A copper-deficient form of mutant Cu/Zn-superoxide dismutase as an early pathological species in amyotrophic lateral sclerosis

Eiichi Tokuda, Takao Nomura, Shinji Ohara, Seiji Watanabe, Koji Yamanaka, Yuta Morisaki, Hidemi Misawa, Yoshiaki Furukawa

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Dominant mutations in the gene encoding copper and zinc-binding superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS). Abnormal accumulation of misfolded SOD1 proteins in spinal motoneurons is a major pathological hallmark in SOD1-related ALS. Dissociation of copper and/or zinc ions from SOD1 has been shown to trigger the protein aggregation/oligomerization in vitro, but the pathological contribution of such metal dissociation to the SOD1 misfolding still remains obscure. Here, we tested the relevance of the metal-deficient SOD1 in the misfolding in vivo by developing a novel antibody (anti-apoSOD), which exclusively recognized mutant SOD1 deficient in metal ions at its copper-binding site. Notably, anti-apoSOD-reactive species were detected specifically in the spinal cords of the ALS model mice only at their early pre-symptomatic stages but not at the end stage of the disease. The cerebrospinal fluid as well as the spinal cord homogenate of one SOD1-ALS patient also contained the anti-apoSOD-reactive species. Our results thus suggest that metal-deficiency in mutant SOD1 at its copper-binding site is one of the earliest pathological features in SOD1-ALS.

Original languageEnglish
Pages (from-to)2119-2130
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number6
DOIs
Publication statusPublished - 2018 Jun 1

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Amyotrophic Lateral Sclerosis
Copper
Metals
Zinc
Spinal Cord
Binding Sites
Ions
Motor Neurons
Superoxide Dismutase
Cerebrospinal Fluid
Anti-Idiotypic Antibodies
Superoxide Dismutase-1
Mutation
Genes
Proteins

Keywords

  • Amyotrophic lateral sclerosis
  • Copper ion
  • Cu/Zn-superoxide dismutase
  • Protein misfolding

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

A copper-deficient form of mutant Cu/Zn-superoxide dismutase as an early pathological species in amyotrophic lateral sclerosis. / Tokuda, Eiichi; Nomura, Takao; Ohara, Shinji; Watanabe, Seiji; Yamanaka, Koji; Morisaki, Yuta; Misawa, Hidemi; Furukawa, Yoshiaki.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1864, No. 6, 01.06.2018, p. 2119-2130.

Research output: Contribution to journalArticle

Tokuda, Eiichi ; Nomura, Takao ; Ohara, Shinji ; Watanabe, Seiji ; Yamanaka, Koji ; Morisaki, Yuta ; Misawa, Hidemi ; Furukawa, Yoshiaki. / A copper-deficient form of mutant Cu/Zn-superoxide dismutase as an early pathological species in amyotrophic lateral sclerosis. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2018 ; Vol. 1864, No. 6. pp. 2119-2130.
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