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

  1. Hideki Nishitoh1,
  2. Atsushi Matsuzawa1,
  3. Kei Tobiume1,
  4. Kaoru Saegusa1,
  5. Kohsuke Takeda1,
  6. Kiyoshi Inoue2,
  7. Seiji Hori2,3,
  8. Akira Kakizuka2,3,4, and
  9. Hidenori Ichijo1,4,5
  1. 1Laboratory of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan; 2The Fourth Department, Osaka Bioscience Institute, Osaka 565-0874, Japan; 3Kyoto University Graduate School of Biostudies, Kyoto 606-8501, Japan; 4Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation

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.

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Footnotes

  • 5 Corresponding author.

  • E-MAIL ichijo.csi{at}tmd.ac.jp; FAX 81-3-5803-0192.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.992302.

    • Received March 18, 2002.
    • Accepted April 11, 2002.
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