title: Cysteine residues in Cu,Zn-superoxide dismutase are essential to toxicity in Caenorhabditis elegans model of amyotrophic lateral sclerosis.
abstract: Dominant mutations in Cu,Zn-superoxide dismutase (SOD1) cause a familial form of amyotrophic lateral sclerosis (ALS). A pathological hallmark of the familial ALS is the formation of mutant SOD1 aggregates, leading to the proposal that SOD1 gains toxicities through protein misfolding triggered by mutations. Nevertheless, molecular requirements for mutant SOD1 to acquire pathogenicity still remain obscure. Here, we show that Cys residues in SOD1 are essential to exerting toxicities of SOD1 in a Caenorhabditis elegans model. Exogenous expression of wild-type as well as pathogenic mutant SOD1 fused with a fluorescent protein in C. elegans resulted in the accumulation of disulfide-reduced SOD1 and retarded the worm's motility. In contrast, little effects of exogenously expressed SOD1 on the motility were observed when all four Cys residues in SOD1 were replaced with Ser. Taken together, we propose that deregulation of Cys chemistry in SOD1 proteins is involved in the pathogenesis of SOD1-related ALS.
authors.affiliation: Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Center for Biosciences and Informatics, Keio University, Yokohama 223-8522, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shidara
authors.affiliation: Center for Biosciences and Informatics, Keio University, Yokohama 223-8522, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Oka
authors.affiliation: CREST (Core Research for Evolutionary Science and Technology), JST, Tokyo 102-0076, Japan; Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Kurosawa
authors.affiliation: CREST (Core Research for Evolutionary Science and Technology), JST, Tokyo 102-0076, Japan; Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
authors.affiliation: Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Japan. Electronic address: furukawa@chem.keio.ac.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology*; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects*; D003545:Cysteine / Q000378:metabolism*; D004195:Disease Models, Animal; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D013482:Superoxide Dismutase; D003545:Cysteine
keywords: Amyotrophic lateral sclerosis; Neurodegenerative diseases; Protein misfolding; Superoxide dismutase; Thiol-disulfide