ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats

Hideki Nishitoh, Atsushi Matsuzawa, Kei Tobiume, Kaoru Saegusa, Kohsuke Takeda, Kiyoshi Inoue, Seiji Hori, Akira Kakizuka, Hidenori Ichijo

Research output: Contribution to journalArticle

1022 Citations (Scopus)

Abstract

Expansion of CAG trinucleotide repeats that encode polyglutamine is the underlying cause of at least nine inherited human neurodegenerative disorders, including Huntington's disease and spinocerebellar ataxias. PolyQ fragments accumulate as aggregates in the cytoplasm and/or in the nucleus, and induce neuronal cell death. However, the molecular mechanism of polyQ-induced cell death is controversial. Here, we show the following: (1) polyQ with pathogenic repeat length triggers ER stress through proteasomal dysfunction; (2) ER stress activates ASK 1 through formation of an IRE1-TRAF2-ASK1 complex; and (3) ASK1-/- primary neurons are defective in polyQ-, proteasome inhibitor-, and ER stress-induced JNK activation and cell death. These findings suggest that ASK1 is a key element in ER stress-induced cell death that plays an important role in the neuropathological alterations in polyQ diseases.

Original languageEnglish
Pages (from-to)1345-1355
Number of pages11
JournalGenes and Development
Volume16
Issue number11
DOIs
Publication statusPublished - 2002 Jun 1
Externally publishedYes

Keywords

  • ASK1
  • Apoptosis
  • Endoplasmic reticulum stress
  • JNK
  • Polyglutamine disease
  • Ubiquitine-proteasome system

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Nishitoh, H., Matsuzawa, A., Tobiume, K., Saegusa, K., Takeda, K., Inoue, K., Hori, S., Kakizuka, A., & Ichijo, H. (2002). ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes and Development, 16(11), 1345-1355. https://doi.org/10.1101/gad.992302