title: A cysteine residue affects the conformational state and neuronal toxicity of mutant SOD1 in mice: relevance to the pathogenesis of ALS.
abstract: We previously showed by in vitro experiments that the cysteine residue (Cys111) near the dimer interface is critical for monomerization and resultant aggregate formation of mutant Cu, Zn-superoxide dismutase (SOD1) protein, which is toxic to motor neurons in familial amyotrophic lateral sclerosis (ALS). To verify the importance of Cys111 in the mutant SOD1-associated ALS pathogenesis in vivo, we analyzed the disease phenotype of SOD1 transgenic mice harboring H46R mutation alone (H46R mice) or H46R/C111S double mutations (H46R/C111S mice). Behavioral, histological and biochemical analyses of the spinal cord showed that the onset and progression of the disease phenotype were delayed in H46R/C111S mice compared with H46R mice. We found that peroxidized Cys111 of H46R SOD1 plays a role in promoting formation of high molecular weight insoluble SOD1 species that is correlated with the progression of the motor neuron disease phenotype. These results support that Cys111 is a critical residue for the neuronal toxicity of mutant SOD1 in vivo, and the blockage of peroxidation of this residue in mutant SOD1 may constitute a future target for developing ALS treatment.
authors.affiliation: Department of Peripheral Nervous System Research.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Nagano
authors.affiliation: Department of Peripheral Nervous System Research.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Division of Laboratory Animals Resources, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masutani
authors.affiliation: Department of Biochemistry, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan and.
authors.forename: Noriko
authors.initials: N
authors.lastname: Fujiwara
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8705, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Urushitani
authors.affiliation: Department of Peripheral Nervous System Research, taraki@ncnp.go.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Araki
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000818:Animals; D003545:Cysteine; D004195:Disease Models, Animal; D018628:Gene Dosage; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D010084:Oxidation-Reduction; D010641:Phenotype; D005082:Physical Exertion; D066263:Protein Aggregation, Pathological; D011487:Protein Conformation; D017510:Protein Folding; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D019076:Transgenes
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003545:Cysteine