Superoxide dismutase-1 mutation-related neurotoxicity in familial amyotrophic lateral sclerosis

Shibata, Noriyuki; Hirano, Atsushi; Yamamoto, Tomoko; Kato, Yoichiro; Kobayashi, Makio

doi:10.1080/14660820050515151

Cited by 29 publications

(61 citation statements)

References 227 publications

(236 reference statements)

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“…This finding is consistent with previous reports establishing that mutant SOD1-mediated toxicity is dose-dependent in vitro and in vivo. Disease phenotype in mutant SOD1 transgenic animals, for instance, depends on transgene copy number, and mice with high transgene copy number display pathological symptoms at an earlier age and have more rapidly progressing disease than do mice with low transgene copy number (5,13,14). Taken together, these results support the hypothesis that even a partial reduction of mutant SOD1 in vivo could impart a significant therapeutic benefit.…”

Section: Discussionsupporting

confidence: 77%

“…In cell culture and in rodent models of ALS, mutant SOD1 proteins exert dose-dependent toxic effects (5,13,14); inhibition of mutant SOD1 expression therefore represents an attractive target for therapy. Therapeutic inhibition of mutant SOD1 could be feasible by using RNA-mediated interference (RNAi), an evolutionarily conserved mechanism for sequence-specific posttranscriptional gene silencing in which double-stranded RNAs promote selective degradation of homologous cellular mRNAs (15,16).…”

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confidence: 99%

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RNA interference-mediated silencing of mutant superoxide dismutase rescues cyclosporin A-induced death in cultured neuroblastoma cells

Maxwell

Pasinelli

Kazantsev

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder resulting from selective death of motor neurons in the brain and spinal cord. In Ϸ25% of familial ALS cases, the disease is caused by dominantly acting point mutations in the gene encoding cytosolic Cu,Zn superoxide dismutase (SOD1). In cell culture and in rodent models of ALS, mutant SOD1 proteins exhibit dose-dependent toxicity; thus, agents that reduce mutant protein expression would be powerful therapeutic tools. A wealth of recent evidence has demonstrated that the mechanism of RNA-mediated interference (RNAi) can be exploited to achieve potent and specific gene silencing in vitro and in vivo. We have evaluated the utility of RNAi for selective silencing of mutant SOD1 expression in cultured cells and have identified small interfering RNAs capable of specifically inhibiting expression of ALS-linked mutant, but not wild-type, SOD1. We have investigated the functional effects of RNAi-mediated silencing of mutant SOD1 in cultured murine neuroblastoma cells. In this model, stable expression of mutant, but not wild-type, human SOD1 sensitizes cells to cytotoxic stimuli. We find that silencing of mutant SOD1 protects these cells against cyclosporin A-induced cell death. These results demonstrate a positive physiological effect caused by RNAi-mediated silencing of a dominant disease allele. The present study further supports the therapeutic potential of RNAi-based methods for the treatment of inherited human diseases, including ALS.A myotrophic lateral sclerosis (ALS) is an age-dependent, paralytic disorder resulting from selective death of motor neurons in the brain and spinal cord. ALS is characterized by progressive muscle weakness and atrophy and is usually fatal within 5 years of clinical presentation (1). Although the majority of ALS cases are sporadic, Ϸ10% of cases are familial (FALS) and display autosomal dominant inheritance (2). Approximately 25% of FALS cases are caused by mutations in the gene encoding the cytosolic Cu,Zn superoxide dismutase (SOD1) (3), an abundant cellular homodimeric enzyme whose normal function is the scavenging of superoxide radicals. To date, Ͼ100 FALS-linked mutations in human SOD1 have been identified (4), and the vast majority of these are missense mutations resulting in single amino acid substitutions.Both the association of SOD1 mutations with dominantly inherited human disease and compelling data gleaned from expression of FALS-linked mutant SOD1 in experimental model systems suggest that mutant SOD1 causes ALS through an acquired toxic property (or properties) of the mutant proteins. Transgenic mice (5-7) and rats (8) that express clinically relevant forms of mutant human SOD1 quite remarkably recapitulate the major features of the disease; in contrast, mice in which endogenous SOD1 expression has been eliminated by means of targeted deletion develop normally and do not exhibit ALS-like symptoms (9). Further, in vitro studies demonstrate that forced expression of mutant, but not wild...

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Section: Discussionsupporting

confidence: 77%

mentioning

confidence: 99%

RNA interference-mediated silencing of mutant superoxide dismutase rescues cyclosporin A-induced death in cultured neuroblastoma cells

Maxwell

Pasinelli

Kazantsev

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Histopathologically, most cases of ALS with SOD1 mutation show Lewy body-like hyaline inclusions, which are immunoreactive for SOD1 [7][8][9]. The posterior funiculus, Clarke's nucleus and posterior spinocerebellar tract were also involved.…”

Section: Introductionmentioning

confidence: 99%

FALS with Gly72Ser mutation in SOD1 gene: Report of a family including the first autopsy case

Kobayashi

Tsuchiya

Kubodera

et al. 2011

Journal of the Neurological Sciences

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Clinical information on familial amyotrophic lateral sclerosis (FALS) with Gly72Ser mutation in the Cu/Zn superoxide dismutase-1 (SOD1) gene has been limited and autosy findings remain to be clarified. We describe one Japanese family with ALS carrying Gly72Ser mutation in the SOD1 gene, in which autopsy was performed on one affected member. The autopsied female patient developed muscle weakness of the left thigh at age 66 and showed transient upper motor neuron signs. She died of respiratory failure 13 months after onset without artificial respiratory support. There were no symptoms suggesting bladder or rectal dysfunction throughout the clinical course. Her brother with ALS was shown to have Gly72Ser mutation in the SOD1 gene. Histopathologically, motor neurons were markedly decreased throughout the whole spinal cord, whereas corticospinal tract involvement was very mild and was demonstrated only by CD68 immunohistochemistry. Degeneration was evident in the posterior funiculus, Clarke's nucleus, posterior cerebellar tract, and Onuf's nucleus.Neuronal hyaline inclusions were rarely observed in the neurons of the spinal cord anterior horn including Onuf's nucleus, and were immunoreactive for SOD1. To date, neuron loss in Onuf's nucleus has hardly been seen in ALS, except in the patients showing prolonged disease duration with artificial respiratory support. Involvement of Onuf's nucleus may be a characteristic pathological feature in FALS with Gly72Ser mutation in the SOD1 gene.

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“…Several potential mechanisms of motor neuron degeneration in ALS have been proposed based on clinical studies, animal model and cell culture system analyses. Increased oxidative stress, glutamate toxicity, protein *Corresponding author: Rugao Liu, Ph.D., Associate Professor, Department of Anatomy and Cell Biology, University of North Dakota School of Medicine, 501 N. Columbia Road, Grand Forks, ND 58202, Telephone: (701)-777-2559, Fax: (701)-777-2477, E-mail: rliu@medicine.nodak.edu Section Editor: Dr. Werner Sieghart aggregation and Cu/Zn cytotoxicity have all been suggested to contribute to motor neuron degeneration (Cleveland and Rothstein, 2001;Li et al, 2003;Liu et al, 2002;Shaw et al, 2001;Shaw and Eggett, 2000;Shibata et al, 2000). Of these, increased oxidative stress appears to be an early and sustained event in association with motor neuron death in ALS (Bogdanov et al, 1998;Liu et al, 1998), although the specific mechanism leading to oxidative damage on motor neurons remains to be defined.…”

Section: Introductionmentioning

confidence: 99%

Depletion of reduced glutathione enhances motor neuron degeneration in vitro and in vivo

et al. 2007

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The mechanism of selective and age-dependent motor neuron degeneration in human amyotrophic lateral sclerosis (ALS) has not been defined and the role of glutathione (GSH) in association with motor neuron death remains largely unknown. A motor neuron-like cell culture system and a transgenic mouse model were used to study the effect of cellular GSH alteration on motor neuron cell death. Exposure of NSC34 motor neuron-like cells to Ethacrynic Acid (EA) or L-Buthionine Sulfoximine (BSO) dramatically reduced the cellular GSH levels, and was accompanied by increased production of reactive oxygen species (ROS) measured by the DCF fluorescent oxidation assay. In addition, GSH depletion enhanced oxidative stress markers, AP-1 transcriptional activation, c-Jun, c-Fos and HO-1 expression in NSC34 cells analyzed by a luciferase reporter, western blotting and quantitative PCR assays respectively. Furthermore, depletion of GSH decreased mitochondrial function, facilitated apoptosis inducing factor (AIF) translocation, cytochrome c release, and caspase 3 activation, and consequently led to motor neuron-like cell apoptosis. In an ALS-like transgenic mouse model overexpressing mutant G93A-SOD1 gene, we showed that the reduction of GSH in the spinal cord and motor neuron cells is correlated with AIF translocation, caspase 3 activation, and motor neuron degeneration during ALS-like disease onset and progression. Taken together, the in vitro and in vivo data presented in the current report demonstrated that decreased GSH promotes multiple apoptotic pathways contributing, at least partially, to motor neuron degeneration in ALS.

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Superoxide dismutase-1 mutation-related neurotoxicity in familial amyotrophic lateral sclerosis

Cited by 29 publications

References 227 publications

RNA interference-mediated silencing of mutant superoxide dismutase rescues cyclosporin A-induced death in cultured neuroblastoma cells

RNA interference-mediated silencing of mutant superoxide dismutase rescues cyclosporin A-induced death in cultured neuroblastoma cells

FALS with Gly72Ser mutation in SOD1 gene: Report of a family including the first autopsy case

Depletion of reduced glutathione enhances motor neuron degeneration in vitro and in vivo

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