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

Genes & development | Jun 1, 2002

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.

Pubmed ID: 12050113 RIS Download

Mesh terms: Animals | Apoptosis | Arabidopsis Proteins | Cell Death | Cell Line | Cell Nucleus | Cysteine Endopeptidases | Cytoplasm | Endoplasmic Reticulum | Endoribonucleases | Humans | Immunoblotting | In Situ Nick-End Labeling | Membrane Proteins | Mitogen-Activated Protein Kinase 8 | Mitogen-Activated Protein Kinases | Multienzyme Complexes | Neurons | PC12 Cells | Peptides | Plant Proteins | Plasmids | Precipitin Tests | Proteasome Endopeptidase Complex | Protein-Serine-Threonine Kinases | Rats | Recombinant Proteins | Reverse Transcriptase Polymerase Chain Reaction | Signal Transduction | Thapsigargin | Time Factors | Transfection

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Gene Ontology (Data, Gene Annotation)

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