Cysteine residues in Cu,Zn-superoxide dismutase are essential to toxicity in Caenorhabditis elegans model of amyotrophic lateral sclerosis

Mariko Ogawa, Hisashi Shidara, Kotaro Oka, Masaru Kurosawa, Nobuyuki Nukina, Yoshiaki Furukawa

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1196-1202
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume463
Issue number4
DOIs
Publication statusPublished - 2015 Jul 13

Keywords

  • Amyotrophic lateral sclerosis
  • Neurodegenerative diseases
  • Protein misfolding
  • Superoxide dismutase
  • Thiol-disulfide

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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