ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats.
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.
Nishitoh
Hideki
H
Laboratory of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku 113-8549, Japan.
Matsuzawa
Atsushi
A
Tobiume
Kei
K
Saegusa
Kaoru
K
Takeda
Kohsuke
K
Inoue
Kiyoshi
K
Hori
Seiji
S
Kakizuka
Akira
A
Ichijo
Hidenori
H
D000818:Animals; D017209:Apoptosis; D029681:Arabidopsis Proteins; D016923:Cell Death; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000502:physiology*; D004722:Endoribonucleases; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008565:Membrane Proteins; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D010940:Plant Proteins / Q000378:metabolism* / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
C120363:ASK1 protein, Arabidopsis; D029681:Arabidopsis Proteins; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D010455:Peptides; D010940:Plant Proteins; D011994:Recombinant Proteins; C097188:polyglutamine; D019284:Thapsigargin; C403982:ERN2 protein, human; C486557:Ern2 protein, rat; D017346:Protein Serine-Threonine Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D004722:Endoribonucleases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex