Complete loss of post-translational modifications triggers fibrillar aggregation of SOD1 in the familial form of amyotrophic lateral sclerosis

Yoshiaki Furukawa, Kumi Kaneko, Koji Yamanaka, Thomas V. O'Halloran, Nobuyuki Nukina

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

Dominant mutations in Cu,Zn-superoxide dismutase (SOD1) cause a familial form of amyotrophic lateral sclerosis (fALS), and aggregation of mutant SOD1 has been proposed to play a role in neurodegeneration. A growing body of evidence suggests that fALS-causing mutations destabilize the native structure of SOD1, leading to aberrant protein interactions for aggregation. SOD1 becomes stabilized and enzymatically active after copper and zinc binding and intramolecular disulfide formation, but it remains unknown which step(s) in the SOD1 maturation process is important in the pathological aggregation. In this study we have shown that apoSOD1 without disulfide is the most facile state for formation of amyloid-like fibrillar aggregates. fALS mutations impair either zinc binding, disulfide formation, or both, leading to accumulation of the aggregation-prone, apo, and disulfide-reduced SOD1. Moreover, we have found that the copper chaperone for SOD1 (CCS) facilitates maturation of SOD1 and that CCS overexpression ameliorates intracellular aggregation of mutant SOD1 in vivo. Based on our in vivo and in vitro results, we propose that facilitation of post-translational modifications is a promising strategy to reduce SOD1 aggregation in the cell.

Original languageEnglish
Pages (from-to)24167-24176
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number35
DOIs
Publication statusPublished - 2008 Aug 29
Externally publishedYes

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Post Translational Protein Processing
Disulfides
Agglomeration
Copper
Amyotrophic Lateral Sclerosis
Mutation
Zinc
Cell Aggregation
Amyloid
Amyotrophic lateral sclerosis 1
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Complete loss of post-translational modifications triggers fibrillar aggregation of SOD1 in the familial form of amyotrophic lateral sclerosis. / Furukawa, Yoshiaki; Kaneko, Kumi; Yamanaka, Koji; O'Halloran, Thomas V.; Nukina, Nobuyuki.

In: Journal of Biological Chemistry, Vol. 283, No. 35, 29.08.2008, p. 24167-24176.

Research output: Contribution to journalArticle

Furukawa, Yoshiaki ; Kaneko, Kumi ; Yamanaka, Koji ; O'Halloran, Thomas V. ; Nukina, Nobuyuki. / Complete loss of post-translational modifications triggers fibrillar aggregation of SOD1 in the familial form of amyotrophic lateral sclerosis. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 35. pp. 24167-24176.
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