A misfolded dimer of Cu/Zn-superoxide dismutase leading to pathological oligomerization in amyotrophic lateral sclerosis

Itsuki Anzai, Eiichi Tokuda, Atsushi Mukaiyama, Shuji Akiyama, Fumito Endo, Koji Yamanaka, Hidemi Misawa, Yoshiaki Furukawa

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Misfolding of mutant Cu/Zn-superoxide dismutase (SOD1) is a pathological hallmark in a familial form of amyotrophic lateral sclerosis. Pathogenic mutations have been proposed to monomerize SOD1 normally adopting a homodimeric configuration and then trigger abnormal oligomerization of SOD1 proteins. Despite this, a misfolded conformation of SOD1 leading to the oligomerization at physiological conditions still remains ambiguous. Here, we show that, around the body temperature (∼37°C), mutant SOD1 maintains a dimeric configuration but lacks most of its secondary structures. Also, such an abnormal SOD1 dimer with significant structural disorder was prone to irreversibly forming the oligomers crosslinked via disulfide bonds. The disulfide-crosslinked oligomers of SOD1 were detected in the spinal cords of the diseased mice expressing mutant SOD1. We hence propose an alternative pathway of mutant SOD1 misfolding that is responsible for oligomerization in the pathologies of the disease.

Original languageEnglish
Pages (from-to)484-496
Number of pages13
JournalProtein Science
Volume26
Issue number3
DOIs
Publication statusPublished - 2017 Mar 1

Keywords

  • ALS
  • Cu/Zn-superoxide dismutase
  • SOD1
  • amyotrophic lateral sclerosis
  • circular dichroism spectroscopy
  • protein misfolding
  • small-angle X-ray scattering

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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