1SOD11.7muscle strength decline and it increased the longevity of SOD1(G37R) SOD1 G37R mice by approximately 5 weeks for approximately 70% of 
12270689SOD1SOD11.7end stage of disease in the spinal cord of SOD1(G37R) SOD1 G37R mice treated with minocycline 
12417341SOD1SOD13.9missense mutations in the Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 gene 1 while others are considered to be sporadic ALS 
12417341ALS1ALS13.9One SALS case (ALS1) ALS1 and a control (C1) C1 were used for the molecular 
12417341ALS1ALS13.9SALS (ALS1) ALS1 and control (C1) C1 spinal cords were used for molecular 
12417341SOD1SOD13.9FALS and SALS bound and ubiquitinated various mutant forms of SOD1 in vitro and protected from mutant SOD1-mediated neurotoxicity in mutant 
12417341SOD1SOD1-mediated3.9mutant forms of SOD1 in vitro and protected from mutant SOD1-mediated neurotoxicity in mutant SOD1 culture cells 15 
12417341SOD1SOD13.9in vitro and protected from mutant SOD1-mediated neurotoxicity in mutant SOD1 culture cells 15 
12417341SOD1SOD1-mediated3.9dorfin has a crucial role in the pathomechanism of mutant SOD1-mediated FALS 
12417341SOD1SOD13.9The elevation of MT-3 expression in G93A SOD1 transgenic mice was reported 21 and 22 and reduction of 
12417341SOD1SOD13.9MT-3 promotes the onset of disease and death in G93A SOD1 transgenic mice 23 
12843244SOD1SOD15.5upregulated in the spinal cord of superoxide dismutase 1 (SOD1) SOD1 G93A transgenic mice a mouse model of amyotrophic lateral sclerosis 
12843244SOD1SOD15.5in the spinal cord of symptomatic caspase-11 -/-;SOD1 - - SOD1 G93A mice compared with that of caspase-11 +/-; - SOD1 
12843244SOD1SOD15.5SOD1 G93A mice compared with that of caspase-11 +/-; - SOD1 G93A mice 
12843244SOD1SOD15.5neurodegeneration inflammatory responses and the disease onset and progression in SOD1 G93A transgenic mice were not altered by the ablation of 
12843244SOD1SOD15.5Key words ALS motor neuron degeneration neurodegeneration SOD1 caspase apoptosis 
12843244SOD1SOD15.5several mutations in the Cu /Zn Zn superoxide dismutase (SOD1) SOD1 are causally responsible for a subset of familial ALS (FALS) 
12843244SOD1SOD15.5Consistent with a causal role of SOD1 mutations in FALS transgenic mice expressing human SOD1 mutants develop 
12843244SOD1SOD15.5role of SOD1 mutations in FALS transgenic mice expressing human SOD1 mutants develop age-dependent progressive motor neuron degeneration with cellular pathological 
12843244SOD1SOD15.5of caspase-1 and caspase-3 in the spinal cords of mutant SOD1 mice and ALS patients has been reported previously (Martin, Martin 
12843244SOD1SOD15.5the onset and progression of the disease symptoms in G93A SOD1 (G93A) G93A transgenic mice (Friedlander Friedlander et al. 1997 Li 
12843244SOD1SOD1-mediated3.2of ALS a critical role of individual caspases in mutant SOD1-mediated neurodegeneration has not been examined in different caspase mutant mice 
12843244SOD1SOD15.5in relation to the early events of pathogenesis in mutant SOD1 transgenic mice such as mitochondrial dilation neurofilament abnormality and glutamate 
12843244SOD1SOD15.5Mouse lines expressing human SOD1 mutant G93A [C57BL/6J-TgN(SOD1-G93A)1Gurdl] C57BL 6J-TgN SOD1-G93A 1Gurdl were obtained from 
12843244SOD1SOD15.5To minimize the variations in genetic background one SOD1 G93A transgenic male mouse was mated with one female caspase-11 
12843244SOD1SOD15.5An F1 male mouse (caspase-11+/-;SOD1 caspase-11 - SOD1 G93A was mated with two caspase-11 - -mice and one 
12843244SOD1SOD15.5Antibodies against human- and mouse-specific SOD1 were obtained from Chemicon (Temecula, Temecula CA 
12843244SOD1SOD15.5demonstrating that the neural degeneration and accelerated death of G37R SOD1 mice are not altered in the background of IL-1 beta- 
12843244SOD1SOD15.5These results suggest that the expression of G93A SOD1 may induce neurodegeneration through multiple pathways that may involve multiple 
12843244SOD1SOD15.5IL-1 beta- -mice did not alter the disease course of SOD1 G37R mice (Nguyen Nguyen et al. 2001 the most likely 
12843244SOD1SOD15.5Motor neurons expressing mutant SOD1 have been shown to have an enhanced sensitivity toward Fas-induced 
12843244SODSOD-expressing3.2-9 was found only at the end stage of mutant SOD-expressing transgenic mice (Gu_amp_eacute;gan Gu_amp_eacute gan et al. 2001 2002 
12843244SOD1SOD15.5The exact parallels between SOD1 mutant transgenic mice and human ALS are not clear because 
12843244SOD1SOD15.5D The expression of the human mutant SOD1 protein is not affected by the absence of caspase-11 in 
12843244SOD1SOD15.5mouse-specific anti-SOD1 antibodies for the detection of introduced and endogenous SOD1 proteins respectively 
12843244SOD1SOD15.5caspase-11 gene affected the expression level of the human mutant SOD1 protein in the double-mutant mice we compared the levels of 
12843244SOD1SOD15.5of caspase-11 did not alter the expression of the mutant SOD1 protein in the double-mutant mice 
12843244SOD1SOD15.5- - G93A mice the inflammatory response induced by mutant SOD1 was not significantly altered 
14511332SOD1SOD12.9gene encoding for the Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 account for a familial form of ALS linked to chromosome 
14511332SOD1SOD12.9Transgenic mice expressing mutant SOD1 develop a phenotype that mimics the clinical and pathological characteristics 
14511332SOD1mSOD13.2the immunohistochemical distribution of COX-2 in the spinal cord of mSOD1 mice over the progression of the disease 
14511332SOD1SOD12.9(2001 2001 demonstrated a role for COX-2 in mutant SOD1 mice and Yasojima et al 
14511332SOD1mSOD13.2of IL-1beta also attenuates the loss of motor neurons in mSOD1 mice ( Friedlander et al . 1997 
14511332SOD1mSOD13.2In agreement with a study in transgenic mSOD1 mice ( Almer et al . 2001 COX-2 was found 
14511332SOD1mSOD13.2a previous study investigating the expression of COX proteins in mSOD1 mice 
14511332SOD1mSOD13.2although no apparent differences in COX-1 expression were seen between mSOD1 mice and controls 
14511332SODSOD2.9fluid GFAP glial fibrillary acidic protein IR immunoreactivity PG prostaglandins SOD superoxide dismutase 
14597108SOD1SOD11.4Cu/Zn Cu Zn form of the superoxide dismutase gene (SOD1), SOD1 an animal model of ALS Alexianu et al. 2001 
14739060SODSOD1.3of motor neurons caused by a missense mutation of CuZn SOD (SOD1) SOD1 is an illustration of how these mechanisms can 
14739060SOD1SOD12.1neurons caused by a missense mutation of CuZn SOD (SOD1) SOD1 is an illustration of how these mechanisms can lead to 
14739060SOD1SOD12.1In transgenic mice expressing the human mutant SOD1 gene syndrome develops with many features of ALS including specific 
14739060SOD1SOD12.1to compare the evolution for motor neurons degeneration in mutant SOD1 transgenic mouse with non-transgenic mouse and normal human SOD1 transgenic 
14739060SOD1SOD12.1mutant SOD1 transgenic mouse with non-transgenic mouse and normal human SOD1 transgenic mouse 46 50 47 48 and 49 
14739060SOD1SOD12.1The toxicity of mutant SOD1 seems to be due to a gain of function of 
14739060SOD1SOD12.1It is also conceivable mutant SOD1 denatures more quickly in vivo than the normal form and 
14739060SOD1SOD12.1Oxidative stress may be involved in misfolding of mutant SOD1 to form abnormal protein aggregates found as early as 1_amp_#xa0 
14739060SOD1SOD12.1disorganization of intermediate filaments could be due also to mutant SOD1 induced toxicity as their proteins are vulnerable to oxidative damage 
14739060SOD1SOD12.1in patients with sporadic ALS and in transgenic mice with SOD1 mutations 
14739060SODSOD1.3of ubiquinated cytoplasmic inclusion bodies some of which contain aggregated SOD 46 
14739060SOD1SOD12.1The studies on mutant SOD1 transgenic mice 46 and 63 revealed an up-regulation of gene 
14960605SOD1SOD13.0expressing a mutant form of the superoxide dismutase 1 (SOD1 SOD1 linked to familial amyotrophic lateral sclerosis were challenged intraperitoneally with 
14960605SOD1SOD13.0At different ages SOD1 mice responded normally to acute endotoxemia 
14960605SOD1SOD13.0Remarkably only a chronic challenge with LPS in presymptomatic 6-month-old SOD1 mice exacerbated disease progression by 3 weeks and motor axon 
14960605SOD1SOD13.0and efferent fiber tracts of the brain from the LPS-treated SOD1 mice 
14960605SOD1SOD13.0mice expressing a mutant form of superoxide dismutase 1 (SOD1 SOD1 linked to amyotrophic lateral sclerosis (ALS), ALS the most common 
14960605SOD1SOD13.0The SOD1 protein is a cytosolic metalloenzyme catalyzing the conversion of superoxide 
14960605SOD1SOD13.0Transgenic mice expressing mutant SOD1 develop motor neuron disease resembling ALS through a gain of 
14960605SOD1SOD13.0Despite these findings the toxicity of SOD1 mutants linked to human ALS remains poorly understood 
14960605SOD1SOD13.0SOD1 is a ubiquitously expressed protein and therefore it is possible 
14960605SOD1SOD13.0Indeed a restricted expression of mutant SOD1 to neurons in transgenic mice was not sufficient to provoke 
14960605SOD1SOD13.0Neither did the selective expression of mutant SOD1 in astrocytes provoke pathology despite astrocytosis (Gong Gong et al. 
14960605SOD1SOD13.0In the present study we triggered the innate immunity of SOD1 mice with systemic administration of lipopolysaccharide (LPS), LPS a potent 
14960605SOD1SOD13.0immunity by systemic LPS is noxious to motor neurons bearing SOD1 linked to ALS 
14960605SOD1SOD13.0Generation of SOD1 mice and protocol for LPS injection 
14960605SOD1SOD13.0The inbred C57BL/6 C57BL 6 SOD1 mice (line line 29 used in this study have a 
14960605SOD1SOD13.0C57BL/6 C57BL 6 SOD1 mice (line line 42 exhibit a life span of 5-6 
14960605SOD1SOD13.0The SOD1 mice were housed at room temperature (21degreeC) 21degreeC and in 
14960605SOD1SOD13.0immune response in the CNS presymptomatic 3- 6- and 9-month-old SOD1 mice received a single intraperitoneal injection of LPS (1 1 
14960605SOD1SOD13.0Another group of presymptomatic 6-month-old SOD1 mice received intraperitoneal LPS or vehicle injections once every 2 
14960605SOD1SOD13.0month 9 (42-43 42-43 weeks of age the chronically LPS-treated SOD1 mice exhibited the first signs of paralysis and the injections 
14960605SOD1SOD13.0At the same time Veh-SOD1 or SOD1 mice that did not show signs of paralysis were killed 
14960605SOD1SOD13.0Some of the Veh-SOD1 or SOD1 were left until they exhibited the paralytic phenotype (3-5 3-5 
14960605SOD1SOD13.0Thus the analysis of the Veh-SOD1 and SOD1 mice was performed strictly before the onset and not at 
14960605SOD1SOD13.0SOD1 mice exhibited a normal innate immune response after an acute 
14960605SOD1SOD13.0and spinal cord of both normal wild-type (WT)] WT and SOD1 mice ( Fig 1 
14960605SOD1SOD13.0several other inflammatory genes takes place in transgenic mice expressing SOD1 linked to ALS (Nguyen Nguyen et al. 2001b 
14960605SOD1SOD13.0the pathogenesis and neuronal death processes of ALS caused by SOD1 mutation 
14960605SOD1SOD13.0Although SOD1 mice responded normally to an acute systemic injection of LPS 
14960605SOD1SOD13.0not accompanied by enhanced expression of both endogenous and transgene SOD1 ( Fig 6 
14960605SOD1SOD13.0As a consequence the chronically LPS-treated SOD1 mice exhibited accelerated disease progression motor axon degeneration and a 
14960605SOD1SOD13.0Interestingly chronically LPS-treated SOD1 mice exhibited a more important loss of astrocytes than Veh-treated 
14960605SOD1SOD13.0a more important loss of astrocytes than Veh-treated or nontreated SOD1 mice 
14960605SOD1SOD13.0and CD8 cells in the brain and spinal cord of SOD1 mice treated chronically with vehicle or LPS 
14960605SOD1SOD13.0response may be toxic for the CNS of the LPS-treated SOD1 and SOD1 mice 
14960605SOD1SOD13.0response may be toxic for the CNS of the LPS-treated SOD1 and SOD1 mice 
14960605SOD1SOD13.0be toxic for the CNS of the LPS-treated SOD1 and SOD1 mice 
14960605SOD1SOD13.0For instance upregulation of the local adaptive immune response in SOD1 mice with Copaxone (glatiramer glatiramer acetate vaccination eliminates destructive self-compounds 
14960605SOD1SOD13.0TNF-alpha gene expression progressively increased in the spinal cord of SOD1 mice (Nadeau Nadeau and Rivest 2000 alpha levels are also 
14960605SOD1SOD13.0the toxicity of chronic administration of LPS in the mutant SOD1 mice our study constitutes a simple example of genetic modulation 
14960605SOD1SOD13.0TLR2 gene expression in the brains and spinal cords of SOD1 mice and their WT littermates 
14960605SOD1SOD13.0within the brain and spinal cord of both WT and SOD1 mice that received an intraperitoneal bolus of LPS 
14960605SOD1SOD13.0endotoxin LPS increases the innate immune response and neurodegeneration in SOD1 mice 
14960605SOD1SOD13.0Exacerbation of motor axon degeneration in chronically LPS-treated SOD1 mice accelerates disease progression 
14960605SOD1SOD13.0A Survival curves of transgenic mice expressing SOD1 challenged systemically with LPS or vehicle every 2 weeks 
14960605SOD1SOD13.0with vehicle (WT-Veh) WT-Veh or LPS (WT-LPS) WT-LPS and from SOD1 mice challenged chronically with vehicle (G37R-Veh) G37R-Veh or LPS (G37R-LPS) 
14960605SOD1SOD13.0Robust inflammatory response in ventral spinal horn of chronically LPS-treated SOD1 mice associated with massive degeneration of astrocytes 
14960605SOD1SOD13.0neurons and astrocytes in this region of spinal cord from SOD1 mice 
14960605SOD1SOD13.0expression levels of TLR2 hybridization signal in the brains of SOD1 mice and their wild-type littermates that received chronic systemic injections 
14960605SOD1SOD13.0Acute and chronic administration of LPS in SOD1 failed to alter expression of endogenous and transgene SOD1 Six-month-old 
14960605SOD1SOD13.0in SOD1 failed to alter expression of endogenous and transgene SOD1 Six-month-old WT and transgenic SOD1 littermates were analyzed for SOD1 
14960605SOD1SOD13.0expression of endogenous and transgene SOD1 Six-month-old WT and transgenic SOD1 littermates were analyzed for SOD1 levels 24 hr after acute 
14960605SOD1SOD13.0SOD1 Six-month-old WT and transgenic SOD1 littermates were analyzed for SOD1 levels 24 hr after acute injection of LPS (1 1 
14960605SOD1mSOD11.7Expression of both endogenous mSOD1 and hSOD1 remained unaffected in spinal cord ( A lanes 
14960605SOD1hSOD11.7Expression of both endogenous mSOD1 and hSOD1 remained unaffected in spinal cord ( A lanes 5-8 and 
14960605SOD1SOD13.0A lanes 5-8 and spleen ( B lanes 5-8 of SOD1 animals in response to saline (Veh) Veh or LPS injection 
14960605SOD1SOD13.0injection as detected by means of an antibody recognizing both SOD1 proteins 
14960605SOD1mSOD11.7The endotoxin also failed to significantly upregulate mSOD1 expression in WT animals ( A B lanes 1-4 
14960605SOD1SOD1s1.7Similar levels of both SOD1s were found in WT and SOD1 mice 48 hr after 
14960605SOD1SOD13.0Similar levels of both SOD1s were found in WT and SOD1 mice 48 hr after LPS or Veh administration (data data 
14960605SOD1SOD13.0In SOD1 mice that were chronically treated with LPS expression of mutant 
14960605SOD1SOD13.0mice that were chronically treated with LPS expression of mutant SOD1 (detected detected with an antibody directed against the human transgene 
14960605SOD1SOD13.0Lysates from SOD1 line 42 (L42) L42 overexpressing 2- to 2.5-fold the levels 
14960605SOD1SOD13.0Thus neither acute nor chronic administration of LPS in SOD1 mice affected expression of endogenous and transgene SOD1 
14960605SOD1SOD13.0LPS in SOD1 mice affected expression of endogenous and transgene SOD1 
14960605SOD1SOD13.0Membranes were incubated with antibodies against SOD1 (Biodesign; Biodesign Santa Cruz Biotechnology Santa Cruz CA alpha-tubulin (B512; 
14960605SOD1SOD13.0in different regions of the CNS in both WT and SOD1 groups of mice challenged acutely with LPS ( Fig 1 
14960605SOD1SOD13.0area postrema (AP) AP and spinal L5 segment of LPS-treated SOD1 mice did not exhibit a different hybridization signal when compared 
14960605SOD1SOD13.0These results indicate that SOD1 are not more sensitive to the endotoxin and therefore exhibit 
14960605SOD1SOD13.0of LPS exacerbate disease progression and motor axon degeneration in SOD1 mice 
14960605SOD1SOD13.0injection of an equal dose of LPS in presymptomatic 6-month-old SOD1 mice had a significant effect on their life span 
14960605SOD1SOD13.0Figure 2 A shows the survival curve of SOD1 mice (line line 29 treated chronically with Veh or LPS 
14960605SOD1SOD13.0The SOD1 mice treated with vehicle ( n = 16 used as 
14960605SOD1SOD13.0is not different from the life span of the nontreated SOD1 mice (Nguyen Nguyen et al. 2000 2001a 
14960605SOD1SOD13.0SOD1 mice treated chronically with LPS ( n = 13 exhibited 
14960605SOD1SOD13.0injections of a nontoxic dose of LPS in presymptomatic 6-month-old SOD1 mice exacerbated disease progression by 3 weeks 
14960605SOD1SOD13.0counted the number of axons in L5 ventral roots of SOD1 mice treated chronically with LPS or vehicle and killed at 
14960605SOD1SOD13.0At this age the L5 ventral roots of LPS-treated SOD1 mice were smaller when compared with those dissected from Veh-SOD1 
14960605SOD1SOD13.0Furthermore LPS-treated SOD1 mice ( n = 5 had 358 _amp_#177 48 axons 
14960605SOD1SOD13.0n = 5 had 358 _amp_#177 48 axons whereas Veh-treated SOD1 mice ( n = 4 had 478 _amp_#177 40 ( 
14960605SOD1SOD13.0there was a more severe loss of motor axons in SOD1 mice that received repeated injections with the endotoxin 
14960605SOD1SOD13.0innate immunity TLR2 and the proapoptotic cytokine TNF-alpha in the SOD1 mice challenged chronically with LPS 
14960605SOD1SOD13.0TLR2 is induced during disease progression of SOD1 mice and especially in late stages where massive neurodegeneration occurs 
14960605SOD1SOD13.0innate immune response was much more pronounced in chronically LPS-treated SOD1 mice than in Veh-treated SOD1 mice (Figs Figs 3 4 
14960605SOD1SOD13.0more pronounced in chronically LPS-treated SOD1 mice than in Veh-treated SOD1 mice (Figs Figs 3 4 5 
14960605SOD1SOD13.0were found in the spinal cord of chronically LPS-treated mutant SOD1 mice ( Fig 4 B 
14960605SOD1SOD13.0Absence of adaptive immunity in the CNS of LPS-treated SOD1 mice 
14960605SOD1SOD13.0of IL-12 in degenerating CNS regions of the chronically LPS-treated SOD1 mice when compared with chronically Veh-treated SOD1 mice 
14960605SOD1SOD13.0the chronically LPS-treated SOD1 mice when compared with chronically Veh-treated SOD1 mice 
14960605SOD1SOD13.0for IFN-gamma transcript in the brain and spinal cord of SOD1 mice treated acutely or chronically with the endotoxin 
14960605SOD1SOD13.0T cells in the CNS of both vehicle- and LPS-treated SOD1 mice (data data not shown 
14960605SOD1SOD13.0Accelerated neurodegeneration in chronically LPS-treated SOD1 mice is not attributable to an upregulation in levels of 
14960605SOD1SOD13.0Emerging evidence indicates that LPS can induce SOD1 which subsequently might play an important role in mediating the 
14960605SOD1SOD13.0the understanding of mechanisms causing accelerated neurodegeneration in chronically LPS-treated SOD1 mice is whether LPS upregulates expression of the transgene SOD1 
14960605SOD1SOD13.0SOD1 mice is whether LPS upregulates expression of the transgene SOD1 
14960605SOD1SOD13.0Indeed transgenic mice having higher levels of SOD1 (line line 42 exhibit a more aggressive pathology with previous 
14960605SOD1SOD13.0To address this question protein levels for both endogenous mouse SOD1 (mSOD1) mSOD1 and human mutant SOD1 (hSOD1) hSOD1 were determined 
14960605SOD1mSOD11.7this question protein levels for both endogenous mouse SOD1 (mSOD1) mSOD1 and human mutant SOD1 (hSOD1) hSOD1 were determined in SOD1 
14960605SOD1SOD13.0for both endogenous mouse SOD1 (mSOD1) mSOD1 and human mutant SOD1 (hSOD1) hSOD1 were determined in SOD1 mice in response to 
14960605SOD1hSOD11.7endogenous mouse SOD1 (mSOD1) mSOD1 and human mutant SOD1 (hSOD1) hSOD1 were determined in SOD1 mice in response to acute or 
14960605SOD1SOD13.0mSOD1 and human mutant SOD1 (hSOD1) hSOD1 were determined in SOD1 mice in response to acute or chronic injection of LPS 
14960605SOD1mSOD11.7As shown in Figure 6 mSOD1 and hSOD1 levels in spinal cord and spleen were unchanged 
14960605SOD1hSOD11.7As shown in Figure 6 mSOD1 and hSOD1 levels in spinal cord and spleen were unchanged 24 hr 
14960605SOD1SOD13.0In addition SOD1 mice chronically challenged with LPS did not display increased levels 
14960605SOD1SOD13.0caused by chronic LPS treatment is not caused by enhanced SOD1 expression 
14960605SOD1SOD13.0San Diego La Jolla CA for the kind gift of SOD1 mice (line line 29 Dr Y Imai (National National Institute 
15081582SOD1SOD11.4mutations in the cytosolic protein copper_amp_#x2013 zinc superoxide dismutase (SOD1) SOD1 were reported in several FALS families 
15081582SOD1SOD11.4Since then over 95 mutations in SOD1 have been identified in patients with FALS ( Mithal et 
15081582SOD1SOD11.4SOD1 is a metalloenzyme that detoxifies the superoxide anion to form 
15081582SOD1SOD11.4However SOD1 mutations account for only 20% of familial ALS ( Feldman 
15081582SOD1SOD11.4Because mutant SOD1 explains only a very small subset of ALS pathology it 
15081582SOD1SOD1-expressing1.4In the spinal cords of transgenic mutant human SOD1-expressing (mSOD1) mSOD1 mice there is increased expression of COX-2 but 
15081582SOD1mSOD11.4In the spinal cords of transgenic mutant human SOD1-expressing (mSOD1) mSOD1 mice there is increased expression of COX-2 but not COX-1 
15081582SOD1mSOD11.4increased in the spinal cord but not the cerebellum of mSOD1 mice 
15081582SOD1mSOD11.4COX-2 levels in mSOD1 mice are increased in both early symptomatic and end-stage disease 
15081582SOD1mSOD11.4In the transgenic mSOD1 mouse the nonselective COX inhibitor acetylsalicylate delays the appearance of 
15081582SOD1mSOD11.4a different selective COX-2 inhibitor also prolongs survival in the mSOD1 mouse model of ALS ( Drachman et al. 2002 
15210305ALS1ALS12.9The first ALS locus (ALS1) ALS1 to be identified on chromosome 21 contains the cytosolic copper_amp_#x2013 
15210305SOD1SOD16.9chromosome 21 contains the cytosolic copper_amp_#x2013 zinc superoxide dismutase (SOD1) SOD1 gene which has been found to harbour at least 100 
15210305SOD1SOD16.9age of onset of disease in FALS cases carrying a SOD1 mutation 
15210305SOD1SOD16.9Similarly when CNTF-deficient mice are crossed with SOD1 G93A transgenic mice an earlier age of onset has been 
15210305SOD1SOD16.9post-mortem tissue and tissues taken from animal models (G93 G93 SOD1 transgenic mouse of ALS have been investigated 
15210305SOD1SOD16.9With the discovery of SOD1 gene mutations oxidative stress has gained momentum as a major 
15210305SOD1SOD16.9The cytosolic SOD1 protein has a widespread expression in different human tissues and 
15210305SOD1SOD16.9Human motor neurones show high levels of expression of SOD1 proteins compared to others neurones and this may reflect a 
15210305SOD1SOD16.9It has been proposed that SOD1 may be crtical for motor neurones in stressful conditions but 
15210305SOD1SOD16.9slowing of axonal transport is an important feature in mutant SOD1 mice 111 where NF aggregates are detected which affect transport 
15210305SOD1SOD16.9reduces neuronal reactive oxygen species (ROS) ROS content and enhances SOD1 protein levels during staurosporine-induced apoptosis in primary cultures from neonatal 
15210305SOD1SOD16.9also been found to be up-regulated in spinal cord from SOD1 G93A transgenic mice 76 
15210305SOD1SOD16.9in spinal cord of transgenic mouse models with the G93A SOD1 gene mutation 37 76 and 115 the molecular profiling of 
15210305SOD1SOD16.9In SOD1 G93A mice the timing of behavioural and pathological changes appears 
15210305SOD1SOD16.9stem cortex and in Purkinje cells of the cerebellum in SOD1 mutant animals 52 
15210305SOD1SOD16.9hypoglossal nerve injury and in erythrocytes of FALS cases with SOD1 mutations 60 61 and 75 
15210305SOD1SOD16.9The study of SOD1 G93A transgenic mice by Olsen et al 76 identified a 
15210305SOD1SOD16.9may also account for diversities in the molecular profile between SOD1 animal models and human tissue studies 
15210305SOD1SOD16.9a markedly increased expression in spinal cord astrocytes of G93A SOD1 transgenic mice particularly in the early stage of disease whereas 
15210305SOD1SOD16.9abnormal copper homeostasis may reflect the activity of the mutated SOD1 enzyme 
15210305SOD1SOD16.9Cystatin B was also found to be close to the SOD1 gene on chromosome 21 
15210305SOD1SOD16.9Time-dependent differential gene expression in spinal cord from the G93A SOD1 gene transgenic mouse model 
15210305SOD1SOD16.9spinal cord of animal model of the disease (G93A G93A SOD1 gene transgenic mouse candidate genes found to have an early 
15453089SOD1SOD13.4gene encoding for the Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 account for a familial form of ALS linked to chromosome 
15453089SOD1SOD13.4has led to the development of transgenic mice expressing mutant SOD1 with phenotype that mimics clinical and pathological characteristics of the 
15453089SOD1SOD13.4spinal cords of ALS patients ( 42 and transgenic mutated SOD1 mice ( 43 
15453089SOD1SOD13.4similar pattern of COX-2 expression was reported for the mutated SOD1 transgenic mice ( 43 
15453089SOD1SOD13.4Subsequently the same group showed that treatment of SOD1 transgenic mice with COX-2 inhibitor celecoxib significantly delayed the onset 
15453089SOD1SOD13.4In transgenic mutated SOD1 mice COX-2 and iNOS are induced with a similar temporal 
15571972SODSOD1.0therapeutic efficacy of the antibiotic has been tested in the SOD G93A (10_amp_#x2013;50 10_amp_#x2013 50 mg/kg mg kg i.p Van Den 
15571972SODSOD1.0al. 2002 and Zhu et al. 2002 and in the SOD G37R (1 1 g/kg g kg in diet Kriz et 
15571972SODSOD1.0against the neurotoxicity of CSF coming from patients carrying the SOD D90A mutation ( Tikka et al. 2002 
15571972SOD1SOD11.0supplements has been shown to be very effective in the SOD1 G37R mouse model of ALS with a major increase of 
15571972SOD1SOD11.0sole therapy significantly delayed disease onset and increased survival of SOD1 G93A mice ( Zhang et al. 2003b as compared to 
15572176SOD1SOD-12.4mutations in the gene encoding copper zinc superoxide dismutase (SOD-1) SOD-1 106 
15572176SOD1SOD-12.4the disease carrying the expression of high levels of mutated SOD-1 genes 
15572176SOD1SOD-12.4Toxicity of mutant SOD-1 involves a dominant gain-of-function rather than simply diminished superoxide-scavenging activity 
15572176SOD1SOD-12.4Spinal motor neurons express high levels of mutant SOD-1 which might explain the selective vulnerability of these neurons 
15572176SOD1SOD-12.4However current evidence indicates that ALS-linked SOD-1 mutations must be expressed in both neuronal and non-neuronal cells 
15572176SOD1SOD-12.4spinal cord nerve or skeletal muscle are required for mutated SOD-1 to initiate neurodegeneration in ALS 
15572176SOD1SOD-12.4of mixtures of normal cells and cells expressing ALS mutant SOD-1 showed that motor neuron degeneration is not necessarily associated with 
15572176SOD1SOD-12.4neuron degeneration is not necessarily associated with the expression of SOD-1 mutations in the motor neuron per se but rather with 
15572176SOD1SOD-12.4animal models of ALS including mice and rats carrying different SOD-1 mutations 
15572176SOD1SOD-12.4In the case of mice expressing the G85R SOD-1 mutation astrocytes display major morphological and functional changes characterized by 
15572176SOD1SOD1-containing1.9major morphological and functional changes characterized by the appearance of SOD1-containing aggregates and decreased expression of glial glutamate transporter GLT-1 18 
15572176SOD1SOD-12.4However the selective expression of the equivalent murine of G86R SOD-1 mutation in astroglia under the control of a GFAP promoter 
15572176SOD1SOD-12.4and disease 52 indicating that glial pathology induced by mutant SOD-1 is not sufficient to initiate neurodegeneration 
15572176SOD1SOD-12.4Thus the selective expression of SOD-1 mutations in glial cells cannot explain per se the striking 
15572176SOD1SOD-12.4earlier and more evident astrocytic alterations compared to the G93A SOD-1 mice 
15572176SOD1SOD-12.4present protein aggregates such as Lewy body-like hyaline inclusions containing SOD-1 are not restricted to motor neurons but are also abundant 
15572176SOD1SOD-12.4deprivation 35 Fas pathway activation 101 or loading with zinc-deficient SOD-1 36 
15572176SOD1SOD-12.4showing that astrocyte and microglia activation around motor neurons in SOD-1 G93A mice occurs after the onset of distal axon degeneration 
15572176SOD1SOD-12.4for motor neurons modulating astrocytes reactivity was provided in G93A SOD-1 mice expressing increased levels of insulin growth factor-1 (IGF-1) IGF-1 
15572176SOD1SOD-12.4transporters has also been documented in the spinal cord of SOD-1 G85R transgenic mice 18 and G93A transgenic rats 62 
15572176SOD1SOD11.9be affected in presymptomatic or symptomatic mice carrying the G93A SOD1 mutation and are characterized by less pronounced tardy astrocyte reactivity 
15572176SOD1SOD11.9recently reported in the spinal cord of chronically LPS-treated mutant SOD1 mice 88 
15572176SOD1SOD-12.4cultured motor neurons undergoing apoptosis 35 and 36 in mutant SOD-1 mice 42 and 116 and in sporadic and familial cases 
15572176SODSOD-mimetic1.9Mn-TBAP is a membrane permeant SOD-mimetic and peroxynitrite scavenger 40 
15572176SODSOD1.9Furthermore motor neurons from transgenic mice overexpressing ALS-linked SOD mutations G37R G85R or G93A display an increased susceptibility to 
15572176SODSOD1.9Survival of SOD G93A mice is significantly increased by systemic treatment with an 
15572176SOD1SOD11.9increase in survival was reported in double transgenic mice expressing SOD1 G93A but lacking p75 NTR 73 
15649489SOD1SOD11.7a peroxisome proliferator-activated receptor-gamma (PPAR-_amp_#x3b3;) PPAR-_amp_#x3b3 agonist in the G93A SOD1 transgenic mouse model of ALS 
15649489SOD1SOD11.7the gene coding for copper_amp_#x2013 zinc superoxide dismutase 1 (SOD1) SOD1 in a subset of patients with autosomal dominant inherited ALS 
15649489SOD1SOD11.7could delay or slow the disease process in the G93A SOD1 transgenic mouse model of ALS 
15649489SOD1SOD11.7Thirty-nine G93A SOD1 transgenic mice were randomly assigned to control (vehicle) vehicle and 
15649489SOD1SOD11.7Actos was given in food at 1200 ppm to G93A SOD1 mice ( n = 18 and control mice ( n 
15649489SOD1SOD11.7Transcription profiling of the spinal cords of mice with G93A SOD1 mutations showed up-regulation of tumor necrosis factor- CD68 and caspase-1 
15649489SOD1SOD11.7The effect of pioglitazone treatment on motor performance in G93A SOD1 transgenic mice from 72 days to 140 days of age 
15649489SOD1SOD11.7( Pioglitazone-treated G93A mice ( vehicle-treated G93A SOD1 
15649489SOD1SOD11.7of pioglitazone treatment on Nissl-stained neuronal cell count in G93A SOD1 transgenic mice at 110 days of age 
15657392SOD1SOD12.5results from a toxic gain of function associated with dominant SOD1 mutations the etiology of the disease and its specific cellular 
15657392SOD1SOD12.5isoform maintained muscle integrity and enhanced satellite cell activity in SOD1 transgenic mice inducing calcineurin-mediated regenerative pathways 
15657392SOD1SOD12.5in the spinal cord and enhanced motor neuronal survival in SOD1 mice delaying the onset and progression of the disease 
15657392SOD1SOD12.5as a primary target for the dominant action of inherited SOD1 mutation and suggest that muscle fibers provide appropriate factors such 
15657392SOD1SOD12.5factor mIgf-1 local isoform of Igf-1 MyHC myosin heavy chain SOD1 superoxide dismutase1 wt wild-type 
15657392SOD1SOD12.5Transgenic mice ubiquitously overexpressing human SOD1 mutants develop motor neuron disease resembling ALS ( Gurney et 
15657392SOD1SOD12.5Notably restriction of SOD1 mutant expression selectively to post-natal motor neurons failed to produce 
15657392SOD1SOD12.5Indeed analysis of chimeras generated between wild-type and SOD1 mutant mouse embryonic cells revealed that wild-type non neuronal cells 
15657392SOD1SOD12.5neuronal cells in adult chimeric animals extended the survival of SOD1 mutant motor neurons suggesting that the neurodegenerative action of mutant 
15657392SOD1SOD12.5mutant motor neurons suggesting that the neurodegenerative action of mutant SOD1 may operate through a dominant paracrine activity emanating from nonneuronal 
15657392SOD1SOD12.5is an untested component in the motor neurodegenerative effects of SOD1 mutations 
15657392SOD1SOD12.5In a recent study injection of SOD1 mutant mouse muscle with an adeno-associated virus carrying an Igf-1 
15657392SOD1SOD12.5To assess the effects of supplemental Igf-1 directly on atrophic SOD1 skeletal muscle we exploited a transgenic mouse expressing a full-length 
15657392SOD1SOD12.5MLC/mIgf-1 MLC mIgf-1 transgene exclusively in the skeletal muscle of SOD1 mice counteracted the symptoms of ALS induced satellite cell activity 
15657392SOD1SOD12.5junctions and led to a reduction in astrocytosis in the SOD1 spinal cord 
15657392SOD1SOD12.5the progression of the disease and enhances the survival of SOD1 mutant mice 
15657392SODSOD2.2(a) a Western blot analysis of human SOD transgenic protein in wild-type (lane lane 1 MLC/mIgf-1 MLC mIgf-1 
15657392SOD1SOD12.5wild-type (lane lane 1 MLC/mIgf-1 MLC mIgf-1 (lane lane 2 SOD1 (lane lane 3 and SOD1 /mIgf-1 mIgf-1 (lane lane 4 
15657392SOD1SOD12.5MLC mIgf-1 (lane lane 2 SOD1 (lane lane 3 and SOD1 /mIgf-1 mIgf-1 (lane lane 4 transgenic muscle 
15657392SOD1SOD12.5(wt; wt lane 1 MLC/mIgf-1 MLC mIgf-1 (lane lane 2 SOD1 (lane lane 3 and SOD1 /mIgf-1 mIgf-1 (lane lane 4 
15657392SOD1SOD12.5MLC mIgf-1 (lane lane 2 SOD1 (lane lane 3 and SOD1 /mIgf-1 mIgf-1 (lane lane 4 transgenic mice in brain and 
15657392SOD1SOD12.5of MLC/mIgf-1 MLC mIgf-1 (lanes lanes 5 and 7 and SOD1 /mIgf-1 mIgf-1 (lanes lanes 6 and 8 mice 
15657392SOD1SOD12.5(c) c Age of onset of disease symptoms average onset SOD1 ( n = 30 = 111 _amp_#177 1.8 SOD1 /mIgf-1 
15657392SOD1SOD12.5onset SOD1 ( n = 30 = 111 _amp_#177 1.8 SOD1 /mIgf-1 mIgf-1 ( n = 30 = 120.8 _amp_#177 1.0 
15657392SOD1SOD12.5of the progression of the disease average of disease duration SOD1 ( n = 30 =12 _amp_#177 0.6 SOD1 /mIgf-1 mIgf-1 
15657392SOD1SOD12.5disease duration SOD1 ( n = 30 =12 _amp_#177 0.6 SOD1 /mIgf-1 mIgf-1 ( n = 30 = 32 _amp_#177 0.8 
15657392SOD1SOD12.5= 32 _amp_#177 0.8 (e) e survival analysis average survival SOD1 ( n = 30 = 123 _amp_#177 1.4 SOD1 /mIgf-1 
15657392SOD1SOD12.5survival SOD1 ( n = 30 = 123 _amp_#177 1.4 SOD1 /mIgf-1 mIgf-1 ( n = 30 = 152.8 _amp_#177 1.4 
15657392SOD1SOD12.5mIgf-1 expression attenuates muscle wasting and promotes regenerative pathways in SOD1 mice 
15657392SOD1SOD12.5(a) a Histological analysis of wt MLC/mIgf-1, MLC mIgf-1 SOD1 and SOD1 /mIgf-1 mIgf-1 muscle at different age and stage 
15657392SOD1SOD12.5(a) a Histological analysis of wt MLC/mIgf-1, MLC mIgf-1 SOD1 and SOD1 /mIgf-1 mIgf-1 muscle at different age and stage 
15657392SOD1SOD12.5a Histological analysis of wt MLC/mIgf-1, MLC mIgf-1 SOD1 and SOD1 /mIgf-1 mIgf-1 muscle at different age and stage of disease 
15657392SOD1SOD12.5the quadriceps underscores the relative attenuation of muscle atrophy in SOD1 /mIgf-1 mIgf-1 compared with SOD1 mice 
15657392SOD1SOD12.5attenuation of muscle atrophy in SOD1 /mIgf-1 mIgf-1 compared with SOD1 mice 
15657392SOD1SOD12.5wt (lane lane 1 MLC/mIgf-1 MLC mIgf-1 (lane lane 2 SOD1 (lanes lanes 3 and 5 and SOD1 /mIgf-1 mIgf-1 (lanes 
15657392SOD1SOD12.5(lane lane 2 SOD1 (lanes lanes 3 and 5 and SOD1 /mIgf-1 mIgf-1 (lanes lanes 4 and 6 transgenic mice at 
15657392SOD1SOD12.5Immunofluorescence analysis of MyHC-fast performed on soleus muscles of wt SOD1 and SOD1 /mIgf-1 mIgf-1 before (80 80 d and after 
15657392SOD1SOD12.5Immunofluorescence analysis of MyHC-fast performed on soleus muscles of wt SOD1 and SOD1 /mIgf-1 mIgf-1 before (80 80 d and after 
15657392SOD1SOD12.5of MyHC-fast performed on soleus muscles of wt SOD1 and SOD1 /mIgf-1 mIgf-1 before (80 80 d and after symptom onset 
15657392SOD1SOD12.5(e) e Walk test of SOD1 (closed closed circles and SOD1 /mIgf-1 mIgf-1 (open open circles 
15657392SOD1SOD12.5(e) e Walk test of SOD1 (closed closed circles and SOD1 /mIgf-1 mIgf-1 (open open circles transgenic mice 
15657392SOD1SOD12.5Transgenic mIgf-1 expression induces chronic CnA-_amp_#223 1 expression in SOD1 mice 
15657392SOD1SOD12.5wt (lane lane 1 MLC/mIgf-1 MLC mIgf-1 (lane lane 2 SOD1 (lane lane 3 and SOD1 /mIgf-1 mIgf-1 (lane lane 4 
15657392SOD1SOD12.5MLC mIgf-1 (lane lane 2 SOD1 (lane lane 3 and SOD1 /mIgf-1 mIgf-1 (lane lane 4 transgenic mice 
15657392SOD1SOD12.5(c) c Immunofluorescence of transverse sections from quadriceps muscles of SOD1 and SOD /mIgf-1 mIgf-1 at paralysis stage 
15657392SODSOD2.2Immunofluorescence of transverse sections from quadriceps muscles of SOD1 and SOD /mIgf-1 mIgf-1 at paralysis stage 
15657392SOD1SOD12.5Maintenance of the neuromuscular junction configuration in SOD1 /mIgf-1 mIgf-1 transgenic mice 
15657392SOD1SOD12.5of transverse sections from muscles of wt MLC/mIgf-1, MLC mIgf-1 SOD1 and SOD1 /mIgf-1 mIgf-1 transgenic mice at 123 d old 
15657392SOD1SOD12.5of transverse sections from muscles of wt MLC/mIgf-1, MLC mIgf-1 SOD1 and SOD1 /mIgf-1 mIgf-1 transgenic mice at 123 d old 
15657392SOD1SOD12.5sections from muscles of wt MLC/mIgf-1, MLC mIgf-1 SOD1 and SOD1 /mIgf-1 mIgf-1 transgenic mice at 123 d old alpha-bungarotoxin antibody 
15657392SOD1SOD12.5d old alpha-bungarotoxin antibody identified diffusion of AChR expression in SOD1 muscle (yellow yellow arrow whereas SOD /mIgf-1 mIgf-1 muscle maintained 
15657392SODSOD2.2of AChR expression in SOD1 muscle (yellow yellow arrow whereas SOD /mIgf-1 mIgf-1 muscle maintained AChR clusters 
15657392SOD1SOD12.5wt (lane lane 1 MLC/mIgf-1 MLC mIgf-1 (lane lane 2 SOD1 (lane lane 3 and SOD1 /mIgf-1 mIgf-1 (lanes lanes 4 
15657392SOD1SOD12.5MLC mIgf-1 (lane lane 2 SOD1 (lane lane 3 and SOD1 /mIgf-1 mIgf-1 (lanes lanes 4 and 5 transgenic muscles at 
15657392SOD1SOD12.5wt (lane lane 1 MLC/mIgf-1 MLC mIgf-1 (lane lane 2 SOD1 (lane lane 3 and SOD1 /mIgf-1 mIgf-1 (lane lane 4 
15657392SOD1SOD12.5MLC mIgf-1 (lane lane 2 SOD1 (lane lane 3 and SOD1 /mIgf-1 mIgf-1 (lane lane 4 transgenic muscles 
15657392SOD1SOD12.5SOD1 and SOD1 /mIgf-1 mIgf-1 mice were analyzed at comparable end-stage 
15657392SOD1SOD12.5SOD1 and SOD1 /mIgf-1 mIgf-1 mice were analyzed at comparable end-stage 
15657392SOD1SOD12.5SOD1 and SOD1 /mIgf-1 mIgf-1 mice were analyzed at comparable end-stage disease 
15657392SOD1SOD12.5surviving motor neurons in the ventral spinal cord of wild-type SOD1 and SOD1 /mIgf-1 mIgf-1 mice at different ages *P _lt_ 
15657392SOD1SOD12.5surviving motor neurons in the ventral spinal cord of wild-type SOD1 and SOD1 /mIgf-1 mIgf-1 mice at different ages *P _lt_ 
15657392SOD1SOD12.5neurons in the ventral spinal cord of wild-type SOD1 and SOD1 /mIgf-1 mIgf-1 mice at different ages *P _lt_ 0.001 **P 
15657392SOD1SOD12.5Immunofluorescence analysis identify GFAP positive astrocytes in ventral horn of SOD1 and SOD1 /mIgf-1 mIgf-1 mice at different ages A and 
15657392SOD1SOD12.5Immunofluorescence analysis identify GFAP positive astrocytes in ventral horn of SOD1 and SOD1 /mIgf-1 mIgf-1 mice at different ages A and 
15657392SOD1SOD12.5identify GFAP positive astrocytes in ventral horn of SOD1 and SOD1 /mIgf-1 mIgf-1 mice at different ages A and B 28 
15657392SOD1SOD12.5shows Western blot for GFAP in the spinal cord of SOD1 (lanes lanes 1 and 3 and SOD1 /mIgf-1 mIgf-1 (lanes 
15657392SOD1SOD12.5spinal cord of SOD1 (lanes lanes 1 and 3 and SOD1 /mIgf-1 mIgf-1 (lanes lanes 2 and 4 mice at 28 
15657392SOD1SOD12.5wt (lane lane 1 MLC/mIgf-1 MLC mIgf-1 (lane lane 2 SOD1 (lane lane 3 and SOD1 /mIgf-1 mIgf-1 (lane lane 4 
15657392SOD1SOD12.5MLC mIgf-1 (lane lane 2 SOD1 (lane lane 3 and SOD1 /mIgf-1 mIgf-1 (lane lane 4 transgenic mice at 123 d 
15657392SOD1SOD12.5progression of the disease and prolongs the life span of SOD1 mice 
15657392SOD1SOD12.5To evaluate the effects of mIgf-1 on the SOD1 neurodegenerative phenotype we compared double transgenic SOD1 and MLC/mIgf-1 MLC 
15657392SOD1SOD12.5mIgf-1 on the SOD1 neurodegenerative phenotype we compared double transgenic SOD1 and MLC/mIgf-1 MLC mIgf-1 transgenic mice to their SOD1 littermates 
15657392SOD1SOD12.5transgenic SOD1 and MLC/mIgf-1 MLC mIgf-1 transgenic mice to their SOD1 littermates 
15657392SODSOD2.2The SOD and SOD1 x MLC/mIgf-1 MLC mIgf-1 (SOD1 SOD1 /mIgf-1) mIgf-1 
15657392SOD1SOD12.5The SOD and SOD1 x MLC/mIgf-1 MLC mIgf-1 (SOD1 SOD1 /mIgf-1) mIgf-1 transgenic mice 
15657392SOD1SOD12.5The SOD and SOD1 x MLC/mIgf-1 MLC mIgf-1 (SOD1 SOD1 /mIgf-1) mIgf-1 transgenic mice were selected for same expression level 
15657392SOD1SOD12.5expressed in skeletal muscle of both MLC/mIgf-1 MLC mIgf-1 and SOD1 /mIgf-1 mIgf-1 mice ( Fig 1 b lanes 2 and 
15657392SODSOD2.2b lanes 5-8 or in skeletal muscle of wild-type and SOD mice ( Fig 1 b lanes 1 and 3 
15657392SOD1SOD12.51.8 d old disease onset was observed in the mutant SOD1 transgenic mice ( n = 30 Fig 1 c 
15657392SOD1SOD12.5Notably the SOD1 mice died within 10 d _amp_#177 0.6 of clinical disease 
15657392SOD1SOD12.5( Fig 1 d of disease increasing the survival of SOD1 /mIgf-1 mIgf-1 mice ( n = 30 by ~30 d 
15657392SOD1SOD12.5Differences between SOD1 and SOD1 /mIgf-1 mIgf-1 were significantly relevant for onset ( 
15657392SOD1SOD12.5Differences between SOD1 and SOD1 /mIgf-1 mIgf-1 were significantly relevant for onset ( 
15657392SOD1SOD12.5Differences between SOD1 and SOD1 /mIgf-1 mIgf-1 were significantly relevant for onset ( LR = 
15657392SOD1SOD12.5mIgf-1 expression attenuates muscle atrophy increasing satellite cell activation in SOD1 mice 
15657392SOD1SOD12.5SOD1 ( n = 7 and SOD1 /mIgf-1 mIgf-1 ( n 
15657392SOD1SOD12.5SOD1 ( n = 7 and SOD1 /mIgf-1 mIgf-1 ( n = 7 transgenic mice were analyzed 
15657392SOD1SOD12.5At 123 d motor neuronal degeneration of SOD1 mice was accompanied by severe muscle atrophy ( Fig 2 
15657392SOD1SOD12.5In contrast at the same age SOD1 /mIgf-1 mIgf-1 transgenic mice did not show evident signs of 
15657392SOD1SOD12.5Moreover muscle atrophy was substantially attenuated in SOD1 /mIgf-1 mIgf-1 offspring even after onset of denervation and paralysis 
15657392SODSOD2.2Pax-7 and desmin were increased to varying extents in affected SOD mice ( Fig 2 c whereas hallmarks of satellite cell 
15657392SOD1SOD12.5heavy chain (MyHC) MyHC expression were present exclusively in the SOD1 /mIgf-1 mIgf-1 muscles at all stages of disease including at 
15657392SOD1SOD12.52 d revealed that fiber type composition was altered in SOD1 soleus muscle even before overt disease (80 80 d with 
15657392SOD1SOD12.5muscle fibers was maintained for a more extended period in SOD1 /mIgf-1 mIgf-1 mice which showed shifts in fiber composition only 
15657392SOD1SOD12.5there was not significant difference in fiber type composition between SOD1 and SOD1 /mIgf-1 mIgf-1 mice (not not depicted 
15657392SOD1SOD12.5there was not significant difference in fiber type composition between SOD1 and SOD1 /mIgf-1 mIgf-1 mice (not not depicted 
15657392SOD1SOD12.5not significant difference in fiber type composition between SOD1 and SOD1 /mIgf-1 mIgf-1 mice (not not depicted 
15657392SOD1SOD12.5The alteration in the heterogeneity of SOD1 muscle fibers indicate an alteration in motor neuron activity even 
15657392SOD1SOD12.5e performed at different ages revealed that at 112 d SOD1 mice ( n = 7 showed symptom onset without evident 
15657392SOD1SOD12.5The condition of SOD1 mice rapidly deteriorated at 117 d as shown by the 
15657392SOD1SOD12.5In contrast the pathological sign of disease were delayed in SOD1 /mIgf-1 mIgf-1 transgenic mice ( n = 7 as shown 
15657392SOD1SOD12.5_amp_#177 5.6 cm further when analyzed at same age as SOD1 mice and by their ability to move for a more 
15657392SOD1SOD12.5An activated calcineurin isoform is induced in SOD1 /mIgf-1 mIgf-1 muscle 
15657392SOD1SOD12.5low levels of CnA-_amp_#223 1 expression were not raised in SOD1 muscles ( Fig 3 a lane 3 Fig 3 b 
15657392SOD1SOD12.5( Fig 3 a and b lanes 1 and 2 SOD1 /mIgf-1 mIgf-1 regenerating muscle dramatically increased CnA-_amp_#223 1 transcripts (73 
15657392SOD1SOD12.5Preservation of neuromuscular junctions in SOD1 /mIgf-1 mIgf-1 mice 
15657392SOD1SOD12.5neuron diseases also affect the configuration of neuromuscular junctions in SOD1 mice characterized by the diffusion of acetylcholine receptor (AChR) AChR 
15657392SOD1SOD12.5At 123 d SOD1 paralyzed muscle showed 56 _amp_#177 0.2% of diffuse AChR expression 
15657392SOD1SOD12.5( Fig 4 a were preserved in muscles of age-matched SOD1 /mIgf-1 mIgf-1 mice which showed only 3.3 _amp_#177 0.4% of 
15657392SOD1SOD12.5At comparable end-stage disease SOD1 /mIgf-1 mIgf-1 muscle displayed only 18 _amp_#177 0.4% of diffuse 
15657392SOD1SOD12.5analysis ( Fig 4 b high AChR expression levels in SOD1 muscle were reduced in SOD1 /mIgf-1 mIgf-1 mice at all 
15657392SOD1SOD12.5high AChR expression levels in SOD1 muscle were reduced in SOD1 /mIgf-1 mIgf-1 mice at all stages observed 
15657392SOD1SOD12.5( n = 6 revealed that AChR mRNA expression in SOD1 paralyzed muscle (123 123 d was 68 _amp_#177 2.4% higher 
15657392SOD1SOD12.568 _amp_#177 2.4% higher than that observed in age matched SOD1 /mIgf-1 mIgf-1 mice whereas the increase in mRNA expression in 
15657392SOD1SOD12.5/mIgf-1 mIgf-1 mice whereas the increase in mRNA expression in SOD1 mice was of 32 _amp_#177 1.9% when SOD1 and SOD1 
15657392SOD1SOD12.5expression in SOD1 mice was of 32 _amp_#177 1.9% when SOD1 and SOD1 /mIgf-1 mIgf-1 mice where analyzed at comparable end-stage 
15657392SOD1SOD12.5expression in SOD1 mice was of 32 _amp_#177 1.9% when SOD1 and SOD1 /mIgf-1 mIgf-1 mice where analyzed at comparable end-stage 
15657392SOD1SOD12.5SOD1 mice was of 32 _amp_#177 1.9% when SOD1 and SOD1 /mIgf-1 mIgf-1 mice where analyzed at comparable end-stage disease 
15657392SOD1SOD12.5Agrin expression was significantly down-regulated in paralyzed SOD1 compared with SOD /mIgf-1 mIgf-1 muscle ( Fig 4 c 
15657392SODSOD2.2Agrin expression was significantly down-regulated in paralyzed SOD1 compared with SOD /mIgf-1 mIgf-1 muscle ( Fig 4 c analyzed at comparable 
15657392SOD1SOD12.5Muscle-restricted mIgf-1 prolongs motor neuronal function in SOD1 mice 
15657392SOD1SOD12.5Histological analysis of the ventral spinal cord revealed that SOD1 mice ( n = 7 presented a progressive reduction in 
15657392SOD1SOD12.5Specifically SOD1 mice showed a reduction of 37 and 55% in the 
15657392SOD1SOD12.5In contrast mIgf-1 expression induced motor neuron survival in SOD1 /mIgf-1 mIgf-1 mice ( n = 7 at all ages 
15657392SOD1SOD12.5protein (GFAP) GFAP immunoreactivity were found in spinal cords of SOD1 ( n = 6 and SOD /mIgf-1 mIgf-1 ( n 
15657392SODSOD2.2in spinal cords of SOD1 ( n = 6 and SOD /mIgf-1 mIgf-1 ( n = 6 transgenic mice before the 
15657392SOD1SOD12.5at paralysis stage (123 123 d the spinal cord of SOD1 mice demonstrated a marked increase in astroglial activation ( Fig 
15657392SOD1SOD12.5expression levels displayed in the spinal cord of age matched SOD1 /mIgf-1 mIgf-1 transgenic mice ( Fig 5 b D and 
15657392SOD1SOD12.5disease there were no significant differences in GFAP expression between SOD1 and SOD1 /mIgf-1 mIgf-1 mice although SOD1 mice continued to 
15657392SOD1SOD12.5disease there were no significant differences in GFAP expression between SOD1 and SOD1 /mIgf-1 mIgf-1 mice although SOD1 mice continued to 
15657392SOD1SOD12.5were no significant differences in GFAP expression between SOD1 and SOD1 /mIgf-1 mIgf-1 mice although SOD1 mice continued to express 13% 
15657392SOD1SOD12.5GFAP expression between SOD1 and SOD1 /mIgf-1 mIgf-1 mice although SOD1 mice continued to express 13% more GFAP as compared with 
15657392SOD1SOD12.5mice continued to express 13% more GFAP as compared with SOD1 /mIgf-1 mIgf-1 mice (unpublished unpublished data 
15657392SOD1SOD12.5states and contribute to the progression of neurological dysfunction in SOD1 mice ( Elliott 2001 
15657392SOD1SOD12.51 and 2 it accumulated in the spinal cord of SOD1 mice at paralysis stage (123 123 d Fig 5 c 
15657392SOD1SOD12.5TNF-alpha expression was not apparent in the spinal cord of SOD1 /mIgf-1 mIgf-1 transgenic mice ( Fig 5 c lane 4 
15657392SOD1SOD12.5determined whether the dramatic prolongation of CNS tissue integrity in SOD1 /mIgf-1 mIgf-1 mice derives from the direct retrograde transport of 
15657392SODSOD2.2endogenous Igf-1 expression or through other trophic factors secreted by SOD /mIgf-1 mIgf-1 muscle 
15657392SODSOD2.2SOD transgenic mice (Jackson Jackson Laboratory express a transgenic human mutant 
15657392SOD1SOD12.5transgenic mice (Jackson Jackson Laboratory express a transgenic human mutant SOD1 allele containing the Gly93 Ala (G93A) G93A substitution driven by 
15657392SOD1SOD12.5The SOD1 B6J mice were crossed with MLC/mIgf-1 MLC mIgf-1 FVB mice 
15657392SOD1SOD12.5Musar_amp_ograve et al. 2001 for seven different generations to obtain SOD1 /mIgf-1 mIgf-1 B6J inbred transgenic mice 
15657392SODSOD2.2isolated from spinal cord of wild-type MLC/mIgf-1, MLC mIgf-1 and SOD and SOD1 /mIgf-1 mIgf-1 transgenic mice 
15657392SOD1SOD12.5spinal cord of wild-type MLC/mIgf-1, MLC mIgf-1 and SOD and SOD1 /mIgf-1 mIgf-1 transgenic mice 
15657392SODhSOD2.2Filters were blotted with antibodies against hSOD Pax7 myogenin desmin neo-MyHC (from from S Schiaffino University of 
15691215SOD1SOD11.4familial and involve mutation in a superoxide dismutase gene (SOD1) SOD1 led to the development of transgenic mouse models presently widely 
15804265SOD1SOD11.7COX-2 inhibitor Rofecoxib administered by intraperitoneal injection in the SOD1(G93A SOD1 G93A G1H mouse model of the familial form of ALS 
16120782SOD1SOD13.4as potent anti-inflammatory drugs we tested whether superoxide dismutase (SOD1)-G93A SOD1 -G93A transgenic mice a mouse model of ALS benefit from 
16120782SOD1SOD13.4whereas both the mRNA and protein levels of endogenous mouse SOD1 and of transgenic human SOD1 remained unaffected 
16120782SOD1SOD13.4protein levels of endogenous mouse SOD1 and of transgenic human SOD1 remained unaffected 
16120782SOD1SOD13.4human gene encoding for copper/zinc copper zinc superoxide dismutase (SOD1), SOD1 which have been linked to inherited ALS (Gurney Gurney et 
16120782SOD1SOD13.4astrocytes already at an early presymptomatic stage of disease in SOD1 transgenic mice suggests that inflammation may contribute to motor neuron 
16120782SOD1SOD13.4in these studies we tested whether an oral treatment of SOD1 transgenic mice with the PPAR gamma agonist pioglitazone would reduce 
16120782SOD1SOD13.4(The The Jackson Laboratory Bar Harbor ME which harbor human SOD1 with the G93A mutation in high copy number were used 
16120782SOD1SOD13.4( n = 18 for wt n = 13 for SOD1 and nontreated ( n = 17 for wt n = 
16120782SOD1SOD13.4( n = 17 for wt n = 22 for SOD1 groups 
16120782SOD1SOD13.4wt n = 13 for wt-Pio n = 10 for SOD1 n = 7 for SOD1-Pio 
16120782SOD1SOD13.4wt n = 4 for wt-Pio n = 4 for SOD1 n = 5 for SOD1-Pio 
16120782SOD1SOD13.4For the analysis of human and mouse SOD1 2 microg of protein samples was separated in 15% SDS 
16120782SOD1SOD13.4onto nitrocellulose membranes and stained with a rabbit polyclonal anti-human SOD1 antibody at 1 5000 dilution (SOD-100; SOD-100 Stressgen Victoria British 
16120782SOD1SOD13.4Stressgen Victoria British Colombia Canada or a rabbit polyclonal anti-mouse SOD1 antibody at 1 5000 dilution (SOD-101; SOD-101 Stressgen 
16120782SOD1SOD13.4The SOD-101 antibody predominantly detected mouse SOD1 but in addition showed minimal cross-reactivity with human SOD1 
16120782SOD1SOD13.4mouse SOD1 but in addition showed minimal cross-reactivity with human SOD1 
16120782SOD1SOD13.4and reverse 5'-ACA-CTC-ACT-TCC-GCA-CCT-TC-3' SOCS-3 forward 5'-ACC-AGC-GCC-ACT-TCT-TCA-CG-3' and reverse 5'-GTG-GAG-CAT-CAT-ACT-GAT-CC-3' mouse SOD1 forward 5'-GTC-CGT-CGG-CTT-CTC-GTC-T-3' and reverse 5'-CAC-AAC-TGG-TTC-ACC-GCT-TG-3' human SOD1 forward 5'-TGG-TTT-GCG-TCG-TAG-TCT-CCT-3' and 
16120782SOD1SOD13.4reverse 5'-GTG-GAG-CAT-CAT-ACT-GAT-CC-3' mouse SOD1 forward 5'-GTC-CGT-CGG-CTT-CTC-GTC-T-3' and reverse 5'-CAC-AAC-TGG-TTC-ACC-GCT-TG-3' human SOD1 forward 5'-TGG-TTT-GCG-TCG-TAG-TCT-CCT-3' and reverse 5'-AAT-GCT-TCC-CCA-CAC-CTT-CA-3' 
16120782SOD1SOD13.45'-TCA-GGA-TAC-CTC-TCT-TGC-TCT-GG-3' were used as housekeeping control for mouse and human SOD1 
16120782SOD1SOD13.4The SOD1 PCRs were performed using a SYBR Green Jump Start Taq 
16120782SOD1SOD13.4the calculation of the relative abundancies of mouse and human SOD1 transcripts the differences in C T between beta-actin and SOD1 
16120782SOD1SOD13.4SOD1 transcripts the differences in C T between beta-actin and SOD1 were determined and expressed as x -fold difference from beta-actin 
16120782SOD1SOD13.4in SOD1-G93A mice a Probability of survival in nontreated (SOD1; SOD1 n = 10 compared with Pio-treated (SOD1-Pio; SOD1-Pio n = 
16120782SOD1SOD13.4wt-Pio n = 13 wild-type mice compared with their respective SOD1 and SOD1-Pio mice p _lt_ 0.05 p _lt_ 0.01 and 
16120782SOD1SOD13.4c Probability of onset of motor dysfunctions in nontreated (SOD1) SOD1 compared with Pio-treated (SOD1-Pio) SOD1-Pio mice d Time course of 
16120782SOD1SOD13.4the paw grip endurance test p _lt_ 0.001 compared with SOD1 mice 
16120782SOD1SOD13.4n = 5 for wild-type group n = 6 for SOD1 groups and median fiber diameters in the quadriceps muscle ( 
16120782SOD1SOD13.4wt n = 4 for wt-Pio n = 4 for SOD1 n = 5 for SOD1-Pio at day 90 of life 
16120782SOD1SOD13.4p _lt_ 0.05 and p _lt_ 0.01 compared with Pio-treated SOD1 mice 
16120782SOD1SOD13.4= 4 for wt and wt-Pio n = 5 for SOD1 and SOD1-Pio and of COX-2 and iNOS Western blots ( 
16120782SOD1SOD13.4per group are shown p _lt_ 0.001 compared with nontreated SOD1 mice 
16120782SOD1SOD13.4pioglitazone treatment on the expression levels of endogenous and transgenic SOD1 a -d Quantification of mouse SOD1 ( a and human 
16120782SOD1SOD13.4of endogenous and transgenic SOD1 a -d Quantification of mouse SOD1 ( a and human SOD1 ( b mRNA expression levels 
16120782SOD1SOD13.4a -d Quantification of mouse SOD1 ( a and human SOD1 ( b mRNA expression levels and of mouse SOD1 ( 
16120782SOD1SOD13.4human SOD1 ( b mRNA expression levels and of mouse SOD1 ( c and human SOD1 ( d protein levels in 
16120782SOD1SOD13.4expression levels and of mouse SOD1 ( c and human SOD1 ( d protein levels in the spinal cord at day 
16120782SOD1SOD13.4Note the variations in mouse SOD1 expression levels between the groups in a and c 
16120782SOD1SOD13.4treatment does not alter expression levels of endogenous and transgenic SOD1 
16120782SOD1SOD13.4Because the expression level of the mutant SOD1 transgene affects the course of disease in SOD1-G93A mice and 
16120782SOD1SOD13.4an altered expression of either endogenous mouse or transgenic human SOD1 we determined SOD1 gene expression levels in our mice 
16120782SOD1SOD13.4of either endogenous mouse or transgenic human SOD1 we determined SOD1 gene expression levels in our mice 
16120782SOD1SOD13.4for total RNA and protein and both mouse and human SOD1 expression levels were determined using quantitative RT-PCR and Western blotting 
16120782SOD1SOD13.4As shown in Figure 4 neither mouse SOD1 mRNA ( Fig 4 a or protein ( Fig 4 
16120782SOD1SOD13.4a or protein ( Fig 4 c levels nor human SOD1 mRNA ( Fig 4 b or protein ( Fig 4 
16120782SOD1SOD13.4of ischemia (Shimazu Shimazu et al. 2005 suggesting that enhanced SOD1 levels may be protective by reducing oxidative stress 
16120782SOD1SOD13.4changes in the expression levels of neither mouse nor human SOD1 in our mice we can rule out that the reported 
16120782SOD1SOD13.4reported effects of chronic Pio treatment result from altered endogenous SOD1 or transgenic SOD1-G93A expression levels 
16120782SOD1SOD13.4neuron death in ALS has been supported by studies on SOD1 transgenic mice reporting protective effects of cyclooxygenase inhibitors (Drachman Drachman 
16120782SOD1SOD13.4antibody and Dr Albrecht Clement (Mainz, Mainz Germany for donating SOD1 antibodies 
16179515SOD1SOD11.7Effect of neuroprotective drugs on gene expression in G93A/SOD1 G93A SOD1 mice 
16179515SOD1SOD11.7this approach to identify molecular abnormalities in the G93A/SOD1 G93A SOD1 mouse an animal model of amyotrophic lateral sclerosis (ALS) ALS 
16179515SOD1SOD11.7That is we asked whether administration to the G93A/SOD1 G93A SOD1 mice of any of these drugs could reverse the alterations 
16179515SOD1SOD11.73 genes unaffected by the presence of the G93A/SOD1 G93A SOD1 mutation glial fibrillary acidic protein (GFAP), GFAP stroma-derived factor-1 (SDF-1), 
16179515SOD1SOD11.7the effects of these and other candidate drugs in mutant SOD1 mice 
16380619ALSALS0.5of interleukin (IL)-6 IL -6 were described in patients with ALS related to an inflammatory process 
16380619ALSALS0.5and sera from 10 hypoxemics and 10 normoxemics patients with ALS to those of 10 hypoxemics and 10 normoxemics neurologic controls 
16380619ALSALS0.5The same pattern exists in patients with ALS and controls the highest levels are found in hypoxic conditions 
16380619ALSALS0.5Elevated IL-6 levels in ALS could correspond to a normal response to hypoxemia 
16380619ALSALS0.5microglia was demonstrated in the spinal cord of patients with ALS 
16380619SODSOD0.5levels of interleukin (IL)-6 IL -6 was demonstrated in a SOD 1 mouse model suggesting an increase cytotoxic potential of microglia 
16380619ALSALS0.5in IL-6 TNF-alpha or IL-12 was found in patients with ALS and healthy and inflammatory controls or elevated levels of IL-6 
16380619ALSALS0.5in the CSF spinal cords and sera of patients with ALS 
16380619ALSALS0.5the sera and CSF of hypoxemic and normoxemic patients with ALS and neurologic controls 
16380619ALSALS0.5Plasma and CSF from patients with ALS and control subjects were obtained with informed consent as part 
16380619ALSALS0.5-2.5 p = 0.01 in hypoxemic vs normoxemic patients with ALS ( figure 1 
16380619ALSALS0.5( p = 0.001 r = -0.7 in patients with ALS 
16380619ALSALS0.5and sera and TNF-alpha in sera in hypoxemic patients with ALS and hypoxemic neurologic controls vs normoxemic ones but no difference 
16380619ALSALS0.5controls vs normoxemic ones but no difference between patients with ALS and controls 
16380619ALSALS0.5thought to play a role in the pathophysiology of sporadic ALS 
16380619ALSALS0.5levels of IL-6 was also observed in animal models of ALS or in the context of excitotoxicity after hypoxemia 
16380619ALSALS0.5levels of PGE-2 and COX-2 were described in patients with ALS 
16380619ALSALS0.5of IL-6 TNF-alpha PGE-2 and COX-2 observed in patients with ALS parallel motor neuronal loss and could correspond to a natural 
16380619ALSALS0.5that COX-2 inhibitors may even be harmful in patients with ALS because they can block the natural upregulation loop of VEGF 
16380619ALSALS0.5Rapidly progressive restrictive respiratory failure with chronic hypoxemia occurs in ALS 
16380619ALSALS0.5levels found after exercise in patients with neuromuscular diseases including ALS 
16380619ALSALS0.5and tumor necrosis factor alpha sera levels in patients with ALS according to the condition of hypoxemia or normoxemia (Pao Pao 
16436205SOD1SOD1-expressing1.4Nonetheless astrocytes cultured from G93A-SOD1 (but but not wild-type human SOD1-expressing transgenic mouse pups demonstrated a significant elevation in either the 
16436205SOD1SOD11.7al created a strain of transgenic mice that express mutant SOD1 specifically in neurons 
16436205SOD1SOD11.7Selective expression of mutant SOD1 only in astroglia causes a type of astrogliosis but fails 
16436205SOD1SOD11.7motor neuron disease 3 in the absence of simultaneous mutant SOD1 expression in neurons 
16436205SOD1SOD11.7recently showed that the rate of disease progression in mutant SOD1 chimeric mice depends on the extraneuronal expression of mutant SOD1 
16436205SOD1SOD11.7SOD1 chimeric mice depends on the extraneuronal expression of mutant SOD1 4 
16436205SOD1SOD11.7The survival of chimeric mice was dependent upon mutant SOD1 expression in neurons but also highly dependent on the number 
16436205SOD1SOD1-expressing1.4but also highly dependent on the number of ambient mutant SOD1-expressing non-neuronal cells 
16436205SOD1SOD11.7Expression of high copy numbers of wild-type human SOD1 had no effect or slightly diminished the inflammatory indices 
16436205SOD1SOD11.7These findings suggest that SOD1 mutations fundamentally alter the phenotype of astrocytes placing the cells 
16436205SOD1SOD11.7Jackson Laboratories (Bar Bar Harbor ME strain designation B6SJL-Tg(SOD1 B6SJL-Tg SOD1 G93A)1Gur/J; G93A 1Gur J 15 -17 
16436205SOD1SOD11.7were used that express equivalent protein levels of wild-type human SOD1 (B6SJL-TgN-(SOD1 B6SJL-TgN- SOD1 G93A -2Gur Jackson Laboratories 
16436205SOD1SOD11.7express equivalent protein levels of wild-type human SOD1 (B6SJL-TgN-(SOD1 B6SJL-TgN- SOD1 G93A -2Gur Jackson Laboratories 
16436205SOD1SOD11.7methods 18 from G93A-SOD1 mice matched nontransgenic littermates or wildtype-human SOD1 expressing mice 
16436205SOD1SOD11.7or from mice expressing high copy numbers of wildtype human SOD1 (wt-hSOD1) wt-hSOD1 were stimulated with IFN_amp_#x003b3 TNF_amp_#x003b1 or both for 
16436205SOD1SOD11.7glial arachidonic acid metabolism as a function of the mutant SOD1 transgene 
16436205SOD1SOD11.7Curiously no major protein carbonylation band assignable to SOD1 was found in any G93A-SOD1 astrocyte lysates whereas a major 
16436205SOD1SOD11.7G93A-SOD1 astrocyte lysates whereas a major carbonylated protein identifiable as SOD1 was previously demonstrated in spinal cord extracts from symptomatic G93A-SOD1 
16436205SOD1SOD11.7relevant pathways that are perturbed by the insertion of mutant SOD1 transgenes and has slowed the development of new therapeutic modalities 
16436205SOD1SOD11.7studies of signal transduction pathways that are sensitive to mutant SOD1 
16436205SOD1SOD11.7recent reports of cytokine hyper-expression in the CNS of mutant SOD1 mice preceding motor neuron death 6 -8 
16436205SOD1SOD11.7Thus glial over-expression of mutant SOD1 (but but not wild-type SOD1 elicits a fundamental influence upon 
16436205SOD1SOD11.7Thus glial over-expression of mutant SOD1 (but but not wild-type SOD1 elicits a fundamental influence upon multiple gene regulatory pathways 
16436205SOD1SOD11.7is to elucidate the toxic gain-of-function(s) gain-of-function s inherent to SOD1 mutants 
16436205SOD1SOD11.7One likely mode of action is through accumulation of mutant SOD1 within the mitochondrial intermembrane space 21 22 which may facilitate 
16436205SOD1SOD11.7be released from glial mitochondria secondary to accumulation of mutant SOD1 
16436205SOD1SOD1-expressing1.4primary mouse astrocytes G93A-SOD1 mouse astrocytes or wild type human SOD1-expressing mouse astrocytes 
16510725SOD1SOD11.9FasL immunostaining in the lumbar spinal cord of the G93A SOD1 transgenic mice occurred at 40-60 d well before the onset 
16510725SOD1SOD11.9Key words G93A SOD1 thalidomide lenalidomide TNF-alpha FasL 
16510725SOD1SOD11.9of missense mutations in the enzyme copper-zinc superoxide dismutase (SOD1), SOD1 which is associated with 15-20% of familial ALS cases (Rosen 
16510725SOD1SOD11.9role in the death of motor neurons associated with mutant SOD1 (Raoul Raoul et al. 2002 alpha can induce FasL (Pinkoski 
16510725SOD1SOD11.9G93A SOD1 transgenic familial ALS mice (high high copy number (Gurney Gurney 
16510725SOD1SOD11.9Six N1029 (wild-type wild-type SOD1 transgenic mice and six mice from the thalidomide- and vehicle-treated 
16510725SOD1SOD11.9of the ALS patients had an I113T mutation of the SOD1 gene 
16510725SOD1SOD11.9TNF-alpha and FasL immunoreactivity in G93A SOD1 mouse model of ALS 
16510725SOD1SOD11.9the temporal pattern of TNF-alpha and FasL immunoreactivity in G93A SOD1 mice at 40 and 60 d (asymptomatic), asymptomatic 90 d 
16510725SOD1SOD11.9alpha was increased in the lumbar spinal cord of G37R SOD1 mice at 7 and 10 months of age and the 
16510725SOD1SOD11.9expression at 11 weeks of age (5.3-fold) 5.3-fold in G93A SOD1 mice which increased further at 14 and 17 weeks (8-fold) 
16510725SOD1SOD11.9both lumbar spinal cord motor neurons and glia from G93A SOD1 mice express high levels of TNF-alpha and this occurs at 
16510725SOD1SOD11.9weeks of age in microglia and motor neurons of G93A SOD1 mice (Yoshihara Yoshihara et al. 2002 
16510725SOD1SOD11.9onset and a significant attenuation of disease progression in G93A SOD1 mice ( Figs 4 -6 
16510725SOD1SOD11.9TNF-alpha immunoreactivity in G93A SOD1 and control mice 
16510725SOD1SOD11.9immunoreactivity was examined in the spinal cords of transgenic G93A SOD1 mice at 40 60 90 and 110 d of age 
16510725SOD1hSOD11.4and 110 d of age and in 110-d-old transgenic wild-type hSOD1 (N1029) N1029 control mice 
16510725SOD1SOD11.9FasL immunoreactivity in G93A SOD1 and control mice 
16510725SOD1SOD11.9lumbar spinal cord sections of a familial ALS patient with SOD1 mutation (I113T) I113T and sporadic ALS patients 
16510725SOD1SOD11.9of thalidomide or lenalidomide treatment on motor performance in G93A SOD1 transgenic mice from 89 to 165 d of age 
16510725SOD1SOD11.9mg kg thalidomide 100 mg/kg mg kg lenalidomide vehicle-treated G93A SOD1 
16510725SOD1SOD11.9mg kg thalidomide 100 mg/kg mg kg lenalidomide vehicle-treated G93A SOD1 
16510725SOD1SOD11.9(Lenali) Lenali treatment on Nissl-stained neuronal cell counts in G93A SOD1 transgenic mice at 110 d of age 
16510725SOD1SOD11.9for TNF-alpha expression in the spinal cord tissue of G93A SOD1 control mice and G93A mice treated with thalidomide or lenalidomide 
16510725SOD1SOD11.9cord tissue of 110-d-old N1029/B6SJL N1029 B6SJL controls and G93A SOD1 mice treated with vehicle thalidomide or lenalidomide 
16510725SOD1SOD11.9lumbar spinal cord sections from an ALS patient with a SOD1 mutation (I113T) I113T as well as sporadic ALS patients whereas 
16510725SOD1SOD11.9from total RNA extracted from the spinal cords of G93A SOD1 mice treated with thalidomide or lenalidomide vehicle-treated G93A mice and 
16510725SOD1SOD11.9or lenalidomide vehicle-treated G93A mice and N1029 mice (wild-type wild-type SOD1 overexpressers at 110 d of age 
16510725SOD1SOD11.9TNF-alpha mRNA was increased 10-fold in G93A SOD1 mice compared with control littermates ( p _lt_ 0.005 ( 
16624536SOD1SOD11.7harbour missense mutations in the copper_amp_#x2013 zinc superoxide dismutase (SOD1) SOD1 gene 3 the majority of ALS cases are sporadic (sALS) 
16624536SOD1SOD11.7of motor neuron degeneration in which the fALS associated G93A SOD1 mutation is expressed is dependant on the extent of non-neuronal 
16624536SOD1SOD11.7recent work suggests the robust inflammatory response observed in symptomatic SOD1 G93A transgenic mice is mostly attributable to proliferation of resident 
16624536SOD1SOD11.7It has also been demonstrated that microglia derived from mutant SOD1 transgenic mice have increased cytotoxic potential in culture 37 
16624536SOD1SOD11.7Using a chimeric mutant SOD1 model in which only a proportion of cells express the 
16624536SOD1SOD11.7model non-transgenic motor neurons surrounded by glia expressing the mutant SOD1 transgene degenerated while transgenic motor neurons surrounded by non-transgenic glia 
16624536SOD1SOD11.7This study suggests that SOD1 mutations once thought to selectively confer motor neuron susceptibility can 
16624536SOD1SOD11.7from Don Cleveland's group suggesting that genetic knock-down of mutant SOD1 in cells of the macrophage lineage can significantly slow the 
16624536SOD1SOD11.7neurons such as the skeletal muscle will also express mutant SOD1 and could contribute to the health of motor neurons 
16624536SOD1SOD11.7In contrast to these studies transgenic mice in which SOD1 G37R expression is driven by the mouse prion promoter resulting 
16624536SOD1SOD11.7by the mouse prion promoter resulting in levels of mutant SOD1 expression highest in neurons and astrocytes in the CNS and 
16624536SOD1SOD11.7In both the mutant SOD1 transgenic mice and rat an alteration in the expression and 
16624536SOD1SOD11.7accelerated by chronic stimulation of inflammation using LPS in the SOD1 G37R mouse model of ALS with increasing levels of pro-inflammatory 
16624536SOD1SOD11.7Motor neurons derived from mutant SOD1 transgenic mice exhibit an increased susceptibility to activation of a 
16624536SOD1SOD11.7It is of interest that microglia derived from adult mutant SOD1 transgenic mice show decreased IL-6 production in response to LPS-stimulated 
16624536SOD1SOD11.7interest driving the adaptive immune response is protective against mutant SOD1 induced neurodegeneration 
16624536SOD1SOD11.7Vaccination of SOD1 G93A mice with Copaxone (copolymer-1) copolymer-1 led to an increase 
16624536SOD1SOD11.7Astrocytes isolated from a mutant SOD1 transgenic rat show a 3-fold higher expression of mGluR5 over 
16624536SOD1SOD11.7of motor dysfunction by roughly 9_amp_#x2013 20% in various mutant SOD1 transgenic mice and extends survival by 13_amp_#x2013 25% (in in 
16624536SOD1SOD11.7combined with creatine increased survival by up to 30% in SOD1 mutant mice 139 140 and 141 while treatment with a 
16624536SOD1SOD11.7This is supported by evidence that mutant SOD1 secreted from neurons can activate microglia and lead to neuronal 
16624536SOD1SOD11.7The results of minocycline treatment of mutant SOD1 mice suggest that microglial activation is concomitant with and contributes 
16624536SOD1SOD11.7Although mutant SOD1 models allow for validation of potential treatments they do not 
16647138SOD1SOD12.9Mutations in Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 gene have been reported to occur in familial form of 
16647138SOD1SOD12.9Upregulation of COX-2 mRNA also occurs in SOD1 transgenic mice at the onset of ALS ( Almer et 
16647138SOD1SOD12.9It is not known why mutations of SOD1 are related to the antioxidant activity that leads to ALS 
16647138SOD1SOD12.9another COX-2 inhibitor prolongs the survival of neurons in the SOD1 mouse model of ALS ( Drachman et al. 2002 
16647138SODSOD2.9has increased lipid peroxidation iron levels and superoxide dismutase (SOD) SOD activity 
16737688SOD1SOD14.2expressing a mutated human Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 gene develop a motor neuron disease similar to familial amyotrophic 
16737688SOD1SOD14.2a mutant form of Cu/Zn Cu Zn superoxide dismutase (SOD1; SOD1 Rosen 1993 that normally functions in the regulation of oxidative 
16737688SOD1SOD14.2Mutant SOD1 produces motor neuron injury by a toxic gain of function 
16737688SOD1SOD14.2Now that _amp_#x3e 90 different SOD1 mutations have been described transgenic mouse models with these mutations 
16737688SOD1SOD14.2Overexpression of the human Glycine 93_amp_#xa0 _amp_#x2192 _amp_#xa0 Alanine SOD1 mutation (SOD1-G93A) SOD1-G93A causes a phenotype that closely mimics the 
16737688SOD1SOD14.2copies ( Gurney et al. 1994 of the human mutant SOD1 gene (Cu/Zn-SOD) Cu Zn-SOD containing the Gly 93 _amp_#xa0 _amp_#x2192 
16737688SOD1SOD14.2(PCR) PCR of tail DNA with primers specific for human SOD1 gene 
16737688SOD1SOD14.2SOD1 transgenics died between 5 and 6_amp_#xa0 months of age 
16737688SOD1SOD1-3.2FluoroJade and silver staining as well as SOD1- and tyrosine hydroxylase-IHC (see see below were used to identify 
16737688SOD1SOD14.2Primary antibodies were used to further evaluate neurodegenerative alterations (SOD1 SOD1 and tyrosine hydroxylase to identify the molecular changes associated with 
16737688SOD1SOD14.2in 0.01_amp_#xa0 M citrate buffer pH 6.0 for CD3 PT66 SOD1 TH 
16737688SOD1SOD1-3.2Morphological signs of degeneration were semi-quantitatively evaluated in SOD1- or TH (for for catecholaminergic neurons -immunostained and in Gallyas-stained 
16737688SOD1SOD14.2SOD1 and TH immunoreactivities were observed throughout cellular somata and processes 
16737688SOD1SOD1-3.2The morphological changes in SOD1- or TH-stained sections the amount of Gallyas-positive structures and the 
16737688SOD1SOD14.2Fig 2._amp_#xa0 Gallyas (A, A B D_amp_#x2013 K and SOD1 staining (C) C in transgenics at the age of 2_amp_#xa0 
16737688SOD1SOD14.2F H either silver-stained (A, A B or immunostained for SOD1 (C, C D GFAP (E, E F and PT66 (G, 
16737688SOD1SOD14.2SOD1 immunostaining reveals vacuolar changes already in 3-month-old transgenics (arrows) arrows 
16737688SOD1SOD14.2F H either silver-stained (A, A B or immunostained for SOD1 (C, C D GFAP (E, E F and PT66 (G, 
16737688SOD1SOD14.2arrows in panel C are visible at 4_amp_#xa0 months after SOD1 immunostaining (C), C while Gallyas staining is negative (A) A 
16737688SOD1SOD14.2The SOD1 transgenics showed first signs of hindlimb paresis at 3.5_amp_#x2013 5_amp_#xa0 
16737688SOD1SOD14.2motor activity progressively decreased and at 3.5_amp_#xa0 months of age SOD1 transgenics were significantly ( P _amp_#xa0 _amp_#x2264 _amp_#xa0 0.05 less 
16737688SOD1SOD14.2Most of the SOD1 immunoreactivity was observed in the cytoplasm although less intense staining 
16737688SOD1SOD1-3.2Both SOD1- and TH-ip cells appeared morphologically unaltered in non-transgenic animals 
16737688SOD1SOD14.2describe chronologically the degenerative changes and inflammatory reactions in the SOD1 transgenics while the figures and tables illustrate the pathological changes 
16737688SOD1SOD14.2In the SOD1 transgenics the first morphological signs of degeneration were notable by 
16737688SOD1SOD1-3.2At the age of 3_amp_#xa0 months SOD1- and TH-IHC revealed pathological alterations of the neuropil in the 
16737688SOD1SOD1-3.2In addition SOD1-/TH-IHC SOD1- TH-IHC pointed out lesions in the neuropil of the ventral 
16737688SOD1SOD14.2Despite the close similarities between the histopathology of transgenic SOD1 mice and ALS the experimental model departs from the human 
16781706SOD1hSOD12.7after onset of signs in an ALS mouse model (hSOD1 hSOD1 G93A transgenic mice 
16781706SOD1hSOD12.7progression and improves survival in the ALS mouse model ( hSOD1 G93A transgenic mice even when administered after the onset of 
16781706SOD1SOD12.9Mutations in Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 are the primary cause of up to 20% of familial 
16781706SOD1SOD12.9Transgenic mice expressing human SOD1 mutations have been generated 
16781706SOD1hSOD12.7These hSOD1 mutant transgenic mice exhibit pathologic and cytological neuromuscular degeneration similar 
16781706SOD1hSOD12.7The hSOD1 G93A mice are used for preclinical testing of compounds for 
16781706SOD1hSOD12.7Here we report that AM1241 slows disease progression in hSOD1 G93A mice when administered after onset of disease signs 
16781706SOD1SOD12.9Male transgenic mice expressing the human SOD1 G93A (B6SJL-TgN[SOD1-G93A]1Gur) B6SJL-TgN SOD1-G93A 1Gur ( hSOD1 G93A mice were 
16781706SOD1hSOD12.7expressing the human SOD1 G93A (B6SJL-TgN[SOD1-G93A]1Gur) B6SJL-TgN SOD1-G93A 1Gur ( hSOD1 G93A mice were bred with background matched B6SJL wild type 
16781706SOD1SOD12.9genotyped using primers specific to exon 4 of the human SOD1 gene within the transgenic construct and segregated and used for 
16781706SOD1hSOD12.7hSOD1 G93A mice were injected intraperitoneally with vehicle (18:1:1 18 1 
16781706SOD1hSOD12.7here indicate that AM1241 delays progression of disease in male hSOD1 G93A mice when administered after onset of signs 
16781706SOD1hSOD12.7phytoestrogen delayed disease onset and mortality when given to male hSOD1 G93A mice reversing the sexual dimorphism normally seen in this 
16781706SOD1hSOD12.7found to slow disease progression without ultimately affecting survival of hSOD1 G93A mice including cannabinol another cannabinoid compound ( Weydt et 
16781706SOD1hSOD12.7Microglia from hSOD1 G93A mice possess increased cytotoxic potential ( Weydt et al. 
16877542ALSALS2.2Abstract ALS is a fatal paralytic disorder characterized by a progressive loss 
16877542ALSALS2.2species-producing enzyme during inflammation is activated in spinal cords of ALS patients and in spinal cords in a genetic animal model 
16877542ALSALS2.2We demonstrate that inactivation of NADPH oxidase in ALS mice delays neurodegeneration and extends survival 
16877542ALSALS2.2death and contribute to the selective motor neuronal degeneration in ALS 
16877542ALSALS2.2Keywords Akt ALS microglia oxidation non-cell autonomous 
16877542SOD1SOD12.2Transgenic SOD1 G93A mice [C57BL/6J-TgN(SOD1-G93A)1Gur C57BL 6J-TgN SOD1-G93A 1Gur dl were crossed 
16877542SOD1SOD12.2for details about the timeline of behavioral abnormalities in transgenic SOD1 G93A mice 
16877542ALSALS2.260.5 _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 
16877542ALSALS2.2For the ALS patients the mean duration of disease was 19.3 _amp_#x000b1 2.6 
16877542ALSALS2.2NADPH Oxidase Is Up-Regulated in Inflamed Spinal Cords of ALS Mice 
16877542SOD1SOD12.2stages of the disease in transgenic mice expressing mutant human SOD1 with a substitution of glycine to alanine in position 93 
16877542SOD1SOD12.2a substitution of glycine to alanine in position 93 (SOD1 SOD1 G93A the most widely studied model of ALS 
16877542ALSALS2.293 (SOD1 SOD1 G93A the most widely studied model of ALS 
16877542ALSALS2.2cord which carries the brunt of the pathology in this ALS model was determined by analyzing its catalytic subunit gp91 phox 
16877542SOD1SOD12.2whole-tissue extracts of spinal cord rose over time in transgenic SOD1 G93A mice ( Fig 1 A B D and E 
16877542SOD1SOD12.2in membrane fractions of spinal cord extracts from symptomatic transgenic SOD1 G93A mice ( Fig 1 C indicating that this cytosolic 
16877542SOD1SOD12.2Histological evaluation of the spinal cord of symptomatic transgenic SOD1 G93A mice showed numerous gp91 phox -positive cells primarily in 
16877542SOD1SOD12.2NADPH Oxidase Causes Protein Oxidation in Transgenic SOD1 G93A Mice 
16877542SOD1SOD12.2characterized the status of spinal cord NADPH oxidase in transgenic SOD1 G93A mice by probing for formation of ROS and evidence 
16877542SOD1SOD12.2In contrast in symptomatic transgenic SOD1 G93A mice carrying the wild-type gp91 phox allele (SOD SOD 
16877542SODSOD2.2SOD1 G93A mice carrying the wild-type gp91 phox allele (SOD SOD G93A /gp91 gp91 phox spinal cord ethidium fluorescence was intense 
16877542SOD1SOD12.2In symptomatic transgenic SOD1 G93A mice carrying the nonfunctional mutant allele (SOD SOD G93A 
16877542SODSOD2.2transgenic SOD1 G93A mice carrying the nonfunctional mutant allele (SOD SOD G93A /gp91 gp91 phox_amp_#x02212 ( 12 spinal cord ethidium fluorescence 
16877542SOD1SOD12.2Symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice but not age-matched SOD1 G93A 
16877542SOD1SOD12.2transgenic SOD1 G93A /gp91 gp91 phox mice but not age-matched SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice had increased levels of spinal 
16877542SOD1SOD12.2for protein carbonyl adducts occurred in spinal cord sections from SOD1 G93A /gp91 gp91 phox mice at the level of cells 
16877542ALSALS2.2NADPH Oxidase Induction and Neuronal Protein Carbonylation in Sporadic ALS 
16877542SOD1SOD12.2to determine whether the NADPH oxidase alterations identified in transgenic SOD1 G93A mice were also present in human sporadic ALS the 
16877542ALSALS2.2transgenic SOD1 G93A mice were also present in human sporadic ALS the most common form of the disease ( 1 
16877542ALSALS2.2was _amp_#x02248 3-fold higher and its immunoreactivity robust in sporadic ALS spinal cords ( Fig 2 E 
16877542ALSALS2.22 F and were identified in all of the typical ALS loci of neurodegeneration including the anterior horn and the lateral 
16877542ALSALS2.2protein carbonyl adducts in postmortem spinal cord sections from sporadic ALS cases which seemed to be mainly associated with large motor 
16877542ALSALS2.2for protein carbonyl adducts per lumbar spinal cord section in ALS patients whereas no such immunoreactive motor neurons were seen in 
16877542SOD1SOD12.2Deletion of gp91 phox Mitigates the Disease Phenotype in Transgenic SOD1 G93A Mice 
16877542SOD1SOD12.2of NADPH oxidase activation on the disease phenotype in the SOD1 G93A mouse model of ALS 
16877542ALSALS2.2the disease phenotype in the SOD1 G93A mouse model of ALS 
16877542SOD1SOD12.2Transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice reached end-stage paralysis (defined defined 
16877542SOD1SOD12.2a loss of the righting reflex later than their transgenic SOD1 G93A /gp91 gp91 phox counterparts ( Fig 3 A which 
16877542SOD1SOD12.23 A which resulted in a longer lifespan of transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice (log-rank log-rank test = 15.3 
16877542SOD1SOD12.2Compared with end-stage transgenic SOD1 G93A /gp91 gp91 phox mice age-matched transgenic SOD1 G93A /gp91 
16877542SOD1SOD12.2end-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 
16877542SOD1SOD12.2the glial cytokine IL-1_amp_#x003b2 did not differ between age-matched transgenic SOD1 G93A /gp91 gp91 phox mice and SOD1 G93A /gp91 gp91 
16877542SOD1SOD12.2between age-matched transgenic SOD1 G93A /gp91 gp91 phox mice and SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice (Fig Fig 7 which is 
16877542SOD1SOD12.2the deficit of gp91 phox were the levels of human SOD1 in transgenic SOD1 G93A mice (Fig Fig 7 or the 
16877542SOD1SOD12.2gp91 phox were the levels of human SOD1 in transgenic SOD1 G93A mice (Fig Fig 7 or the size of muscle 
16877542SOD1SOD12.2Insulin-Like Growth Factor 1 (IGF1)/Akt IGF1 Akt Pathway in Transgenic SOD1 G93A Mice 
16877542ALSALS2.2explored whether NADPH oxidase-mediated protein modifications might promote neurodegeneration in ALS by damaging essential surviving pathways for motor neurons such as 
16877542SOD1SOD12.2kinase cognate receptor in the spinal cord of symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice ( Fig 4 A and 
16877542SOD1SOD12.2receptor signaling ( 15 did not differ between symptomatic transgenic SOD1 G93A mice and their nontransgenic littermates 
16877542ALSALS2.2molecular pathway is not oxidatively modified by inflammation in this ALS model 
16877542SOD1SOD12.2Although mutant SOD1 is expressed in all cells markers of IGF1 transduction such 
16877542SOD1SOD12.2smaller glia-like cells in spinal cord sections of symptomatic transgenic SOD1 G93A mice 
16877542SOD1SOD12.2phospho-IGF1 receptor-immunoreactive cells in spinal cord sections from symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice than from age-matched SOD1 G93A 
16877542SOD1SOD12.2transgenic SOD1 G93A /gp91 gp91 phox mice than from age-matched SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice ( Fig 4 C _amp_#x02013 
16877542SOD1SOD12.2ratios ( Fig 4 K and L in symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice compared with their age-matched SOD1 
16877542SOD1SOD12.2SOD1 G93A /gp91 gp91 phox mice compared with their age-matched SOD1 G93A /gp91 gp91 phox_amp_#x02212 counterparts 
16877542SOD1SOD12.2idea that oxidative modification of IGF1 receptor in symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice is associated with a range 
16877542ALSALS2.2Experimental evidence supports a model for ALS neurodegeneration in which nonneuronal cells such as microglia contribute to 
16877542SOD1SOD12.2Conversely in transgenic SOD1 G93A mice paralleling the worsening of the ALS phenotype there 
16877542ALSALS2.2in transgenic SOD1 G93A mice paralleling the worsening of the ALS phenotype there was an intensification of spinal cord microgliosis accompanied 
16877542ALSALS2.2of oxidatively damaging nearby macromolecules and cells homed within inflamed ALS tissues 
16877542SOD1SOD12.2were markedly elevated in spinal cord extracts of symptomatic transgenic SOD1 G93A mice for the most part in a NADPH oxidase-dependent 
16877542ALSALS2.2was also found in postmortem spinal cords from human sporadic ALS cases ( Fig 2 supporting the conclusion that the occurrence 
16877542ALSALS2.2occurrence of inflammation-mediated oxidative damage is not restricted to familial ALS caused by SOD1 mutations but is also a pathological hallmark 
16877542SOD1SOD12.2oxidative damage is not restricted to familial ALS caused by SOD1 mutations but is also a pathological hallmark of the prevalent 
16877542ALSALS2.2a pathological hallmark of the prevalent nonfamilial sporadic form of ALS 
16877542SOD1SOD12.2of the gp91 phox subunit of NADPH oxidase in transgenic SOD1 G93A mice eliminates the production of microglial-derived ROS ( Fig 
16877542ALSALS2.2M and importantly prolongs survival and retards neurodegeneration in this ALS model ( Fig 3 
16877542SOD1SOD12.2Deletion of gp91 phox in transgenic SOD1 G93A mice did not alter the spinal cord microglial response 
16877542SOD1SOD12.2the spinal cord microglial response or the expression of human SOD1 in transgenic SOD1 G93A mice (Fig Fig 7 which is 
16877542SOD1SOD12.2microglial response or the expression of human SOD1 in transgenic SOD1 G93A mice (Fig Fig 7 which is a known determinant 
16877542ALSALS2.2which is a known determinant of disease severity in this ALS model ( 18 
16877542SOD1SOD12.2Consequently the attenuated phenotype seen in transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice is attributable to the lack 
16877542SOD1SOD12.2either an impaired microglial response or expression of the human SOD1 G93A transgene 
16877542ALSALS2.2NADPH oxidase contributes to the degeneration of motor neurons in ALS 
16877542ALSALS2.2in the pathogenesis of chronic noninfectious pathological conditions such as ALS 
16877542SOD1SOD12.2magnitude of benefit afforded by gp91 phox deletion in transgenic SOD1 G93A mice argues that targeting neuroinflammation by inhibiting just one 
16877542ALSALS2.2not be sufficient to produce robust and lasting neuroprotection in ALS patients 
16877542ALSALS2.2However the chronic nature of ALS suggests that neuroinflammation is likely protracted and not as strong 
16877542ALSALS2.2oxidative stress with the selective demise of motor neurons in ALS 
16877542ALSALS2.2of those already compromised as motor neurons probably are in ALS 
16877542SOD1SOD12.2was impaired by a NADPH oxidase-dependent mechanism in symptomatic transgenic SOD1 G93A mice ( Fig 4 
16877542SOD1SOD12.2to withstand the toxicity of etiologic agents such as mutant SOD1 
16877542SOD1SOD12.2the spinal cord and enhances motor neuronal survival in transgenic SOD1 G93A mice ( 23 
16877542SOD1SOD12.2Nevertheless whether transgenic SOD1 G93A mice carrying the gp91 phox null mutation reach end-stage 
16877542SOD1SOD12.2Injection of transgenic SOD1 G93A mice with an adeno-associated virus carrying an IGF1 gene 
16877542ALSALS2.2may blunt the motor neuron survival response to IGF1 in ALS 
16877542ALSALS2.2Perhaps the modest change in ALS progression that is seen in patients treated with human recombinant 
16877542ALSALS2.2that optimal therapeutic response to IGF1 in diseases such as ALS may rely on a concomitant administration of this trophic factor 
16877542SOD1SOD12.2oxidase stimulates carbonylation of spinal cord motor neurons in transgenic SOD1 G93A mice 
16877542SOD1SOD12.2E in 1-month-old (asymptomatic) asymptomatic to 4-month-old (end-stage) end-stage transgenic SOD1 (more more ... 
16877542ALSALS2.2with motor neuron carbonylation in the spinal cord of sporadic ALS patients 
16877542ALSALS2.2spinal cord extracts from six normal controls and six age-matched ALS patients 
16877542SOD1SOD12.2of gp91 phox increases lifespan and lessens neurodegeneration in transgenic SOD1 G93A mice 
16877542SOD1SOD12.2( A Survival comparison of transgenic SOD1 G93A /gp91 gp91 phox mice (red) red (122.0 122.0 _amp_#x000b1 
16877542SOD1SOD12.2(122.0 122.0 _amp_#x000b1 1.7 days n = 19 and transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 littermates (more more ... 
16877542SOD1SOD12.2ROS reactive oxygen species SOD1 superoxide dismutase 1 IGF1 insulin-like growth factor 1 
16877542ALSALS2.2ALS is the most common adult-onset paralytic disease and is characterized 
16877542SOD1SOD12.2dominant mutations in the gene for superoxide dismutase 1 (SOD1) SOD1 cause familial ALS ( 2 3 
16877542ALSALS2.2the gene for superoxide dismutase 1 (SOD1) SOD1 cause familial ALS ( 2 3 
16877542SOD1SOD12.2Overexpression of SOD1 mutants in rodents emulate clinical and pathological hallmarks of ALS 
16877542ALSALS2.2SOD1 mutants in rodents emulate clinical and pathological hallmarks of ALS through a toxic gain of function ( 4 
16877542SOD1SOD12.2mixture of neuronal and nonneuronal cells expressing wild-type or mutant SOD1 ( 5 investigation of these animals suggested that nonneuronal cells 
16877542SOD1SOD12.2Corroborating this hypothesis is the demonstration that reduction of mutant SOD1 selectively in microglia extended survival in transgenic SOD1 G37R mice 
16877542SOD1SOD12.2of mutant SOD1 selectively in microglia extended survival in transgenic SOD1 G37R mice ( 6 
16877542ALSALS2.2we undertook the study of NADPH oxidase in both human ALS and one of its genetic models 
16877542ALSALS2.2and mouse postmortem tissues indicate that spinal cord microgliosis in ALS is accompanied with an up-regulation of NADPH oxidase 
16892030ALSALS1.2ALS life and death in a bad neighborhood 
16909005SOD1SOD11.7to the pathogenesis of motor neuron degeneration in the G93A SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS) ALS 
16909005SOD1SOD11.7We administered it in the diet to G93A SOD1 mice starting at 30 days of age 
17008387SOD1SOD12.5effect of oral PDTC treatment on G93A-superoxide dismutase 1 (SOD1) SOD1 transgenic (TG) TG rat model of human ALS and observed 
17008387SOD1SOD12.5suggesting that increased copper may enhance the neurotoxicity of mutant SOD1 
17008387SOD1SOD12.5suggest that PDTC acts as an immunoproteasome inhibitor in mutant SOD1 rats and that immunoproteasome may help the nervous system to 
17008387SOD1SOD12.51986 kappaB accompany motor neuron degeneration either in ALS or SOD1 mutant mice (Migheli Migheli et al. 1997 Tortarolo et al. 
17008387SOD1SOD12.5of several proinflammatory mediators is increased both in ALS and SOD1 mutant mice (Alexianu Alexianu et al. 2001 Elliott 2001 Nguyen 
17008387SOD1SOD12.5al. 2001 and numerous anti-inflammatory compounds prolong survival of TG SOD1 mutant mice (Drachman Drachman et al. 2002 Kriz et al. 
17008387SOD1SOD12.5In addition animal models that express mutant SOD1 exclusively either in motor neurons (Pramatarova Pramatarova et al. 2001 
17008387SOD1SOD1-mediated2.2beta (Drachman Drachman et al. 2002 beta pathway reduced mutant SOD1-mediated motor neuron cell death in vitro (Koh Koh et al. 
17008387SOD1SOD12.5models could increase the accumulation of ubiquitinated proteins including ubiquitinated SOD1 which has been suggested to gain neurotoxic functions such as 
17008387SODSOD2.2the survivalsupporting role of some NF-kappaB-regulated genes such as manganese SOD and Bcl-2 (Mattson Mattson and Camandola 2001 kappaB binding activity 
17008387SOD1SOD1-containing2.7in non-neuronal cells and thereby accelerating the formation of toxic SOD1-containing protein aggregates 
17008387SOD1SOD12.5be important for coping with the toxic consequences of mutant SOD1 in tissues affected by ALS 
17008387SOD1SOD12.5Because SOD1 is a major contributor to the cellular Cu concentration copper 
17008387SODSOD2.2sclerosis EMSA electrophoretic mobility shift assay NF-kappaB nuclear factor kappaB SOD superoxide dismutase WT wild type TG transgenic GLT glutamate transporter 
17015226ALS1ALS14.5motor neuron diseases ( Table 1 have been defined as ALS1 through ALS8 as well as ALS with frontotemporal dementia (ALS-FTD) 
17015226ALS1ALS14.5that affects motor neurons the nomenclature is misleading since only ALS1 ALS3 ALS6 ALS7 mutations in angiogenin and VEGF and a 
17015226ALS1ALS14.5all of these disease incidences only the genes responsible for ALS1 ALS8 and ALS-FTDP have been identified 
17015226SOD1SOD17.8ALS1_amp_#x2014 Mutation in SOD1 
17015226ALS1ALS14.5The lion's share of work has focused on ALS1 caused by_amp_#xa0 mutations in Cu/Zn Cu Zn superoxide dismutase (SOD1) 
17015226SOD1SOD17.8caused by_amp_#xa0 mutations in Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 
17015226SOD1SOD17.8Mutations in the SOD1 gene are the most common form of inherited ALS accounting 
17015226SOD1SOD17.8Since the first SOD1 missense mutations were reported in 1993 ( Rosen et_amp_#xa0 al. 
17015226SOD1SOD17.8With the exception of a few instances all SOD1 mutations are dominant 
17015226SOD1SOD17.8Sporadic and SOD1 mutant-mediated familial ALS are clinically indistinguishable and affect the same 
17015226SOD1SOD17.8The alanine-to-valine substitution at position 4 of SOD1 (SOD1 SOD1 A4V is the most prominent mutation in North 
17015226SOD1SOD17.8The alanine-to-valine substitution at position 4 of SOD1 (SOD1 SOD1 A4V is the most prominent mutation in North America responsible 
17015226SOD1SOD17.8Mice and rats expressing mutant forms of human or mouse SOD1 develop progressive motor neuron degeneration ( Bruijn et_amp_#xa0 al. 1997 
17015226SOD1SOD17.81984b and are also seen in ALS mice expressing mutant SOD1 ( Bruijn et_amp_#xa0 al. 1997 and Dal Canto and Gurney 
17015226SOD1SOD17.8no affect on disease course in mice having an ALS-causing SOD1 mutation ( Lariviere et_amp_#xa0 al. 2003 
17015226SOD1SOD17.8Motor Neuron Death from Toxicity of Mutant SOD1 Not Loss of Dismutase Activity 
17015226SOD1SOD17.8SOD1 is an abundant ubiquitously expressed cytosolic enzyme 
17015226SOD1SOD17.8Since the known activity of SOD1 is to dismutate (or or convert superoxide a natural byproduct 
17015226SOD1hSOD14.2However animals expressing dismutase active (hSOD1 hSOD1 G37R Wong et_amp_#xa0 al. 1995 and hSOD1 G93A Gurney et_amp_#xa0 
17015226SOD1hSOD14.2dismutase active (hSOD1 hSOD1 G37R Wong et_amp_#xa0 al. 1995 and hSOD1 G93A Gurney et_amp_#xa0 al. 1994 and Howland et_amp_#xa0 al. 2002 
17015226SOD1hSOD14.2and Howland et_amp_#xa0 al. 2002 as well as inactive (hSOD1 hSOD1 G85R Bruijn et_amp_#xa0 al. 1997 mSOD1 G86R Ripps et_amp_#xa0 al. 
17015226SOD1mSOD14.2well as inactive (hSOD1 hSOD1 G85R Bruijn et_amp_#xa0 al. 1997 mSOD1 G86R Ripps et_amp_#xa0 al. 1995 hSOD1 G127X Jonsson et_amp_#xa0 al. 
17015226SOD1hSOD14.2Bruijn et_amp_#xa0 al. 1997 mSOD1 G86R Ripps et_amp_#xa0 al. 1995 hSOD1 G127X Jonsson et_amp_#xa0 al. 2004 hSOD1 Quad Wang et_amp_#xa0 al. 
17015226SOD1hSOD14.2Ripps et_amp_#xa0 al. 1995 hSOD1 G127X Jonsson et_amp_#xa0 al. 2004 hSOD1 Quad Wang et_amp_#xa0 al. 2003 hSOD1 H46R Nagai et_amp_#xa0 al. 
17015226SOD1hSOD14.2Jonsson et_amp_#xa0 al. 2004 hSOD1 Quad Wang et_amp_#xa0 al. 2003 hSOD1 H46R Nagai et_amp_#xa0 al. 2001 forms of the enzyme develop 
17015226SOD1SOD17.8Furthermore SOD1 gene deletion in mice does not lead to motor neuron 
17015226SOD1SOD17.8In addition deletion of the endogenous mouse SOD1 in mice expressing dismutase inactive hSOD1 G85R does not affect 
17015226SOD1hSOD14.2of the endogenous mouse SOD1 in mice expressing dismutase inactive hSOD1 G85R does not affect disease course ( Bruijn et_amp_#xa0 al. 
17015226SOD1SOD17.8Mice expressing high levels of wild-type human SOD1 (hSOD1 hSOD1 WT transgene are healthy ( Gurney et_amp_#xa0 al. 
17015226SOD1hSOD14.2Mice expressing high levels of wild-type human SOD1 (hSOD1 hSOD1 WT transgene are healthy ( Gurney et_amp_#xa0 al. 1994 and 
17015226SOD1hSOD14.2Indeed increased hSOD1 WT accompanied by chronic elevation of dismutase activity has either 
17015226SOD1SOD17.8SOD1 activity is dependent on a catalytic copper 
17015226SOD1SOD17.8is highly reactive and toxic it must be loaded onto SOD1 by a copper chaperone for SOD1 (CCS; CCS Corson et_amp_#xa0 
17015226SOD1SOD17.8must be loaded onto SOD1 by a copper chaperone for SOD1 (CCS; CCS Corson et_amp_#xa0 al. 1998 and Wong et_amp_#xa0 al. 
17015226SOD1SOD17.82002 it was postulated that inefficient incorporation of copper into SOD1 and/or and or a decreased shielding of copper (due due 
17015226SOD1SOD17.8a decreased shielding of copper (due due to changes in SOD1 structure as a result of mutation could provide an opportunity 
17015226SOD1SOD17.8using mice in which the incorporation of copper into mutant SOD1 was significantly reduced by disruption of the CCS gene 
17015226SOD1hSOD14.2in which all four copper-binding histidines have been eliminated (hSOD1 hSOD1 Quad resulting in dismutase inactive SOD1 still develop typical ALS-like 
17015226SOD1SOD17.8have been eliminated (hSOD1 hSOD1 Quad resulting in dismutase inactive SOD1 still develop typical ALS-like motor neuron disease ( Wang et_amp_#xa0 
17015226SOD1SOD17.8toxic property (or or properties acquired as a result of SOD1 mutation (1) 1 are independent of dismutase and CCS activities 
17015226SOD1SOD17.8Misfolded SOD1 as a Common Feature of ALS-Causing Mutations 
17015226SOD1SOD17.8sporadic and familial ALS cases as well as in mutant SOD1 transgenic mice ( Bruijn et_amp_#xa0 al. 1997 Bruijn et_amp_#xa0 al. 
17015226SOD1SOD17.8used to define accumulations of detergent-insoluble forms of proteins including SOD1 that are detected by immunoblotting of filter-trappable material as well 
17015226SOD1SOD1-4.5detected by immunoblotting of filter-trappable material as well as small SOD1- or ubiquitin-positive fibrillar inclusions in spinal cord sections ( Deng 
17015226SOD1SOD17.8Detergent-insoluble species are detectable only in affected tissues of mutant SOD1 mice and are most prominent at symptomatic stages ( Furukawa 
17015226SOD1SOD17.8A propensity to form aggregates following synthesis of mutant SOD1 in primary cells is selective to motor neurons as aggregates 
17015226SOD1SOD17.8The most misfolded unstable SOD1 mutants (with with the shortest in vivo half-lives are most 
17015226SOD1hSOD14.2unexplained aspect of disease is that the very unstable mutant hSOD1 A4V ( Sato et_amp_#xa0 al. 2005 which provokes a very 
17015226SOD1hSOD14.2in mice except in the context of high levels of hSOD1 WT ( Deng et_amp_#xa0 al. 2006 
17015226SOD1hSOD14.2Similarly increased hSOD1 WT accelerated disease from a second unstable mutant hSOD1 L126Z 
17015226SOD1hSOD14.2increased hSOD1 WT accelerated disease from a second unstable mutant hSOD1 L126Z 
17015226SOD1hSOD14.2be mediated by_amp_#xa0 stabilization of the mutant via heterodimerization with_amp_#xa0 hSOD1 WT protein 
17015226SOD1hSOD14.2Indeed in both cases increased levels_amp_#xa0 of hSOD1 WT generated detergent-insoluble forms of SOD1 that were not seen 
17015226SOD1SOD17.8cases increased levels_amp_#xa0 of hSOD1 WT generated detergent-insoluble forms of SOD1 that were not seen in spinal cord extracts of hSOD1 
17015226SOD1hSOD14.2SOD1 that were not seen in spinal cord extracts of hSOD1 A4V or hSOD1 L126Z mice alone 
17015226SOD1hSOD14.2not seen in spinal cord extracts of hSOD1 A4V or hSOD1 L126Z mice alone 
17015226SOD1SOD17.8Are SOD1 Aggregates Toxic 
17015226SOD1SOD17.8Indeed the degradation of SOD1 itself and aggregates of SOD1 is proteasome mediated ( Basso 
17015226SOD1SOD17.8Indeed the degradation of SOD1 itself and aggregates of SOD1 is proteasome mediated ( Basso et_amp_#xa0 al. 2006 Niwa et_amp_#xa0 
17015226SOD1hSOD14.2In hSOD1 G93A mice which accumulate mutant protein to high levels proteasome 
17015226SOD1SOD17.8been reported which persists throughout disease course and multiple recombinant SOD1 mutants inhibit chaperone function in vitro ( Bruening et_amp_#xa0 al. 
17015226SOD1hSOD14.2B-crystallin and Hsp27 are elevated in the spinal cords of hSOD1 G37R and hSOD1 G93A mice but Hsp27 is predominantly present 
17015226SOD1hSOD14.2are elevated in the spinal cords of hSOD1 G37R and hSOD1 G93A mice but Hsp27 is predominantly present in glial cells 
17015226SOD1hSOD14.2are also elevated but only in the spinal cords of hSOD1 G85R mice ( Liu et_amp_#xa0 al. 2005 Vleminckx et_amp_#xa0 al. 
17015226SOD1SOD1-mediated4.5Mutant SOD1-mediated depletion of HSPs is a plausible possibility given that Hsp70 
17015226SOD1SOD17.8plausible possibility given that Hsp70 and Hsp25 preferentially bind mutant SOD1 ( Okado-Matsumoto and Fridovich 2002 
17015226SOD1SOD17.8vivo by increased expression of Hsp70 in four different mutant SOD1 mouse lines did not ameliorate disease or pathology ( Liu 
17015226SOD1hSOD14.2stress response extended life span in a small cohort of hSOD1 G93A mice after treatment with arimoclomol a drug which induces 
17015226SOD1hSOD14.2that develop disease from accumulation of dismutase active mutants (hSOD1 hSOD1 G37R Wong et_amp_#xa0 al. 1995 and hSOD1 G93A mice Dal 
17015226SOD1hSOD14.2active mutants (hSOD1 hSOD1 G37R Wong et_amp_#xa0 al. 1995 and hSOD1 G93A mice Dal Canto and Gurney 1994 Higgins et_amp_#xa0 al. 
17015226SOD1hSOD14.2been described in mice with very high accumulated levels of hSOD1 WT protein ( Jaarsma et_amp_#xa0 al. 2000 and Jaarsma et_amp_#xa0 
17015226SOD1SOD17.8A proportion of the predominantly cytosolic SOD1 localizes to mitochondria in certain contexts 
17015226SOD1SOD17.8In both rodent models and patient samples mutant SOD1 is present in fractions enriched for mitochondria derived from affected 
17015226SOD1SOD17.8Mitochondrial localization of SOD1 has been confirmed by electron microscopy in both isolated mitochondria 
17015226SOD1SOD17.8SOD1 mutants that cause disease at the lowest accumulated levels (hSOD1 
17015226SOD1hSOD14.2mutants that cause disease at the lowest accumulated levels (hSOD1 hSOD1 G85R and hSOD1 G127X all dismutase inactive have the highest 
17015226SOD1hSOD14.2disease at the lowest accumulated levels (hSOD1 hSOD1 G85R and hSOD1 G127X all dismutase inactive have the highest relative proportions that 
17015226SOD1SOD17.8disagreement in defining the submitochondrial compartment(s) compartment s with which SOD1 is localized (or or potentially aggregated 
17015226SOD1SOD17.8Mutant SOD1 has been reported in both the intermembrane space and the 
17015226SOD1SOD17.8apparent contradictions remain to be resolved all reports agree that SOD1 mutant proteins of divergent biochemical characteristics localize to mitochondria consistent 
17015226SOD1SOD17.8there some intrinsic feature of spinal cord mitochondria which permits SOD1 association and/or and or increases mitochondrial vulnerability to mutant SOD1 
17015226SOD1SOD17.8SOD1 association and/or and or increases mitochondrial vulnerability to mutant SOD1 
17015226SOD1SOD17.8Of relevance here the endogenous wild-type SOD1 protein is largely excluded from spinal cord mitochondria but all 
17015226SOD1SOD17.8is largely excluded from spinal cord mitochondria but all human SOD1 mutants examined to date are mitochondrially associated 
17015226SOD1SOD17.8Liu et_amp_#xa0 al. 2004 despite a proportion of endogenous mouse SOD1 localized to the intermembrane space of those mitochondria ( Liu 
17015226SOD1SOD17.8How mutant SOD1 affects mitochondrial function is not yet clear but differences in 
17015226SOD1SOD17.8Mutant SOD1 associated with or aggregated onto the mitochondrial surface could impede 
17015226SOD1hSOD14.2example ATP synthesis has been reported as unchanged in aged hSOD1 G85R mice ( Damiano et_amp_#xa0 al. 2006 or depleted in 
17015226SOD1hSOD14.2( Damiano et_amp_#xa0 al. 2006 or depleted in late symptomatic hSOD1 G93A mice ( Mattiazzi et_amp_#xa0 al. 2002 or ATP levels 
17015226SOD1hSOD14.2Creatine which extended survival in hSOD1 G93A mice by alleviating presumed energy deficits ( Browne et_amp_#xa0 
17015226SOD1SOD17.8Early impairment in mitochondrial calcium-buffering capacity in mutant SOD1 spinal cord prior to symptoms and only in disease-relevant tissues 
17015226SOD1SOD17.8symptoms and only in disease-relevant tissues in two different mutant SOD1 models ( Damiano et_amp_#xa0 al. 2006 is perhaps the most 
17015226SOD1SOD17.8et_amp_#xa0 al. 1999 and Mu et_amp_#xa0 al. 1996 and mutant SOD1 mice ( Gonzalez de Aguilar et_amp_#xa0 al. 2000 and Vukosavic 
17015226SOD1SOD17.8An alternate mechanism in which SOD1 is proposed to interact with Bcl-2 and possibly interferes with 
17015226SOD1SOD1-mediated4.5spectrum caspase inhibitor ( Li et_amp_#xa0 al. 2000 slowed mutant SOD1-mediated neuronal death disease onset was also delayed in the absence 
17015226SOD1SOD17.8different subsets of muscle fibers have different susceptibilities to mutant SOD1 toxicity 
17015226SOD1SOD17.8Specifically in two different mutant SOD1 models the fast-fatiguable motor neurons were shown to be affected 
17015226SOD1SOD17.8followed next with the slow type partially resistant to mutant SOD1 and actually attempting to reinnervate previously denervated regions ( Frey 
17015226SOD1SOD17.8s failed to provide a benefit in three different mutant SOD1 models ( Fischer et_amp_#xa0 al. 2005 and Vande Velde et_amp_#xa0 
17015226SOD1SOD17.8et_amp_#xa0 al. 1984b and Kawamura et_amp_#xa0 al. 1981 and mutant SOD1 mice ( Bruijn et_amp_#xa0 al. 1998 Kong and Xu 1998 
17015226SOD1SOD17.8Neurofilament accumulations are seen early in mutant SOD1 mice ( Kong and Xu 1998 
17015226SOD1hSOD14.2axonal neurofilaments by deletion of NF-L substantially prolonged survival of hSOD1 G85R and hSOD1 G37R mice ( Nguyen et_amp_#xa0 al. 2001 
17015226SOD1hSOD14.2deletion of NF-L substantially prolonged survival of hSOD1 G85R and hSOD1 G37R mice ( Nguyen et_amp_#xa0 al. 2001 and Williamson et_amp_#xa0 
17015226SOD1SOD17.8Absence of those tail domains sharply slows SOD1 mutant-induced disease ( Lobsiger et_amp_#xa0 al. 2005 
17015226SOD1SOD17.8deficit of slow axonal transport has been described in mutant SOD1 mice ( Ackerley et_amp_#xa0 al. 2003 Williamson and Cleveland 1999 
17015226SOD1hSOD14.22005 or Cra1 ( Teuchert et_amp_#xa0 al. 2006 mutation to hSOD1 G93A mice significantly improves survival 
17015226SOD1SOD17.8This unexpected amelioration of SOD1 mutant toxicity by a mutation expected to alter retrograde axonal 
17015226SOD1SOD17.8caused by mutations in genes that are ubiquitously expressed ( SOD1 and VAPB or expressed in multiple cells types ( VEGF 
17015226SOD1SOD17.8type was required for disease came from expression of mutant SOD1 only within motor neurons ( Lino et_amp_#xa0 al. 2002 and 
17015226SOD1SOD17.8neuron degeneration or death (albeit albeit the expression of mutant SOD1 selectively within motor neurons might have been at levels too 
17015226SOD1hSOD14.2construction and analysis of chimeric mice that were mixtures of hSOD1 mutant-expressing cells and normal cells ( Clement et_amp_#xa0 al. 2003 
17015226SOD1SOD17.8These efforts conclusively demonstrated that expression of mutant SOD1 within individual motor neurons even at levels that cause early 
17015226SOD1SOD17.8analysis of mice carrying a deletable (_amp_#x201c;floxed_amp_#x201d;) _amp_#x201c floxed_amp_#x201d mutant SOD1 gene that can be excised by the action of the 
17015226SOD1SOD17.8Excision of the floxed mutant SOD1 gene exclusively within motor neurons (by by action of Cre 
17015226SOD1SOD17.8NF-H subunits Lobsiger et_amp_#xa0 al. 2005 provide extended survival of SOD1 mutant mice but only by slowing disease onset 
17015226SOD1SOD17.8In contrast diminishing mutant SOD1 levels within microglia and peripheral macrophages (using using a Cre 
17015226SOD1SOD17.8was replaced by transplantation of normal bone marrow cells into SOD1 mutant mice that were themselves unable to synthesize their own 
17015226SOD1hSOD14.2Transplantation at birth_amp_#xa0 with hSOD1 G93A mutant-expressing myeloid cells (which which populate both the CNS 
17015226SOD1hSOD14.2and the periphery produced onset and survival typical of the hSOD1 G93A mutant line 
17015226SOD1SOD17.8Thus both approaches demonstrated that mutant SOD1 within macrophages/microglial macrophages microglial cells accelerates disease progression while mutant 
17015226SOD1SOD1-expressing4.2Importantly introducing mutant SOD1-expressing microglial cells into control animals did not give rise to 
17015226SOD1SOD1-expressing4.2not give rise to motor neuron disease demonstrating that mutant SOD1-expressing macrophages/microglial macrophages microglial cells themselves are not sufficient to cause 
17015226SOD1SOD17.8macrophages/microglial macrophages microglial cells in the spinal cord of mutant SOD1 mice have been shown to enter from the periphery during 
17015226SOD1SOD17.8al. 2004 and in the spinal cord of different mutant SOD1 mouse models ( Hall et_amp_#xa0 al. 1998 Henkel et_amp_#xa0 al. 
17015226SOD1hSOD14.2have been reported in spinal cords of ALS patients and hSOD1 G93A mice during the disease course ( Henkel et_amp_#xa0 al. 
17015226SOD1SOD17.8Such treatment exacerbated SOD1 mutant-mediated disease in mice ( Nguyen et_amp_#xa0 al. 2004 
17015226SOD1SOD17.8receptor expressed by microglia mildly accelerated neuronal loss in mutant SOD1 mice ( Cardona et_amp_#xa0 al. 2006 
17015226SOD1SOD17.8factors have been described in the spinal cords of mutant SOD1 mice even before motor neuron loss ( Elliott 2001 Hensley 
17015226SOD1SOD17.8One particularly interesting cytokine upregulated in mutant SOD1 mouse spinal cords which could play a role in motor 
17015226SOD1hSOD14.2been shown to be produced in higher levels by adult hSOD1 G93A microglial cells when stimulated with LPS compared to nontransgenic 
17015226SOD1SOD17.8TNF_amp_#x3b1 antagonist yielded a mild increase in survival in mutant SOD1 mice ( West et_amp_#xa0 al. 2004 
17015226SOD1SOD17.8In addition mutant SOD1 which has now been reported to be released by motor 
17015226SOD1SOD17.8a partial explanation for the selectivity of motor neurons to SOD1 mutant toxicity has arisen from identification of a motor-neuron-specific cell-death 
17015226SOD1SOD17.8surprisingly embryonic motor neurons extracted from spinal cords of mutant SOD1 mice are more susceptible to toxic insults ( Kruman et_amp_#xa0 
17015226SOD1hSOD14.2neurons from normal mice or mice expressing high levels of hSOD1 WT protein 
17015226SOD1SOD17.8Cultured motor neurons from transgenic mutant SOD1 mice have an increased susceptibility to activation of this pathway 
17015226SOD1SOD17.8acceleration of disease by mutant microglia it is plausible that SOD1 mutant-induced release of nitric oxide by microglia drives this death 
17015226SOD1hSOD14.2Altered efficiency of editing was not found in hSOD1 G93A or hSOD1 H46R rats ( Kawahara et_amp_#xa0 al. 2006 
17015226SOD1hSOD14.2efficiency of editing was not found in hSOD1 G93A or hSOD1 H46R rats ( Kawahara et_amp_#xa0 al. 2006 thereby demonstrating that 
17015226SOD1SOD17.8activation is seen in spinal cords of ALS patients and SOD1 mutant mice ( Hall et_amp_#xa0 al. 1998 Levine et_amp_#xa0 al. 
17015226SOD1hSOD14.2Indeed for mice expressing the dismutase inactive mutant hSOD1 G85R a very prominent early pathology that increases markedly during 
17015226SOD1SOD1-containing4.2that increases markedly during disease course is the presence of SOD1-containing inclusions within activated astrocytes ( Bruijn et_amp_#xa0 al. 1997 
17015226SOD1SOD17.8one of the few firm mechanistic links between sporadic and SOD1 mutant-caused ALS 
17015226SOD1SOD17.81995 and Sasaki et_amp_#xa0 al. 2000 spinal cords of mutant SOD1 mice ( Bruijn et_amp_#xa0 al. 1997 and rats ( Howland 
17015226SOD1hSOD14.2This is functionally of consequence for familial ALS in that hSOD1 G93A mice heterozygous for EAAT2 develop earlier-onset disease ( Pardo 
17015226SOD1hSOD14.2ceftriaxone as_amp_#xa0 a transcriptional inducer that modestly extends survival in hSOD1 G93A mice ( Rothstein et_amp_#xa0 al. 2005 
17015226SOD1hSOD14.2to resting astrocytes activated astrocytes in the spinal cord of hSOD1 G93A mice have increased NGF synthesis ( Pehar et_amp_#xa0 al. 
17015226SOD1SOD1-mediated4.5Among the earliest events in the human ALS- and SOD1-mediated disease is withdrawal of the motor axons from the neuromuscular 
17015226SOD1SOD17.8Mutant SOD1 is also expressed by muscle but whether its presence there 
17015226SOD1hSOD14.2beneficial in ALS has been attempted by repetitive injection into hSOD1 G93A mice of an antibody to myostatin a secreted protein 
17015226SOD1SOD17.8During this phase mutant SOD1 primarily acts directly within motor neurons with aggregation of misfolded 
17015226SOD1SOD17.8primarily acts directly within motor neurons with aggregation of misfolded SOD1 damaging cellular machinery especially mitochondria so as to inhibit one 
17015226SOD1SOD17.8SOD1 mutant action within the motor neuron is amplified by action 
17015226SOD1SOD17.8Misfolded SOD1 mutant within astrocytes as well as their activation in response 
17015226SOD1SOD17.8SOD1 mutant action directly within microglial and astrocytic cells may provoke 
17015226SOD1SOD17.8of toxic factors (e.g., e.g. nitric oxide TNF_amp_#x3b1 or mutant SOD1 secreted or released by cell leakage or lysis 
17015226SOD1SOD17.8Mutant SOD1 can itself activate microglia 
17015226SOD1SOD17.8Thus selective sensitivity of motor neurons to ubiquitously expressed SOD1 mutants derives from the combination of risk factors shared by 
17015226SOD1hSOD14.2Use of this strategy slowed disease progression in hSOD1 G93A mice even when initiated after disease onset ( Kaspar 
17015226SOD1hSOD14.2pseudocoated so as to be retrogradely transported extended survival of hSOD1 G93A mice ( Azzouz et_amp_#xa0 al. 2004 
17015226SOD1hSOD14.2of VEGF also has been reported to slow disease in hSOD1 G93A mice ( Zheng et_amp_#xa0 al. 2004 raising the possibility 
17015226SOD1SOD17.8that the instances of ALS caused by dominant mutation in SOD1 derive from a toxic property of the mutant protein and 
17015226SOD1SOD17.8efforts using siRNA to catalyze degradation of the mRNA encoding SOD1 have proven successful in hSOD1 G93A mice 
17015226SOD1hSOD14.2degradation of the mRNA encoding SOD1 have proven successful in hSOD1 G93A mice 
17015226SOD1SOD17.8After retrograde transport to motor neuron cell bodies reducing SOD1 mutant synthesis in motor neurons had a remarkable effect in 
17015226SOD1SOD17.8H This approach has been successfully used for lowering mutant SOD1 levels by 50% throughout the brain and at all levels 
17015226SOD1hSOD14.2brain and at all levels of the spinal cord of hSOD1 G93A rats 
17015226SOD1hSOD14.2Other strategies with hSOD1 G93A mice have used (1) 1 human neural stem cells 
17015226SOD1hSOD14.2In hSOD1 G93A mice an increase in neural progenitor cell proliferation migration 
17015226SOD1hSOD14.2was initiated on the predominantly symptomatic side of asymmetrically paralyzed hSOD1 G93A rats ( de Hemptinne et_amp_#xa0 al. 2006 
17015226SOD1hSOD14.2cell neuroprogenitor niches of the forebrain has revealed alterations in hSOD1 G93A mice ( Liu and Martin 2006 
17015226SOD1SOD17.8Figure_amp_#xa0 1._amp_#xa0 Proposed Toxicities of ALS-Causing SOD1 Protein Aggregates 
17015226SOD1SOD1-Mediated4.5Figure_amp_#xa0 2._amp_#xa0 Mutant SOD1-Mediated Damage to Mitochondria 
17015226SOD1SOD17.8Motor Neuron Degeneration and Glial Activation during the Course of SOD1 Mutant-Initiated ALS Disease 
17018025SOD1mSOD11.3is supported by the fact that selective overexpression of the mSOD1 transgene in neurons is not sufficient to cause motoneuron disease 
17018025SODSOD-inhibitable1.3assay The release of superoxide ( was determined by the SOD-inhibitable reduction of ferricytochrome c ( Gao et al 2002 Mayer 
17018025SODSOD1.6SOD effectively inhibited the reduction of ferricytochrome c which confirmed that 
17034351SOD1SOD11.4ALS based on overexpressed mutant human Cu Zn-superoxide dismutase (SOD1) SOD1 are cases in point 
17034351SOD1SOD11.4Lesions to redox signal-transduction pathways in mutant SOD1 glial cells may stimulate broad-spectrum upregulation of proinflammatory genes including 
17034351SOD1SOD11.4what has been learned to date from studies of mutant SOD1 transgenic animals and demonstrates that the G93A-SOD1 mouse in particular 
17191135SOD1SOD11.9antioxidant enzymatic activities such as GPx GSSG reductase CAT and SOD1 were also found elevated in several regions of AD brain 
17214440SOD1SOD11.7familial ALS cases mutations in the superoxide dismutase 1 (SOD1) SOD1 gene were discovered 
17306794SOD1SOD12.4copies ( Gurney et al. 1994 of the human mutant SOD1 gene (Cu/Zn-SOD) Cu Zn-SOD containing the Gly 93 _amp_#x2192 Ala 
17306794SOD1SOD12.4blot analysis the first changes of CATX immunostaining in the SOD1 transgenics were notable at the age of 3_amp_#xa0 months a 
17350694SOD1SOD10.5anti-inflammatory agents prolong the survival of transgenic mice expressing human SOD1 with a G93A mutation (hSOD1G93A), hSOD1G93A an animal model of 
17418957SOD1SOD10.5the onset of MN degeneration in mice expressing a mutant SOD1 ( Kong and Xu 1998 
17418957SOD1SOD10.5ultrastructural studies of anterior horn cells of ALS patients and SOD1 mouse model show accumulation of mitochondria in the axonal hillock 
17418957SOD1SOD10.5TNF-_amp_#x3b1 blocker thalidomide on the progression of ALS in the SOD1 mouse model ( Wong et al 2004 and Kiaei et 
17418957SOD1SOD10.5increasing survival and delaying progression of ALS phenotypes in the SOD1 G93A mouse model ( Wong et al 2004 and Kiaei 
17418957SOD1SOD10.5( Sriram et al. 2002 yet generation of mice expressing SOD1 G37R or SOD1 G93A mutants in the context of TNF-_amp_#x3b1 
17418957SOD1SOD10.5al. 2002 yet generation of mice expressing SOD1 G37R or SOD1 G93A mutants in the context of TNF-_amp_#x3b1 gene knockout did 
17418957SOD1SOD10.5affect the lifespan or the extent of MN loss in SOD1 transgenic mice ( Gowing et al. 2006 
17555556SOD1mSOD11.9studies suggest that microglia over-expressing mutant human superoxide dismutase (mSOD1 mSOD1 G93A may contribute to motoneuron death in a transgenic mouse 
17555556SOD1mSOD11.9To further assess the relative neurotoxicity of wild-type microglia mSOD1 G93A microglia and microglia over-expressing wild-type human SOD1 we used 
17555556SOD1SOD11.9wild-type microglia mSOD1 G93A microglia and microglia over-expressing wild-type human SOD1 we used primary cultures of microglia and motoneurons in the 
17555556SOD1mSOD11.9Following activation with lipopolysaccharide mSOD1 G93A microglia released more nitric oxide more superoxide and less 
17555556SOD1mSOD11.9In microglia/motoneuron microglia motoneuron co-cultures mSOD1 G93A microglia induced more motoneuron death and decreased neurite numbers 
17555556SOD1SOD11.9Mutant SOD1 G93A microglia also induced more motoneuron injury than microglia over-expressing 
17555556SOD1SOD11.9also induced more motoneuron injury than microglia over-expressing wild-type human SOD1 in microglia/motoneuron microglia motoneuron co-cultures 
17555556SOD1mSOD11.9Motoneuron survival was inversely correlated with nitrate nitrite concentrations in mSOD1 G93A co-cultures suggesting the important role of nitric oxide in 
17555556SOD1mSOD11.9Thus relative to wild-type microglia mSOD1 G93A microglia were more neurotoxic and induced more motoneuron injury 
17555556SOD1mSOD11.9human mutant Cu 2 /Zn Zn 2 superoxide dismutase (mSOD1), mSOD1 an animal model of familial ALS immune/inflammatory immune inflammatory changes 
17555556SOD1mSOD11.9The selective over-expression of mSOD1 in motoneurons alone does not appear to be sufficient to 
17555556SOD1mSOD11.9be sufficient to fully reproduce the motoneuron disease observed in mSOD1 mice ( Pramatarova et al 2001 Lino et al 2002 
17555556SOD1mSOD11.9In mSOD1 transgenic mice microglial activation is evident prior to the onset 
17555556SOD1mSOD11.9An earlier in vivo study with chimeric mice suggested that mSOD1 glia may contribute to motoneuron injury while wild-type glia may 
17555556SOD1mSOD11.9viability was confirmed in vivo by bone marrow transplantation of mSOD1 G93A /PU.1 PU.1 _amp_#8722;/_amp_#8722; _amp_#8722 _amp_#8722 mice in which replacing 
17555556SOD1SOD11.9G93A /PU.1 PU.1 _amp_#8722;/_amp_#8722; _amp_#8722 _amp_#8722 mice in which replacing SOD1 G93A microglia with wild-type microglia significantly slowed motoneuron loss prolonged 
17555556SOD1mSOD11.9(2006) 2006 used the Cre-Lox system to document that reducing mSOD1 expression in mSOD1 G37R microglia also resulted in longer disease 
17555556SOD1mSOD11.9the Cre-Lox system to document that reducing mSOD1 expression in mSOD1 G37R microglia also resulted in longer disease duration and survival 
17555556SOD1mSOD11.9evidence comparing the relative toxicity of primary microglia cultures from mSOD1 G93A mice with microglia from their wild-type littermates ( Beers 
17555556SOD1mSOD11.9microglia expressing the human G93A mutation the present paper compares mSOD1 G93A microglia with microglia from mice over-expressing wild-type human SOD1 
17555556SOD1SOD11.9mSOD1 G93A microglia with microglia from mice over-expressing wild-type human SOD1 (wt-hSOD1) wt-hSOD1 as well as microglia from wild-type mice 
17555556SOD1mSOD11.9Our results demonstrate that mSOD1 G93A mouse microglia release more nitric oxide more superoxide and 
17555556SOD1mSOD11.9Furthermore mSOD1 G93A microglia induced more motoneuron injury than both wild-type microglia 
17555556SOD1mSOD11.9Experimental animals Mice over-expressing mutant human G93A-SOD1 (mSOD1 mSOD1 G93A B6SJL-TgN SOD1-G93A 1Gur wt-hSOD1 (B6SJL-TgN[SOD1]2Gur), B6SJL-TgN SOD1 2Gur and 
17555556SOD1SOD11.9G93A-SOD1 (mSOD1 mSOD1 G93A B6SJL-TgN SOD1-G93A 1Gur wt-hSOD1 (B6SJL-TgN[SOD1]2Gur), B6SJL-TgN SOD1 2Gur and their non-transgenic littermates were bred and maintained in 
17555556SOD1mSOD11.9Microglial cultures were prepared from 8-day-old mSOD1 G93A mice wt-hSOD1 mice and their non-transgenic littermates as previously 
17555556SOD1mSOD11.9Western blots Wild-type or mSOD1 mouse microglia were incubated at 37_amp_deg C with or without 
17555556SODSOD1.9Superoxide assay Superoxide production from microglia was assessed by SOD reduction of ferricytochrome c using a modified protocol of Gao 
17555556SOD1SOD11.9Mutant SOD1 G93A microglia produce more neurotoxins and less IGF-1 than wild-type 
17555556SOD1mSOD11.9In this study nitric oxide release was compared between primary mSOD1 G93A and wild-type microglia by measuring the nitrate nitrite concentrations 
17555556SOD1mSOD11.9Although nitrate nitrite concentrations from untreated mSOD1 G93A and wild-type microglia were below the linear range of 
17555556SOD1mSOD11.9of nitrate nitrite were within the linear range with both mSOD1 G93A and wild-type microglia 
17555556SOD1mSOD11.9Following 10 ng/mL ng mL LPS treatment mSOD1 G93A microglia produced 4.1 _amp_plusmn 0.58 _amp_#x03BC;mol/L _amp_#x03BC mol L 
17555556SOD1mSOD11.9representing a 73% increase of nitrate/nitrite nitrate nitrite release from mSOD1 G93A microglia compared with wild-type microglia ( p _lt_ 0.01 
17555556SOD1mSOD11.9_amp_plusmn 0.72 _amp_#x03BC;mol/L _amp_#x03BC mol L in the supernatant from mSOD1 G93A microglia and 5.8 _amp_plusmn 0.52 _amp_#x03BC;mol/L _amp_#x03BC mol L 
17555556SOD1mSOD11.9This represents a 51% increase of nitrate nitrite from mSOD1 G93A microglia compared with wild-type microglia ( p _lt_ 0.05 
17555556SOD1mSOD11.9However after treatment with 1 _amp_#x03BC;g/mL _amp_#x03BC g mL LPS mSOD1 G93A microglia expressed 170% more iNOS than wild-type microglia ( 
17555556SOD1mSOD11.9et al 2004 therefore superoxide levels were compared between primary mSOD1 G93A and wild-type microglia 
17555556SOD1mSOD11.9Untreated mSOD1 G93A microglia produced 40% more superoxide than wild-type untreated microglia 
17555556SOD1mSOD11.9After treatment with 1 _amp_#x03BC;g/mL _amp_#x03BC g mL LPS mSOD1 G93A microglia produced 73% more superoxide than similarly treated wild-type 
17555556SOD1mSOD11.9than similarly treated wild-type microglia (370 370 _amp_plusmn 16% in mSOD1 G93A microglia vs 220 _amp_plusmn 23% in wild-type microglia p 
17555556SODSOD1.9the reduction of ferricytochrome c we added superoxide dismutase (SOD) SOD to the assay to test if the reduction of ferricytochrome 
17555556SODSOD1.9The addition of SOD to the assay abolished the reduction of ferricytochrome c suggesting 
17555556SOD1mSOD11.9Untreated mSOD1 G93A microglia released 22% less IGF-1 compared with untreated wild-type 
17555556SOD1mSOD11.9mL LPS less IGF-1 was measured in both wild-type and mSOD1 G93A microglia 
17555556SOD1mSOD11.9However using either concentrations of LPS mSOD1 G93A microglia released significantly less IGF-1 than wild-type microglia (10 
17555556SOD1mSOD11.9(10 10 ng/mL ng mL LPS 21 _amp_plusmn 3.4% from mSOD1 G93A microglia and 27 _amp_plusmn 2.4% from wild-type microglia a 
17555556SOD1mSOD11.91 _amp_#x03BC;g/mL _amp_#x03BC g mL LPS 18 _amp_plusmn 1.7% in mSOD1 G93A microglia and 23 _amp_plusmn 2.2% in wild-type microglia a 
17555556SOD1mSOD11.9Without LPS treatment mSOD1 G93A microglia released significantly more superoxide and less IGF-1 than 
17555556SOD1mSOD11.9more superoxide and less IGF-1 than wild-type microglia suggesting that mSOD1 G93A microglia are more activated than wild-type microglia 
17555556SOD1mSOD11.9wild-type microglia did not significantly produce more nitric oxide than mSOD1 G93A microglia treated with 10 ng/mL ng mL LPS 
17555556SOD1mSOD11.9wild-type microglia did not significantly produce more superoxide than untreated mSOD1 G93A microglia 
17555556SOD1mSOD11.9less LPS although the amount of IGF-1 released was small mSOD1 G93A microglia did not release significantly more IGF-1 than wild-type 
17555556SOD1mSOD11.9These data demonstrated that mSOD1 G93A microglia are more responsive to stimuli than wild-type microglia 
17555556SODSOD1.9Mutant SOD G93A microglia co-cultured with motoneurons produce more nitric oxide and 
17555556SOD1mSOD11.9Following treatment with 1 _amp_#x03BC;g/mL _amp_#x03BC g mL LPS mSOD1 G93A microglia co-cultured with motoneurons produced significantly more nitrate nitrite 
17555556SOD1mSOD11.9motoneurons (5.4 5.4 _amp_plusmn 0.37 _amp_#x03BC;mol/L _amp_#x03BC mol L in mSOD1 G93A microglia vs 3.3 _amp_plusmn 0.43 _amp_#x03BC;mol/L _amp_#x03BC mol L 
17555556SOD1mSOD11.9The IGF-1 levels in untreated mSOD1 G93A microglia/motoneuron microglia motoneuron co-cultures were 14% lower than those 
17555556SOD1mSOD11.9_amp_plusmn 2.1% in wild-type microglia and 26 _amp_plusmn 2.9% in mSOD1 G93A microglia 500 _amp_plusmn 84 pg/mL pg mL corresponds to 
17555556SOD1mSOD11.9However mSOD1 G93A microglia/motoneuron microglia motoneuron co-cultures released significantly less IGF-1 (30% 
17555556SOD1SOD11.9Mutant SOD1 G93A microglia induce more motoneuron injury than wild-type microglia Because 
17555556SOD1mSOD11.9G93A microglia induce more motoneuron injury than wild-type microglia Because mSOD1 G93A microglia co-cultured with motoneurons produced more nitric oxide and 
17555556SOD1mSOD11.9oxide and less IGF-1 than wild-type microglia we asked whether mSOD1 G93A microglia would induce more motoneuron injury compared with wild-type 
17555556SOD1mSOD11.9When co-cultured with motoneurons untreated mSOD1 G93A microglia resulted in 17.9% less motoneuron survival than untreated 
17555556SOD1mSOD11.9were decreased 28% when co-cultured with wild-type microglia compared with mSOD1 G93A microglia (12 12 _amp_plusmn 0.7/cell 0.7 cell in WT-Mc 
17555556SOD1mSOD11.9decreased 28% respectively when co-cultured with wild-type microglia compared with mSOD1 G93A microglia (520 520 _amp_plusmn 31 _amp_#x03BC;m/cell _amp_#x03BC m cell 
17555556SOD1mSOD11.9LPS compared with wild-type microglia/motoneuron microglia motoneuron co-cultures co-cultures with mSOD1 G93A microglia had less surviving motoneurons and decreased number and 
17555556SOD1mSOD11.9length were again decreased when the motoneurons were co-cultured with mSOD1 G93A microglia and were compared with similarly treated co-cultures using 
17555556SOD1mSOD11.9More importantly after treatment with 100-fold less LPS mSOD1 G93A microglia did not significantly alter the number of surviving 
17555556SOD1mSOD11.9number and length of motoneuron neurites were significantly less in mSOD1 G93A co-cultures treated with 10 ng/mL ng mL LPS than 
17555556SOD1mSOD11.9L-NIL also partially rescued motoneurons in both mSOD1 G93A and wild-type co-cultures ( Fig 4b 
17555556SOD1mSOD11.9Motoneuron survival was increased significantly (mSOD1 mSOD1 G93A co-cultures 71 _amp_plusmn 0.9% wild-type co-cultures 86 _amp_plusmn 0.8% 
17555556SOD1mSOD11.9_amp_plusmn 0.8% compared with those treated with LPS only (mSOD1 mSOD1 G93A co-cultures 48 _amp_plusmn 1.8% p _lt_ 0.001 wild-type co-cultures 
17555556SOD1mSOD11.9the more nitrate nitrite produced the fewer motoneuron survived in mSOD1 G93A and wild-type-co-cultures ( r = _amp_#8722 0.90 p _lt_ 
17555556SOD1SOD11.9Mutant SOD1 G93A microglia are more neurotoxic than wt-hSOD1 microglia Having demonstrated 
17555556SOD1mSOD11.9microglia are more neurotoxic than wt-hSOD1 microglia Having demonstrated that mSOD1 G93A mouse microglia induced more motoneuron injury than wild-type microglia 
17555556SOD1mSOD11.9induced more motoneuron injury than wild-type microglia we asked whether mSOD1 microglia were more neurotoxic than microglia from mice over-expressing wt-hSOD1 
17555556SOD1mSOD11.9of motoneurons fewer neurites and shortening of motoneuron neurites in mSOD1 G93A microglia/motoneuron microglia motoneuron co-cultures compared with wt-hSOD1-microglia/motoneuron wt-hSOD1-microglia motoneuron 
17555556SOD1mSOD11.9Therefore mSOD1 G93A microglia induced more motoneuron injury than wt-hSOD1 microglia 
17555556SOD1mSOD11.9comparison of the relative neurotoxicity versus neuroprotection of wild-type and mSOD1 microglia from mSOD1 G93A mice and their non-transgenic littermates in 
17555556SOD1mSOD11.9relative neurotoxicity versus neuroprotection of wild-type and mSOD1 microglia from mSOD1 G93A mice and their non-transgenic littermates in the absence and 
17555556SOD1mSOD11.92006 the present in vitro study demonstrates that microglia from mSOD1 G93A transgenic mice were more activated and more responsive to 
17555556SOD1mSOD11.9Additionally when compared with wild-type microglia mSOD1 G93A microglia caused more motoneuron injury in microglia/motoneuron microglia motoneuron 
17555556SOD1mSOD11.9In the present study we demonstrated that mSOD1 G93A microglia expressed more iNOS and released more nitric oxide 
17555556SOD1mSOD11.9nitrate nitrite produced the fewer motoneurons survived in wild-type or mSOD1 G93A microglia/motoneuron microglia motoneuron co-cultures 
17555556SOD1mSOD11.9motoneuron disease in double transgenic iNOS _amp_#8722;/_amp_#8722; _amp_#8722 _amp_#8722 /mSOD1 mSOD1 G93A or nNOS _amp_#8722;/_amp_#8722; _amp_#8722 _amp_#8722 /mSOD1 mSOD1 G93A mice 
17555556SOD1mSOD11.9_amp_#8722 /mSOD1 mSOD1 G93A or nNOS _amp_#8722;/_amp_#8722; _amp_#8722 _amp_#8722 /mSOD1 mSOD1 G93A mice ( Facchinetti et al 1999 Son et al 
17555556SOD1mSOD11.9(2007) 2007 demonstrated that mSOD1 G93A mice with both iNOS alleles deleted have a delayed 
17555556SOD1SOD11.9shown that nitric oxide can induce Fas signaling in mutant SOD1 motoneurons which resulted in mutant SOD1 motoneuron death but not 
17555556SOD1SOD11.9Fas signaling in mutant SOD1 motoneurons which resulted in mutant SOD1 motoneuron death but not wild-type motoneurons 
17555556SOD1mSOD11.9spinal cord of transgenic mice expressing the G93A form of mSOD1 delayed the onset of disease and extended survival ( Nagano 
17555556SOD1mSOD11.9that wild-type microglia released more free IGF-1 than microglia from mSOD1 G93A transgenic mice either with or without LPS stimulation 
17555556SOD1mSOD11.9Relative to wild-type microglia increased mSOD1 G93A microglial activation induced more motoneuron injury and decreased neurite 
17555556SOD1mSOD11.9motoneuron injury and decreased neurite number and length suggesting that mSOD1 G93A microglia are functionally more toxic by releasing more nitric 
17555556SOD1mSOD11.9may be more neuroprotective by secreting more IGF-1 compared to mSOD1 G93A microglia 
17555556SOD1mSOD11.9(2004) 2004 found that adult (60 60 days mSOD1 G93A microglia produced significantly more TNF-A and less IL-6 than 
17555556SOD1mSOD11.9data is consistent with their results and showed that neonatally-derived mSOD1 G93A microglia released more nitric oxide more superoxide and less 
17555556SOD1mSOD11.9In addition we further provide evidence that mSOD1 G93A microglia are more neurotoxic than wild-type microglia in microglia/motoneuron 
17555556SOD1mSOD11.9PU.1 _amp_#8722;/_amp_#8722; _amp_#8722 _amp_#8722 mice expressing the G93A form of mSOD1 (mSOD1 mSOD1 G93A /PU.1 PU.1 _amp_#8722;/_amp_#8722; _amp_#8722 _amp_#8722 wild-type microglia 
17555556SOD1mSOD11.9_amp_#8722 _amp_#8722 mice expressing the G93A form of mSOD1 (mSOD1 mSOD1 G93A /PU.1 PU.1 _amp_#8722;/_amp_#8722; _amp_#8722 _amp_#8722 wild-type microglia significantly slowed 
17555556SOD1mSOD11.9prolonged disease duration and survival when compared with mice receiving mSOD1 G93A microglia 
17555556SOD1SOD11.9(2006) 2006 used transgenic mice with a different SOD1 mutation mSOD1 G37R and a different technique to reduce the 
17555556SOD1mSOD11.9(2006) 2006 used transgenic mice with a different SOD1 mutation mSOD1 G37R and a different technique to reduce the expression of 
17555556SOD1mSOD11.9G37R and a different technique to reduce the expression of mSOD1 G37R (i.e i.e the Cre-Lox system to reach a similar 
17555556SOD1mSOD11.9to reach a similar conclusion namely that the reduction of mSOD1 in microglia prolonged disease duration and survival 
17555556SOD1mSOD11.9of disease may be more related to the expression of mSOD1 in motoneurons while in accord with our data duration of 
17555556SOD1mSOD11.9data duration of disease may be related to expression of mSOD1 in microglia 
17555556SOD1mSOD11.9increase in a neurotrophic molecule from wild-type microglia relative to mSOD1 G93A microglia suggesting potential mechanisms for how wild-type microglia either 
17555556SOD1mSOD11.9wild-type microglia either by the reduction or the elimination of mSOD1 expression are less toxic in vivo 
17555556SOD1mSOD11.9Because wt-hSOD1 is another control for the neurotoxicity of mSOD1 G93A we compared the relative neurotoxicity of wt-hSOD1 expressing microglia 
17555556SOD1mSOD11.9the relative neurotoxicity of wt-hSOD1 expressing microglia to that of mSOD1 G93A expressing microglia 
17555556SOD1mSOD11.9extent of neurotoxicity was significantly less than that mediated by mSOD1 G93A microglia 
17555556SOD1mSOD11.9Furthermore unlike mSOD1 G93A microglia wt-hSOD1 microglia produce similar amounts of nitric oxide 
17555556SOD1mSOD11.9When backcrossed into mSOD1 mice the disease progresses more rapidly in these double transgenic 
17555556SOD1mSOD11.9The reasons that mSOD1 G93A microglia are more activated and more responsive to LPS 
17555556SOD1mSOD11.9Firstly over-expressing mSOD1 may impair the self-feedback systems in microglia and regulate activation 
17555556SOD1mSOD11.9al 2002 and may well influence the toxic effects of mSOD1 microglia 
17555556SOD1mSOD11.9Secondly mSOD1 may lead to microglial activation either by directly stimulating the 
17555556SOD1SOD11.9mechanism for ALS based on chromogranin-mediated secretion of misfolded mutant SOD1 but not wild-type SOD1 from cells and extracellular mutant SOD1 
17555556SOD1SOD11.9on chromogranin-mediated secretion of misfolded mutant SOD1 but not wild-type SOD1 from cells and extracellular mutant SOD1 could trigger microgliosis ( 
17555556SOD1SOD11.9SOD1 but not wild-type SOD1 from cells and extracellular mutant SOD1 could trigger microgliosis ( Urushitani et al 2005 
17555556SOD1mSOD11.9In summary we demonstrate that microglia from mSOD1 G93A transgenic mice are more activated and more responsive to 
17555556SOD1mSOD11.9Relative to wild-type microglia mSOD1 G93A microglia may gain modulatory mechanisms that enhance microglial activation 
17555556SOD1mSOD11.9neurotoxic substances and the decreased production of neurotrophic molecules by mSOD1 G93A microglia may enhance neurotoxicity or lessen neuroprotection 
17569578SOD1SOD10.5whereas both the mRNA and protein levels of endogenous mouse SOD1 and of transgenic human SOD1 remained unaffected 154 
17569578SOD1SOD10.5protein levels of endogenous mouse SOD1 and of transgenic human SOD1 remained unaffected 154 
17582695SOD1SOD10.5cortex and brainstem although not in spinal cord of transgenic SOD1 (G93A) G93A mice models of ALS 25 
17853944SOD1SOD13.9influenced the progression of motor neuron disease caused by mutant SOD1 G93A expression 
17853944SOD1SOD13.9can be caused by dominant mutations in superoxide dismutase-1 (SOD1) SOD1 ( 1 
17853944SOD1SOD13.9Transgenic mice overexpressing a mutant form of SOD1 found in ALS patients (SOD1 SOD1 G93A develop motor neuron 
17853944SOD1SOD13.9a mutant form of SOD1 found in ALS patients (SOD1 SOD1 G93A develop motor neuron disease similar to that seen clinically 
17853944SOD1SOD13.9Recent studies using conditional reduction of mutant SOD1 in either motor neurons or glia of mice have suggested 
17853944SOD1SOD13.9transplants or chimeric animals other studies have demonstrated that mutant SOD1 expression in microglia leads to neuronal toxicity ( 5 and 
17853944SOD1SOD13.9toxicity ( 5 and that non-neuronal cells lacking the mutant SOD1 protein can protect from disease ( 6 
17853944SOD1SOD13.9Indeed recent studies have shown that SOD1 G93A ALS transgenic mice produce elevated levels of Nox2 gp91phox 
17853944SOD1SOD13.9Nox2 expression increases in microglia of the spinal cord of SOD1 G93A transgenic mice deletion of Nox2 on a C57BL/6J C57BL 
17853944SOD1SOD13.9of Nox2 on a C57BL/6J C57BL 6J inbred background of SOD1 G93A transgenic mice led to only a marginal increase in 
17853944SOD1SOD13.9Nox2 or Nox1 deletion on disease progression in mixed hybrid SOD1 G93A ALS mice 
17853944SOD1SOD13.9X_amp_#x02013 and KO Nox X_amp_#x02013;/X_amp_#x02013; X_amp_#x02013 X_amp_#x02013 mice on the SOD1 G93A transgenic background using siblings from F2 generations 
17853944SOD1SOD13.9significantly delayed the progression of motor neuron disease in a SOD1 G93A transgenic mouse model of ALS 
17853944SOD1SOD13.9(a) a Transgenic mice overexpressing the human SOD1 G93A mutant ( 22 were used as a model of 
17853944SOD1SOD13.9used as a model of ALS strain name B6SJL-Tg( B6SJL-Tg SOD1 G93A )1Gur/J; 1Gur J stock no 002726 The Jackson Laboratory 
17853944SOD1SOD13.9The generation of SOD1 G93A transgenic mice on the Nox2 -KO or Nox1 -KO 
17853944SOD1SOD13.9Hemizygous SOD1 G93A transgenic males were bred to Nox2 _amp_#x02013;/_amp_#x02013; _amp_#x02013 _amp_#x02013 
17853944SOD1SOD13.9females were used for the next round of breeding against SOD1 G93A hemizygous Nox -KO males (i.e., i.e. Nox2 +/_amp_#x02013; _amp_#x02013 
17853944SOD1SOD13.9hemizygous Nox -KO males (i.e., i.e. Nox2 +/_amp_#x02013; _amp_#x02013 _amp_#x000d7 SOD1 G93A / Nox2 _amp_#x02013;/Y _amp_#x02013 Y or Nox1 +/_amp_#x02013; _amp_#x02013 
17853944SOD1SOD13.9/ Nox2 _amp_#x02013;/Y _amp_#x02013 Y or Nox1 +/_amp_#x02013; _amp_#x02013 _amp_#x000d7 SOD1 G93A / Nox1 _amp_#x02013;/Y _amp_#x02013 Y to give rise to 
17853944SOD1SOD13.9(male male only genotypes either lacking or hemizygous for the SOD1 G93A transgene 
17853944SOD1SOD13.9Similarly Nox -HET females were also bred against SOD1 G93A hemizygous Nox -WT males (i.e., i.e. Nox2 +/_amp_#x02013; _amp_#x02013 
17853944SOD1SOD13.9hemizygous Nox -WT males (i.e., i.e. Nox2 +/_amp_#x02013; _amp_#x02013 _amp_#x000d7 SOD1 G93A / Nox2 +/Y Y or Nox1 +/_amp_#x02013; _amp_#x02013 _amp_#x000d7 
17853944SOD1SOD13.9G93A / Nox2 +/Y Y or Nox1 +/_amp_#x02013; _amp_#x02013 _amp_#x000d7 SOD1 G93A / Nox1 +/Y Y to give rise to mixed 
17853944SOD1SOD13.9male and female genotypes either lacking or hemizygous for the SOD1 G93A transgene 
17853944SOD1SOD13.9Genotyping for Nox2 and SOD1 G93A mice was performed by standard PCR protocols using primer 
17853944SOD1SOD13.9Methods Real-time quantitative PCR determination of SOD1 G93A transgene copy number 
17853944SOD1hSOD12.2in threshold cycle (_amp_#x00394;CT) _amp_#x00394 CT between the transgene ( hSOD1 and a reference gene ( mIL2 following a previously published 
17853944SOD1hSOD12.2The following primers were used for the transgene hSOD1 forward 5_amp_#x02032 -CATCAGCCCTAATCCATCTGA-3_amp_#x02032 reverse 5_amp_#x02032 -CGCGACTAACAATCAAAGTGA-3_amp_#x02032 
17853944SOD1hSOD12.2The final concentration of the primers for hSOD1 and mIL2 were 0.4 and 0.5 _amp_#x003bc M respectively 
17853944SOD1SOD13.9_amp_#x00394 CT was calculated as the difference between the human SOD1 CT and the mouse IL2 CT for all mice in 
17853944SOD1SOD13.924 and _amp_#x00394 CT (6.967) 6.967 of the B6SJL-TgN( B6SJL-TgN SOD1 G93A 1Gur as known values ( 26 
17853944SOD1SOD13.9B6SJL-Tg( B6SJL-Tg SOD1 G93A )1Gur/J 1Gur J mice hemizygous for a highly expressed 
17853944SOD1SOD13.9)1Gur/J 1Gur J mice hemizygous for a highly expressed mutant SOD1 G93A transgene develop disease onset at approximately 110 days of 
17853944SOD1SOD13.9our hands 50% survival was 123 days for B6SJL-Tg( B6SJL-Tg SOD1 G93A )1Gur/J 1Gur J males ( n = 30 and 
17853944SOD1SOD13.9Nox2 -KO mice also hemizygous for the SOD1 G93A transgene were susceptible to superficial eye infections 
17853944SOD1SOD13.9that antibiotic treatment did not alter the course of disease SOD1 G93A / Nox2 -WT mice were put on antibiotic water 
17853944SOD1SOD13.9Eye infection in Nox2 -HET females hemizygous for the SOD1 G93A transgene was only observed in 1 of the 8 
17853944SOD1SOD13.9and was never observed in Nox2 -KO mice lacking the SOD1 G93A transgene 
17853944SOD1SOD13.9spinal cord lysates made from the lumbar region of 120-day-old SOD1 G93A Nox2 -WT SOD1 G93A Nox2 -KO and nontransgenic mice 
17853944SOD1SOD13.9from the lumbar region of 120-day-old SOD1 G93A Nox2 -WT SOD1 G93A Nox2 -KO and nontransgenic mice 
17853944SOD1SOD13.9Nox1 or Nox2 increases survival and slows disease progression in SOD1 G93A transgenic mice 
17853944SOD1SOD13.92 potential Nox genes responsible for ROS generation in hemizygous SOD1 G93A transgenic mice and their affect on the progression of 
17853944SOD1SOD13.9female Nox1 -KO and Nox2 -KO mice to hemizygous male SOD1 G93A ALS mice (Supplemental Supplemental Figures 1 and 2 supplemental 
17853944SOD1SOD13.9Mutant SOD1 transgene copy number was also stable throughout the F2 generations 
17853944SOD1SOD13.9a previous study evaluating deletion of the Nox2 gene in SOD1 G93A C57BL/6J C57BL 6J inbred transgenic mice ( 8 our 
17853944SOD1SOD13.9C57BL 6J inbred transgenic mice ( 8 our study used SOD1 G93A B6SJL mice on a mixed hybrid background (F1 F1 
17853944SOD1SOD13.9either Nox1 or Nox2 significantly delayed the death of hemizygous SOD1 G93A ALS mice (Figure Figure 1 A 
17853944SOD1SOD13.9The finding of an increased survival index in Nox2 -KO SOD1 G93A transgenic mice is significant because to our knowledge no 
17853944SOD1SOD13.9Given the significant 97-day increase in survival of Nox2 -KO SOD1 G93A B6SJL mice in our study compared with the 13-day 
17853944SOD1SOD13.913-day increase observed in a previous study using Nox2 -KO SOD1 G93A congenic C57BL/6J C57BL 6J mice ( 8 we investigated 
17853944SOD1SOD13.9were similar to those observed in the previous Nox2 -KO SOD1 G93A congenic C57BL/6J C57BL 6J study ( 8 
17853944SOD1SOD13.9Figure 1 D were both significantly reduced in Nox2 -KO SOD1 G93A mice compared with Nox2 -WT SOD1 G93A mice 
17853944SOD1SOD13.9in Nox2 -KO SOD1 G93A mice compared with Nox2 -WT SOD1 G93A mice 
17853944SOD1SOD13.9To determine whether Nox2 deficiency protected SOD1 G93A mice from muscle atrophy the weight fiber area and 
17853944SOD1SOD13.9At 100 days Nox2 -KO SOD1 G93A mice demonstrated significant protection from loss in hind-limb muscle 
17853944SOD1SOD13.9from loss in hind-limb muscle mass compared with Nox2 -WT SOD1 G93A mice (Supplemental Supplemental Figure 5 A and B 
17853944SOD1SOD13.9These differences in muscle mass between the Nox2 genotypes of SOD1 G93A mice correlated with changes in muscle fiber area (Supplemental 
17853944SOD1SOD13.9Furthermore Nox2 -KO SOD1 G93A mice were indistinguishable from nontransgenic littermates for both these 
17853944SOD1SOD13.9Breeding of hemizygous SOD1 G93A B6SJL mice onto the C57BL/6 C57BL 6 background has 
17853944SOD1SOD13.9to increase survival by approximately 13 to 14 days ( SOD1 G93A B6SJL hybrid mice 130.2 _amp_#x000b1 11.2 days SOD1 G93A 
17853944SOD1SOD13.9( SOD1 G93A B6SJL hybrid mice 130.2 _amp_#x000b1 11.2 days SOD1 G93A C57BL/6 C57BL 6 congenic mice 143.6 _amp_#x000b1 7.5 days 
17853944SOD1SOD13.9analysis demonstrated increases in survival averaging 28 days when comparing SOD1 G93A B6SJL hybrid mice (128.9 128.9 _amp_#x000b1 9.1 days with 
17853944SOD1SOD13.9G93A B6SJL hybrid mice (128.9 128.9 _amp_#x000b1 9.1 days with SOD1 G93A C57BL/6J C57BL 6J congenic mice (157.1 157.1 _amp_#x000b1 9.3 
17853944SOD1SOD13.9However the mean survival times for Nox -WT SOD1 G93A mice seen in our studies (129 129 and 132 
17853944SOD1SOD13.9for Nox1 and Nox2 backgrounds respectively were very similar to SOD1 G93A B6SJL hybrid mice in these previous reports 
17853944SOD1SOD13.9a previous study using inbred C57BL/6 C57BL 6 Nox2 -KO SOD1 G93A mice demonstrated much smaller increases in survival ( 8 
17853944SOD1SOD13.9( 8 compared with our mixed B6SJL background Nox2 -KO SOD1 G93A mice we hypothesize that multiple SJL-derived modifier genes likely 
17853944SOD1SOD13.9in concert with Nox2 deficiency to significantly enhance survival of SOD1 G93A mice 
17853944SOD1SOD13.9in survival among siblings for the various Nox1 and Nox2 SOD1 G93A genotypes in the F1 and F2 generations (Supplemental Supplemental 
17853944SOD1SOD13.9for the increased survival seen in the B6SJL Nox2 -KO SOD1 G93A mice for 2 reasons 
17853944SOD1SOD13.9First studies that have evaluated 129 modifier genes on the SOD1 G86R C57BL/6 C57BL 6 background suggest that they do not 
17853944SOD1SOD13.9previous study that used inbred C57BL/6 C57BL 6 Nox2 -KO SOD1 G93A mice ( 8 
17853944SOD1SOD13.9breeding yet observed widely divergent survival rates of Nox2 -KO SOD1 G93A mice it is unlikely this 129-linked segment can solely 
17853944SOD1SOD13.9Results and Discussion Female SOD1 G93A transgenic mice heterozygous for X-linked Nox genes have increased 
17853944SOD1SOD13.9Nox activity in the spinal cords of female Nox2 -HET SOD1 G93A mice fell between that of female Nox2 -KO and 
17853944SOD1SOD13.9fell between that of female Nox2 -KO and Nox2 -WT SOD1 G93A mice (Figure Figure 1 C 
17853944SOD1SOD13.9suggests that X-inactivation likely occurs randomly in female Nox2 -HET SOD1 G93A mice with about 50% of the microglia and neuronal 
17853944SOD1SOD13.9significantly influences survival but not the survival index in female SOD1 G93A transgenic mice 
17853944SOD1SOD13.9reports generating chimeric mice composed of mixtures of normal and SOD1 mutant_amp_#x02013 expressing non-neuronal cells significantly attenuated toxicity associated with mutant-expressing 
17853944SOD1SOD13.9Given that Nox2 is highly expressed in microglia of SOD1 G93A transgenic mice ( 8 chimerism of Nox2 gene expression 
17853944SOD1SOD13.9dictated by an altered redox-balance within cells expressing the mutant SOD1 through an as-yet undefined gain of function ( 2 3 
17853944SOD1SOD13.9A recent study using conditional elimination of mutant SOD1 in neurons or glial cells has also demonstrated that these 
17853944SOD1SOD13.9in female ALS mice with chimeric Nox2 expression suggest that SOD1 G93A expression in microglia may directly influence deleterious cell-autonomous function 
17853944SOD1SOD13.9leads to an enhanced predisposition to lethal eye infections in SOD1 G93A transgenic mice 
17853944SOD1SOD13.9Notably in the Nox2 -KO SOD1 G93A transgenic background we observed a high frequency of eye 
17853944SOD1SOD13.9infections were never observed in Nox2 -KO littermates lacking the SOD1 G93A transgene 
17853944SOD1SOD13.9accumulation of secretions around the eye from affected Nox2 -KO SOD1 G93A transgenic mice suffering from infections (Supplemental Supplemental Figure 6A 
17853944SOD1SOD13.9the Harderian gland and lacrimal gland of affected Nox2 -KO SOD1 G93A transgenic mice compared with Nox2 -WT SOD1 G93A transgenic 
17853944SOD1SOD13.9Nox2 -KO SOD1 G93A transgenic mice compared with Nox2 -WT SOD1 G93A transgenic mice ( n = 3 per group 
17853944SOD1SOD13.9First the Harderian gland of Nox2 -WT SOD1 G93A transgenic mice always contained accumulated porphyrin aggregates in the 
17853944SOD1SOD13.9glandular tubules that were never seen in affected Nox2 -KO SOD1 G93A transgenic mice (Supplemental Supplemental Figure 6 C and F 
17853944SOD1SOD13.9altered secretions from the Harderian gland of affected Nox2 -KO SOD1 G93A transgenic mice influence the observed increased predisposition to bacterial 
17853944SOD1SOD13.9the lacrimal glands were also observed in affected Nox2 -KO SOD1 G93A transgenic mice (Supplemental Supplemental Figure 6 D and G 
17853944SOD1SOD13.9for increased incidence of infection in eyes of Nox2 -KO SOD1 G93A transgenic mice 
17853944SOD1SOD13.9It is presently unclear why overexpression of SOD1 G93A manifests these abnormalities only on the Nox2 -KO background 
17853944SOD1SOD13.9However the findings imply potential new functions for both SOD1 and Nox2 in eye innate immunity 
17853944SOD1SOD13.9Interestingly our findings in female SOD1 G93A transgenic mice heterozygous for the Nox2 X-linked gene and 
17853944SOD1SOD13.9find substantial protection against motor neuron defects in Nox2 -KO SOD1 G93A transgenic mice 
17853944SOD1SOD13.9activity can significantly alter the progression of disease in this SOD1 G93A transgenic model of ALS 
17853944SODSOD2.2used ALS amyotrophic lateral sclerosis CT threshold cycle HET heterozygous SOD superoxide dismutase 
17853944SOD1SOD13.9and significantly reduces superoxide production in spinal cords of end-stage SOD1 G93A mice 
17853944SOD1SOD13.9death in the spinal cords of mice hemizygous for the SOD1 G93A transgene 
17853944SOD1SOD13.9Figure 3 Disease phenotyping of Nox2 genotypes on the SOD1 G93A ALS background 
17997855SOD1SOD13.2the anti-oxidant enzyme Cu Zn superoxide dismutase (EC EC 1.15.1.1 SOD1 are associated with familial ALS 
17997855SOD1SOD13.2Methods SH-SY5Y neuroblastoma cells transfected with the G93A mutant of SOD1 typical for familial ALS (G93A-SOD1) G93A-SOD1 and SH-SY5Y neuroblastoma cells 
17997855SOD1SOD13.2ALS (G93A-SOD1) G93A-SOD1 and SH-SY5Y neuroblastoma cells transfected with wildtype SOD1 were both exposed to pneumolysin and in co-cultures with cultured 
17997855SOD1SOD13.2Results SH-SY5Y neuroblastoma cells transfected with the G93A mutant of SOD1 typical for familial ALS (G93A-SOD1) G93A-SOD1 were more vulnerable to 
17997855SOD1SOD13.23 CSK 4 than SH-SY5Y cells transfected with wild-type human SOD1 
17997855SOD1SOD13.2the gene encoding Cu Zn superoxide dismutase (EC EC 1.15.1.1 SOD1 
17997855SOD1SOD13.2cases are caused by a mutation in the gene encoding SOD1 4 5 
17997855SOD1SOD13.2the amino acid glycine is replaced by alanine in the SOD1 enzyme 
17997855SOD1SOD13.2model to study the cellular alterations associated with mutations of SOD1 was constructed by transfection of the human neuroblastoma cell line 
17997855SOD1SOD13.2was chosen because it does not affect the activity of SOD1 
17997855SOD1SOD13.2neuroblastoma cell lines constitutively expressing either wild-type (Wt) Wt human SOD1 or the G93A mutant of this enzyme associated with familial 
17997855SOD1SOD13.2that SH-SY5Y neuroblastoma cells transfected with the G93A mutant of SOD1 typical for familial ALS (G93A-SOD1) G93A-SOD1 are more vulnerable to 
17997855SOD1SOD13.2more vulnerable to infectious stimuli than neuroblastoma cells overexpressing normal SOD1 
17997855SOD1SOD13.2than the capacity of neuroblastoma cells not transfected with mutant SOD1 
17997855SOD1SOD13.2production of reactive oxygen species in neuroblastoma cells expressing mutant SOD1 34 
17997855SOD1SOD13.2the attack of activated immune cells than those expressing wild-type SOD1 
17997855SODSOD1.9the disease predominated by motor neuron damage caused by mutant SOD in a later phase of disease progression is linked to 
17997855SOD1SOD13.2increased susceptibility of neurons expressing the G93A mutant in their SOD1 to the attack of activated immune cells may be the 
17997855SOD1SOD13.2Neuronal cells expressing a SOD1 mutant frequently encountered in familial cases of amyotrophic lateral sclerosis 
17997855SOD1SOD13.2attack of activated immune cells than neuronal cells expressing wild-type SOD1 
17997855SOD1SOD13.2Figure 11 Vulnerability of G93A-SOD1 and wild-type SOD1 neuroblastoma cells to the attack of monocytes stimulated with Pam 
17997855SOD1SOD13.2Figure 12 Vulnerability of G93A-SOD1 and wild-type SOD1 neuroblastoma cells to the attack of monocytes stimulated with Pam 
18312546SOD1SOD11.4carrying a transgene for G93A mutant human superoxide dismutase-1 (SOD1) SOD1 (ALS ALS mice and non-transgenic littermates (control control mice performed 
18370853SOD1SOD12.4the gene coding for Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 
18370853SOD1SOD12.4evidence has been collected in rodents made transgenic for mutant SOD1 which represent the best available models for familial ALS 
18370853SOD1SOD12.4Mutant SOD1 likely induces selective vulnerability of motor neurons through a combination 
18370853SOD1SOD12.4by noxious signals originating from nonneuronal neighboring cells where mutant SOD1 induces an inflammatory response that accelerates disease progression 
18397603SODSOD0.8the spinal cord and enhanced motor neuronal survival in SOD(G93A) SOD G93A mice delaying the onset and progression of the disease 
18397603SODSOD0.8Ubiquitin expression and caspase activity resulted markedly increased in SOD(G93A) SOD G93A muscle but maintained at very low levels in the 
18397603SODSOD0.8muscle but maintained at very low levels in the SOD(G93A) SOD G93A x MLC/mIgf-1 MLC mIgf-1 (SOD(G93A)/mIgf-1) SOD G93A mIgf-1 transgenic 
18397603SODSOD0.8in the SOD(G93A) SOD G93A x MLC/mIgf-1 MLC mIgf-1 (SOD(G93A)/mIgf-1) SOD G93A mIgf-1 transgenic muscle 
18397603SODSOD0.8processes in nerve and muscle cells was reduced in SOD(G93A) SOD G93A muscle but increased in SOD(G93A)/mIgf-1 SOD G93A mIgf-1 muscle 
18397603SODSOD0.8reduced in SOD(G93A) SOD G93A muscle but increased in SOD(G93A)/mIgf-1 SOD G93A mIgf-1 muscle 
18397603SODSOD0.8Notably while the toxic p25 protein accumulated in SOD(G93A) SOD G93A muscle no accumulation was evident in the SOD(G93A)/mIgf-1 SOD 
18397603SODSOD0.8SOD G93A muscle no accumulation was evident in the SOD(G93A)/mIgf-1 SOD G93A mIgf-1 muscle 
18436268SOD1SOD13.4Mutations in copper/zinc copper zinc superoxide dismutase (SOD1) SOD1 account for 20% cases of familial ALS (fALS), fALS but 
18436268SOD1SOD13.4Using SOD1 G93A mice model of ALS we demonstrated that mutation in 
18436268SOD1SOD13.4G93A mice model of ALS we demonstrated that mutation in SOD1 caused a significant increase in the level of plasma homocysteine 
18436268SOD1SOD13.4assess the neuroprotective effect of FA and B12 in the SOD1 G93A mice 
18436268SOD1SOD13.4the gene encoding for Cu/Zn Cu Zn superoxide dismutase (SOD1) SOD1 ( Al-Chalabi and Leigh 2000 
18436268SOD1SOD13.4Over-expression of mutant SOD1 gene in mice causes a progressive motor neuron disease resembling 
18436268SOD1SOD13.4In this study we used SOD1 G93A mice model to study the association of homocysteine (Hcy) 
18436268SOD1SOD13.4that Hcy-immunoreactive astrocytes presented in the spinal cord of symptomatic SOD1 G93A mice and Hcy even at the physiological concentration induced 
18436268SOD1SOD13.4concentration induced significant cytotoxicity in neuronal cell-line transfected with mutant SOD1 gene suggesting Hcy may play an important role in the 
18436268SOD1SOD13.4can lower the Hcy level and provide the neuroprotection in SOD1 G93A mice 
18436268SOD1SOD13.4The colony of well-characterized TgN (SOD1 SOD1 G93A Gur transgenic males which resemble most clinical features of 
18436268SOD1SOD13.4The SOD1 G93A mice ( n = 48 were randomized divided into 
18436268SOD1SOD13.4four groups (1) 1 orally administrated vehicle 0.9% saline (SOD1 SOD1 group n = 12 (2) 2 orally administrated 4 mg 
18436268SOD1SOD13.4Among them 36 transgenic mice (SOD1 SOD1 group n = 9 FA-SOD1 group n = 9 B12-SOD1 
18436268SOD1SOD13.410 of the wild-type littermates at the same age as SOD1 G93A mice were used as controls for the histopathological staining 
18436268SOD1SOD13.4The initial sign of disease in SOD1 G93A mice is resting tremor and progressive development of gait 
18436268SOD1SOD13.4SOD1 G93A mice (SOD1 SOD1 group n = 3 FA-SOD1 mice 
18436268SOD1SOD13.4SOD1 G93A mice (SOD1 SOD1 group n = 3 FA-SOD1 mice n = 3 B12-SOD1 
18436268SOD1SOD13.4and B12 on the onset of symptoms and lifespan in SOD1 G93A mice 
18436268SOD1SOD13.4or B12 treatment can influence the onset of symptoms in SOD1 G93A mice we analyzed the motor function of all animals 
18436268SOD1SOD13.4SOD1 G93A mice usually recapitulated the clinical progression of ALS by 
18436268SOD1SOD13.4of the onset of symptoms compared with the mice in SOD1 group (114.4 114.4 _amp_#xb1 1.7 116.3 _amp_#xb1 2.0 vs 107.9 
18436268SOD1SOD13.4In addition FA or FA B12 treated SOD1 G93A mice had significant 9-day and 13-day extension in lifespan 
18436268SOD1SOD13.4had significant 9-day and 13-day extension in lifespan compared with SOD1 group mice respectively (137.7 137.7 _amp_#xb1 1.9 141.4 _amp_#xb1 2.9 
18436268SOD1SOD13.4There was no significant difference between B12-SOD1 group and SOD1 group in the lifespan (132.3 132.3 _amp_#xb1 1.9 vs 128.8 
18436268SOD1SOD13.4was performed to examine the total plasma Hcy level in SOD1 G93A and wild-type litter mate mice at the age of 
18436268SOD1SOD13.4The level of Hcy in SOD1 group was 180% of the level in wild-type mice (6.84 
18436268SOD1SOD13.40.67 vs 6.84 _amp_#xb1 0.4 _amp_#x3bc;mol/L _amp_#x3bc mol L in SOD1 group mice ( Fig._amp_#xa0 2 
18436268SOD1SOD13.4L vs 6.84 _amp_#xb1 0.4 _amp_#x3bc;mol/L _amp_#x3bc mol L in SOD1 group mice ( Fig._amp_#xa0 2 
18436268SOD1SOD13.4alone could significantly reduce the level of Hcy in the SOD1 G93A transgenic mice 
18436268SOD1SOD13.4In SOD1 group mice at the age of 120 days there were 
18436268SOD1SOD13.4were 74.5% and 88.3% more motor neurons than mice in SOD1 group (383.5 383.5 _amp_#xb1 24.43 413.67 _amp_#xb1 32.48 vs 219.67 
18436268SOD1SOD13.4microglia and astrocyte respectively in the spinal cord sections of SOD1 G93A mice 
18436268SOD1SOD13.4overwhelming microglial and astrocytic activation in the spinal cord of SOD1 G93A mice at the age of 120 days whereas the_amp_#xa0 
18436268SOD1SOD13.4activation between the mice treated with B12 alone and control SOD1 G93A mice ( Fig._amp_#xa0 4 
18436268SOD1SOD13.4expression of inflammation-related factors such as iNOS and TNF-_amp_#x3b1 in SOD1 G93A transgenic mice ( Almer et_amp_#xa0 al. 1999 Hensley et_amp_#xa0 
18436268SOD1SOD13.4reduction of iNOS and TNF-_amp_#x3b1 in FA-SOD1 group or FA SOD1 group mice compared with mice in SOD1 group ( Fig._amp_#xa0 
18436268SOD1SOD13.4group or FA SOD1 group mice compared with mice in SOD1 group ( Fig._amp_#xa0 5 A 
18436268SOD1SOD13.4results documented that the inflammation in FA-SOD1 group or FA SOD1 group was strongly suppressed compared with SOD1 group 
18436268SOD1SOD13.4group or FA SOD1 group was strongly suppressed compared with SOD1 group 
18436268SOD1SOD13.4drugs FA and B12 had the anti-apoptotic effects in the SOD1 G93A transgenic mice we determined the protein level of Bcl-2 
18436268SOD1SOD13.4FA B12 treatment can elevate the level of Bcl-2 in SOD1 G93A mice up to the level of wild-type which could 
18436268SOD1SOD13.4that FA B12 is effective in suppressing apoptosis in the SOD1 mice model 
18436268SOD1SOD13.4B12 treatment significantly attenuates the increased level of Hcy in SOD1 G93A mice 
18436268SOD1SOD13.4of iNOS was increased in the spinal cord of the SOD1 G93A transgenic mice and activated microglia and astrocytes increased the 
18436268SOD1SOD13.4expression of iNOS and TNF-_amp_#x3b1 in the spinal cord of SOD1 G93A mice at the age of 120 days 
18436268SOD1SOD13.4Hcy may play a role in the increased inflammation of SOD1 G93A mice model and lowering the level of Hcy by 
18436268SOD1SOD13.4is implicated in the regulation of motor neuron death in SOD1 G93A transgenic mice model and over-expression of Bcl-2 can significantly 
18436268SOD1SOD13.4and over-expression of Bcl-2 can significantly protect motor neurons in SOD1 G93A mice ( Kostic et_amp_#xa0 al. 1997 
18436268SOD1SOD13.4the neuroprotective effect of FA or FA B12 treatment in SOD1 G93A mice 
18436268SOD1SOD13.4apoptosis which may contribute to the motor neuron death in SOD1 G93A mice ( Pasinelli et al. 2000 
18436268SOD1SOD13.4could express cleaved PRAP in the central nervous system in SOD1 G93A mice ( Chung et al. 2004 
18436268SOD1SOD13.4in the level of Hcy inflammation and apoptosis in the SOD1 G93A transgenic mice 
18436268SOD1SOD13.4a result inflammation and apoptosis remain high in B12 treated SOD1 G93A transgenic mice 
18436268SOD1SOD13.4and B12 on the disease onset and the lifespan of SOD1 G93A mice 
18436268SOD1SOD13.4A and the probability of survival (B) B in the SOD1 group B12-SOD1 group FA-SOD1 group and FA B12-SOD1 group * 
18436268SOD1SOD13.4Data showed that the level of Hcy in SOD1 group was increased as compared with the wild-type mice 
18436268SOD1SOD13.4FA B12-SOD1 group mice was significantly decreased as compared with SOD1 group mice 
18436268SOD1SOD13.4group # P _amp_#x3c 0.01 (when when compared with the SOD1 group * N in each group = 8 
18436268SOD1SOD13.4(a) a Wild-type group (b) b SOD1 group (c) c B12-SOD1 group (d) d FA-SOD1 group (e) 
18436268SOD1SOD13.4group # P _amp_#x3c 0.01 (when when compared with the SOD1 group * N in each group = 3 
18436268SOD1SOD13.4in FA-SOD1 or FA B12-SOD1 group mice as compared with SOD1 group mice 
18436268SOD1SOD13.4While there was no difference between B12-SOD1 group mice and SOD1 group mice * N in each group = 3 
18436268SOD1SOD13.4G93A transgenic mice in five groups (WT: WT wild-type group SOD1 SOD1 group B12 B12-SOD1 group FA FA-SOD1 group FA B12 
18436268SOD1SOD13.4transgenic mice in five groups (WT: WT wild-type group SOD1 SOD1 group B12 B12-SOD1 group FA FA-SOD1 group FA B12 FA 
18436268SOD1SOD13.4and ## P _amp_#x3c 0.001 (when when compared with the SOD1 group * N in each group = 3 
18464922SOD1SOD10.5effect of pioglitazone (Actos), Actos a PPAR-_amp_#x003b3 agonist in G93A SOD1 transgenic mouse model of ALS and found significant increase in 
18464922SOD1SOD10.5of ALS and found significant increase in survival of G93A SOD1 mice 
18464922SOD1SOD10.5have tested the neuroprotective effect of pioglitazone in transgenic G93A SOD1 mouse model of ALS and showed that pioglitazone treatment improved 
18464922SOD1SOD10.5another study on the effect of pioglitazone treatment in G93A SOD1 transgenic mouse model of ALS 39 
18464922SOD1SOD10.5of mitochondrial dysfunction in FALS-SOD1 it is hypothesized that mutant SOD1 may directly damage mitochondrial function and integrity 
18464922SOD1SOD10.5Several studies have shown that transgenic mice overexpressing human G93A SOD1 that display most of the ALS symptoms and pathologies have 
18464922SOD1SOD10.5we and others have shown that wild type and mutant SOD1 are found within mitochondrion which was known to be a 
18464922SOD1SOD10.5How SOD1 is interacting with mitochondria is unclear and it is being 
18464922SOD1SOD10.5The toxic action of mutant SOD1 in and out of mitochondria could be partly explained as 
18464922SOD1SOD10.5(i) i Mutant but not wild type SOD1 binds to heat shock proteins causing an inhibition of chaperon 
18464922SOD1SOD10.5Both mutant and wild type SOD1 bind to antiapoptotic protein Bcl-2 on the outer mitochondrial membrane 
18464922SOD1SOD10.5(ii) ii The presence of mutant SOD1 in the mitochondria leads to formation of SOD1 aggregates entrapping 
18464922SOD1SOD10.5of mutant SOD1 in the mitochondria leads to formation of SOD1 aggregates entrapping Bcl-2 blocking protein importation to mitochondria which may 
18464922SOD1SOD10.5target genes expression is attributed to mutant huntingtin similarly mutant SOD1 could impair PGC-1 _amp_#x003b1 and expression of its target genes 
18464922SOD1SOD10.5Whether mutant SOD1 can impair PPAR-_amp_#x003b3 is yet to be determined 
18513389SOD1SOD13.2gene coding for copper/zinc copper zinc superoxide dismutase 1 (SOD1) SOD1 appears to be mutated in 10_amp_#x02013 20% in the familial 
18513389SOD1SOD13.2been extensively studied and some major genes in addition to SOD1 have been recognised as being responsible for the monogenic inheritance 
18513389SOD1SOD13.2of the family and when no mutations were present in SOD1 gene 
18513389SOD1SOD13.2All ALS subjects were screened for SOD1 mutation through PCR amplification and direct sequencing according to standard 
18513389SOD1SOD13.2All patients were previously screened for SOD1 gene mutation by sequence analysis and no genetic variations were 
18513389SOD1SOD13.2Besides all ALS patients were previously screened for SOD1 gene mutations with negative results thus confirming the sporadic nature 
18598679SOD1SOD10.8Expression of mutant human SOD1 selectively in neurons failed to cause ALS-like disease in mice 
18598679SOD1SOD10.8Moreover selective reduction of mutant SOD1 levels in microglia extended survival of transgenic SOD1 G37R mice 
18598679SOD1SOD10.8of mutant SOD1 levels in microglia extended survival of transgenic SOD1 G37R mice ( Boill_amp_#xe9 e et al. 2006 
18598679SOD1SOD10.8In addition in the mutant SOD1 G93A transgenic mice inflammatory responses are present before any evidence 
18598679SOD1SOD10.8Nguyen et al (2004) 2004 triggered the innate immunity of SOD1 G37R transgenic mice with systemic administration of lipopolysaccharide (LPS), LPS 
18598679SOD1SOD10.8of TLR2 was upregulated in the spinal cord of mutant SOD1 G37R transgenic mice ( Nguyen et al. 2004 and MyD88 
18598679SOD1SOD10.8( Nguyen et al. 2004 and MyD88 _amp_#x2212;/_amp_#x2212; _amp_#x2212 _amp_#x2212 -SOD1 G37R chimeric mice ( Kang and Rivest 2007 making it 
18598679SOD1SOD10.8is up-regulated in the spinal cords of ALS patients and SOD1 G93A transgenic mice ( Wu et al. 2006 and deletion 
8605177superoxide dismutasesuperoxide dismutase1.0superoxide dismutase|  
10417811superoxide dismutasesuperoxide dismutase1.0alization of cytosolic phospholipase a 2 in the cns following: 1 focal and global cerebral ischemia 2 facial nerve axotomy 3 human cases of alzheimer's disease 4 transgenic mice overexpressing mutant superoxide dismutase a mouse model of amyotrophic lateral sclerosis and 5 transgenic mice overexpressing mutant amyloid precursor protein which exhibits age related amyloid deposition characteristic of alzheimer's diseas 
10525172superoxide dismutasesuperoxide dismutase1.0because nitric oxide reacts with o 2 _amp_#x2212; three fold faster than superoxide dismutase sod k =2.3_amp_#xd7;10 9 m _amp_#x2212;1 s _amp_#x2212;1 no is the only known biomolecule capable of out competing sod for available o 2 _amp_#x2212; .  
11173059superoxide dismutasesuperoxide dismutase1.0ten percent of amyotrophic lateral sclerosis cases are of familial origin and 15_amp_#x2013;20% of such families show mutations of the cu 2+ /zn 2+ superoxide dismutase gene brown 1997 .  
11173059superoxide dismutasesuperoxide dismutase1.0mutations of the superoxide dismutase gene are also found in rare cases of sporadic amyotrophic lateral sclerosis accounting for 2% of cases brown 1997 .  
11173059superoxide dismutasesuperoxide dismutase1.0however the use of transgenic mouse models expressing different human superoxide dismutase mutated proteins and superoxide dismutase gene knockout mice shows that a loss of function is not the case borchelt and reaume .  
11173059superoxide dismutasesuperoxide dismutase1.0on the contrary several lines of evidence support the hypothesis of a toxic gain of function acquired by the mutant superoxide dismutase.  
11173059superoxide dismutasesuperoxide dismutase1.0mutations may induce structural changes of the superoxide dismutase causing polypeptide unfolding around the active site with abnormal entry of reactive species i.e. c oono and subsequent nitration of tyrosine residues crow et al. 1997 .  
11173059superoxide dismutasesuperoxide dismutase1.0alternatively increased accessibility to the cu 2+ active site of the mutant superoxide dismutase may lead to the use of additional substrates such as hydrogen peroxide and peroxynitrite with the production of highly toxic hydroxyl radicals wiedau pazos et al. 1996 .  
11173059superoxide dismutasesuperoxide dismutase1.0the oxidative stress hypothesis may warrant the search for superoxide dismutase gene mutations in patients with amyotrophic lateral sclerosis regardless of whether it is the sporadic or familial form before treatment is started.  
11173059superoxide dismutasesuperoxide dismutase1.0if abnormal superoxide dismutase activity is demonstrated potential therapeutic approaches may include administration of free radical scavenging drugs or cu 2+ chelators table 1 .  
11173059superoxide dismutasesuperoxide dismutase1.0inhibition of the cu 2+ chaperone for superoxide dismutase a specific protein involved in cu 2+ acquisition by superoxide dismutase could also prevent cu 2+ mediated toxicity.  
11173059superoxide dismutasesuperoxide dismutase1.0gene therapy represents a potential future perspective for superoxide dismutase related amyotrophic lateral sclerosis forms although the simple transfection of the wild type superoxide dismutase gene may not be sufficient to cure the disease as inactivation of mutated superoxide dismutase might be needed.  
11173059superoxide dismutasesuperoxide dismutase1.0 gene may not be sufficient to cure the disease as inactivation of mutated superoxide dismutase might be needed.  
11173059superoxide dismutasesuperoxide dismutase1.0such neurofilaments are often phosphorylated and may also be found within intracellular inclusions in motor neurons of patients with superoxide dismutase related familial amyotrophic lateral sclerosis manetto and murayama .  
11173059superoxide dismutasesuperoxide dismutase1.0neurofilaments may also represent a favorite target for the mutated superoxide dismutase as their light subunits are more susceptible to superoxide dismutase catalyzed nitration than are other proteins of the central nervous system crow et al. 1997 .  
11173059superoxide dismutasesuperoxide dismutase1.0in spinal cord of human mutant superoxide dismutase transgenic mice the expression of bax and bad proapoptotic genes is increased whereas that of bcl 2 and bcl xl anti apoptotic is decreased vukosavic et al. 1999 .  
11173059superoxide dismutasesuperoxide dismutase1.0in double transgenic mice expressing human mutant superoxide dismutase and human bcl 2 the overexpression of bcl 2 is associated with a significant delay in disease onset kostic et al. 1997 .  
11173059superoxide dismutasesuperoxide dismutase1.0furthermore the administration of the caspase inhibitor z val ala asp fluoromethylketone zvad fmk to mutant superoxide dismutase transgenic mice reduces disease progression and increases survival li et al. 2000 .  
11173059superoxide dismutasesuperoxide dismutase1.0free radical mediated cellular damage is commonly prevented by the scavenging activity of superoxide dismutase which converts superoxide ions to hydrogen peroxide and glutathione peroxidase which converts hydrogen peroxide to water and oxidated glutathione disulfide .  
11220737superoxide dismutasesuperoxide dismutase1.0mutations in the copper/zinc superoxide dismutase msod1 gene are associated with a familial form of amyotrophic lateral sclerosis als and their expression in transgenic mice produces an als like syndrome.  
11796754superoxide dismutasesuperoxide dismutase1.0familial amyotrophic lateral sclerosis fals linked mutations in copper zinc superoxide dismutase sod1 cause motor neuron death through one or more acquired toxic properties.  
12060810superoxide dismutase 1superoxide dismutase 11.0familial als accounts for 10_amp_#37; of all cases and mutations of the superoxide dismutase 1 sod1 gene have been identified in about 20_amp_#37; of the familial cases.  
12124437superoxide dismutasesuperoxide dismutase1.0familial amyotrophic lateral sclerosis fals is often caused by gain of function mutations in cu zn superoxide dismutase sod1 .  
12194501superoxide dismutasesuperoxide dismutase1.0among the various biochemical events associated with these conditions emerging evidence suggests the formation of superoxide anion and expression/activity of its endogenous scavenger superoxide dismutase sod as a common denominator.  
12270689superoxide dismutasesuperoxide dismutase1.0n and caspase activation may contribute to neurodegeneration in als we tested the effects of minocycline a second generation tetracycline with anti inflammatory properties in mice expressing a mutant superoxide dismutase sod1 g37r linked to human als.  
12387699superoxide dismutase 1superoxide dismutase 11.0ible for the selective loss of motor neurones are still unknown however several hypotheses have been put forward including oxidative damage and/or toxicity from intracellular aggregates due to mutant superoxide dismutase 1 activity axonal strangulation from cytoskeletal abnormalities loss of trophic factor support and glutamate mediated excitotoxicity.  
12528305superoxide dismutase 1superoxide dismutase 11.0superoxide dismutase 1|superoxide dismutase|  
12843244superoxide dismutase 1superoxide dismutase 11.0we show here that the expression of caspase 11 is upregulated in the spinal cord of superoxide dismutase 1 sod1 g93a transgenic mice a mouse model of amyotrophic lateral sclerosis als before the onset of motor dysfunction and remains at the high levels throughout the course of disease.  
14511332superoxide dismutasesuperoxide dismutase1.0als amyotrophic lateral sclerosis; cox cyclooxygenase; csf cerebrospinal fluid; gfap glial fibrillary acidic protein; ir immunoreactivity; pg prostaglandins; sod superoxide dismutase.  
14597108superoxide dismutasesuperoxide dismutase1.0glial cells the resident macrophages of the cns are present before the onset of clinical symptoms and prior to significant motor neuron loss in transgenic mice with mutations of the cu/zn form of the superoxide dismutase gene sod1 an animal model of als [ alexianu et al. 2001 ].  
14597108superoxide dismutasesuperoxide dismutase1.0interestingly minocycline a broad spectrum antibiotic inhibiting microglial activation and proliferation [ tikka et al. 2001 and yrjanheikki et al. 1999 ] is neuroprotective in mutant superoxide dismutase transgenic mouse models of als [ kriz et al. 2002 van den bosch et al. 2002 and zhu et al. 2002 ].  
14960605superoxide dismutase 1superoxide dismutase 11.0transgenic mice expressing a mutant form of the superoxide dismutase 1 sod1 linked to familial amyotrophic lateral sclerosis were challenged intraperitoneally with a single nontoxic or repeated injections of lps 1 mg/kg .  
14960605superoxide dismutase 1superoxide dismutase 11.0key words: innate immunity ; neurodegeneration ; lipopolysaccharide ; microglia ; amyotrophic lateral sclerosis ; superoxide dismutase 1 ; proinflammatory cytokines ; transgenic mice  
14960605superoxide dismutase 1superoxide dismutase 11.0interestingly numerous proinflammatory genes are induced in the cns of presymptomatic mice expressing a mutant form of superoxide dismutase 1 sod1 linked to amyotrophic lateral sclerosis als the most common form of human motor neuron disease nguyen et al. 2001b ~20% cases of familial als rosen et al. 1993 ; cudkowicz et al. 1997 .  
15081582superoxide dismutasesuperoxide dismutase1.0in 1993 mutations in the cytosolic protein copper_amp_#x2013;zinc superoxide dismutase sod1 were reported in several fals families.  
15210305superoxide dismutasesuperoxide dismutase1.0the first als locus als1 to be identified on chromosome 21 contains the cytosolic copper_amp_#x2013;zinc superoxide dismutase sod1 gene which has been found to harbour at least 100 different genetic mutations which account for up to 20% of fals cases [ 18 90 and 98 ].  
15572176superoxide dismutasesuperoxide dismutase1.0about 10% of als cases show familial inheritance 20% of which are caused by mutations in the gene encoding copper zinc superoxide dismutase sod 1 [ 106 ].  
15649489superoxide dismutase 1superoxide dismutase 11.0a major advance in understanding its pathogenesis came from the genetics that identified mutations in the gene coding for copper_amp_#x2013;zinc superoxide dismutase 1 sod1 in a subset of patients with autosomal dominant inherited als rosen et al. 1993 .  
15657392superoxide dismutase 1superoxide dismutase11.0holine receptor; als amyotrophic lateral sclerosis; cna calcineurin; gfap glial fibrillary acidic protein; igf insulin like growth factor; migf 1 local isoform of igf 1; myhc myosin heavy chain; sod1 superoxide dismutase1; wt wild type.  
15691215superoxide dismutasesuperoxide dismutase1.0the discovery that a small percentage of als cases are familial and involve mutation in a superoxide dismutase gene sod1 led to the development of transgenic mouse models presently widely used for testing possible drugs.  
16120782superoxide dismutasesuperoxide dismutase1.0because peroxisome proliferator activated receptor gamma ppar gamma agonists act as potent anti inflammatory drugs we tested whether superoxide dismutase sod1 g93a transgenic mice a mouse model of als benefit from oral treatment with the ppar gamma agonist pioglitazone pio .  
16120782superoxide dismutasesuperoxide dismutase1.0both pathologies motor neuron loss and neuroinflammation can be found in transgenic mice overexpressing mutant variants of the human gene encoding for copper/zinc superoxide dismutase sod1 which have been linked to inherited als gurney et al. 1994 ; hensley et al. 2002 ; yoshihara et al. 2002 ; kunst 2004 .  
16425674superoxide dismutasesuperoxide dismutase1.0aeol 10150 a small molecule antioxidant analogous to the catalytic site of superoxide dismutase is under development by aeolus formerly incara as a potential subcutaneous treatment for amyotrophic lateral sclerosis als stroke spinal cord injury lung inflammation and mucositis.  
16436205superoxide dismutasesuperoxide dismutase1.0mice expressing a glycine _amp_#x02192; alanine substitution in cytosolic cu zn superoxide dismutase g93a sod1 associated with familial amyotrophic lateral sclerosis als demonstrate age dependent neuroinflammation associated with broad spectrum cytokine eicosanoid and oxidant production.  
16510725superoxide dismutasesuperoxide dismutase1.0a major discovery in the study of als was the finding of missense mutations in the enzyme copper zinc superoxide dismutase sod1 which is associated with 15 20% of familial als cases rosen et al. 1993 .  
16624536superoxide dismutasesuperoxide dismutase1.0while between 5 and 8% of als cases are familial fals of which 20% harbour missense mutations in the copper_amp_#x2013;zinc superoxide dismutase sod1 gene [3] the majority of als cases are sporadic sals .  
16624536superoxide dismutase 1superoxide dismutase 11.0superoxide dismutase 1|superoxide dismutase|  
16647138superoxide dismutasesuperoxide dismutase1.0the substantia nigra has increased lipid peroxidation iron levels and superoxide dismutase sod activity.  
16647138superoxide dismutasesuperoxide dismutase1.0the observation that prp c regulates cu 2+ /zn 2+ superoxide dismutase suggests that prp c is involved in redox balance.  
16753239superoxide dismutase 1superoxide dismutase 11.0recent reports demonstrate that the ppar _amp_#x3b3; agonist pioglitazone protected motor neurons improved motor performance and extended the survival of superoxide dismutase 1 g93a transgenic mice an animal model of als.  
16877542superoxide dismutase 1superoxide dismutase 11.0ros reactive oxygen species sod1 superoxide dismutase 1 igf1 insulin like growth factor 1  
16877542superoxide dismutase 1superoxide dismutase 11.0insights into its neurodegenerative mechanisms followed the discovery that dominant mutations in the gene for superoxide dismutase 1 sod1 cause familial als 2 3 .  
16892030superoxide dismutase 1superoxide dismutase 11.0superoxide dismutase 1|superoxide dismutase|cre recombinase|integrases|  
17008387superoxide dismutase 1superoxide dismutase 11.0because inflammation and oxidative damage are also hallmarks of amyotrophic lateral sclerosis als we studied the effect of oral pdtc treatment on g93a superoxide dismutase 1 sod1 transgenic tg rat model of human als and observed that pdtc treatment significantly decreases the survival.  
17008387superoxide dismutasesuperoxide dismutase1.0abbreviations: pdtc pyrrolidine dithiocarbamate; als amyotrophic lateral sclerosis; emsa electrophoretic mobility shift assay; nf kappab nuclear factor kappab; sod superoxide dismutase; wt wild type; tg transgenic; glt glutamate transporter.  
17015226superoxide dismutase 1superoxide dismutase 11.0superoxide dismutase 1|superoxide dismutase|  
17034351superoxide dismutasesuperoxide dismutase1.0mouse models of familial amyotrophic lateral sclerosis als based on overexpressed mutant human cu zn superoxide dismutase sod1 are cases in point.  
17191135superoxide dismutasesuperoxide dismutase1.0mccord and fridovich first described superoxide dismutase implying a potential physiological role of superoxide [ 2 ] subsequently confirmed in numerous studies [ 3 ].  
17191135superoxide dismutasesuperoxide dismutase1.0in defense against this the cell has developed a number of antioxidant defense systems including superoxide dismutase the peroxidases the glutathione redox cycle with its associated constitutive enzymes as well as glutathione itself.  
17214440superoxide dismutase 1superoxide dismutase 11.0in most cases the cause of als is unknown although in a number of familial als cases mutations in the superoxide dismutase 1 sod1 gene were discovered.  
17555556superoxide dismutasesuperoxide dismutase1.0recent studies suggest that microglia over expressing mutant human superoxide dismutase msod1 g93a may contribute to motoneuron death in a transgenic mouse model of familial amyotrophic lateral sclerosis.  
17555556superoxide dismutasesuperoxide dismutase1.0in transgenic mice over expressing human mutant cu 2+ /zn 2+ superoxide dismutase msod1 an animal model of familial als immune/inflammatory changes have been observed at early symptomatic stages almer et al 1999 ; alexianu et al 2001 ; henkel et al 2006 further suggesting a role f 
17555556superoxide dismutasesuperoxide dismutase1.0because superoxide production from the microglia is assayed by the reduction of ferricytochrome c we added superoxide dismutase sod to the assay to test if the reduction of ferricytochrome c is due to superoxide.  
17853944superoxide dismutase 1superoxide dismutase 11.0amyotrophic lateral sclerosis als is a fatal neurodegenerative disease that can be caused by dominant mutations in superoxide dismutase 1 sod1 1 .  
17853944superoxide dismutasesuperoxide dismutase1.0footnotes nonstandard abbreviations used: als amyotrophic lateral sclerosis; ct threshold cycle; het heterozygous; sod superoxide dismutase.  
17997855superoxide dismutasesuperoxide dismutase1.0mutations in the anti oxidant enzyme cu zn superoxide dismutase ec 1.15.1.1 sod1 are associated with familial als.  
17997855superoxide dismutasesuperoxide dismutase1.0mitochondrial function can be disturbed by mutations in the gene encoding cu zn superoxide dismutase ec 1.15.1.1 sod1 .  
18312546superoxide dismutase 1superoxide dismutase 11.0ulation of neurons astrocytes and microglia in the ventral horns of spinal cord lumbar segments from the pioglitazone treated and non treated groups of mice carrying a transgene for g93a mutant human superoxide dismutase 1 sod1 als mice and non transgenic littermates control mice performed immunohistochemical and immunoblot analyses of ppargamma active form of phosphorylated p38 mitogen activated protein kinase p p38 a 
18436268superoxide dismutasesuperoxide dismutase1.0mutations in copper/zinc superoxide dismutase sod1 account for 20% cases of familial als fals but the underlying pathogenetic mechanisms are largely unknown.  
18513389superoxide dismutase 1superoxide dismutase 11.0the gene coding for copper/zinc superoxide dismutase 1 sod1 appears to be mutated in 10_amp_#x02013;20% in the familial form [ 1 ].