Alteration of familial ALS-linked mutant SOD1 solubility with disease progression: Its modulation by the proteasome and Hsp70

Shingo Koyama, Shigeki Arawaka, Ren Chang-Hong, Manabu Wada, Toru Kawanami, Keiji Kurita, Masaaki Kato, Makiko Nagai, Masashi Aoki, Yasuto Itoyama, Gen Sobue, Pak H. Chan, Takeo Kato

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

Accumulation of misfolded Cu/Zn superoxide dismutase (SOD1) occurs in patients with a subgroup of familial amyotrophic lateral sclerosis (fALS). To identify the conversion of SOD1 from a normally soluble form to insoluble aggregates, we investigated the change of SOD1 solubility with aging in fALS-linked H46R SOD1 transgenic mice. Mutant SOD1 specifically altered to insoluble forms, which were sequentially separated into Triton X-100-insoluble/sodium dodecyl sulfate (SDS)-soluble and SDS-insoluble/formic acid-soluble species. In spinal cords, the levels of SDS-dissociable soluble SOD1 monomers and SDS-stable soluble dimers were significantly elevated before motor dysfunction onset. In COS-7 cells expressing H46R SOD1, treatment with proteasome inhibitors recapitulated the alteration of SOD1 solubility in transgenic mice. In contrast, overexpression of Hsp70 reduced accumulation of mutant-specific insoluble SOD1. SDS-soluble low molecular weight species of H46R SOD1 may appear as early misfolded intermediates when their concentration exceeds the capacity of the proteasome and molecular chaperones.

Original languageEnglish
Pages (from-to)719-730
Number of pages12
JournalBiochemical and biophysical research communications
Volume343
Issue number3
DOIs
Publication statusPublished - 2006 May 12

Keywords

  • Amyotrophic lateral sclerosis
  • Cu/Zn superoxide dismutase
  • Heat shock protein
  • Oligomer
  • Proteasome

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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