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

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.

Roles of CHOP/GADD153 in endoplasmic reticulum stress

“…104,105 Furthermore, accumulation of polyglutamine-containing proteins was found to cause ER stress, presumably due to saturation of the cytosolic protein degradation system. 19 These findings suggest that mutations in the parkin gene or expression of pathogenic polyglutamine proteins in neurons inhibit degradation of misfolded proteins, cause ER stress and lead to ER stress-mediated apoptosis. Therefore, CHOPmediated apoptosis may also be involved in the development of Parkinson's disease and polyglutamine disease.…”

“…23,26,27 MAPKKK ASK1, which is required for activation of JNK by Ire1 during ER stress, can also activate the p38 pathway. 19,55 ASK1 null cells are resistant to ER stress-induced apoptosis. 19 Therefore, it may be worthwhile to see if ASK1 is involved in the phosphorylation of CHOP in ER stress.…”

“…19,55 ASK1 null cells are resistant to ER stress-induced apoptosis. 19 Therefore, it may be worthwhile to see if ASK1 is involved in the phosphorylation of CHOP in ER stress.…”

“…The second is activation of the cJUN NH2-terminal kinase (JNK) pathway, which is mediated by formation of the 'inositol requiring 1 (Ire1)-TNF receptor-associated factor 2 (TRAF2)-apoptosis signal-regulating kinase1 (ASK1)' complex. 18,19 The third is activation of ER-associated caspase-12 (see Yuan, this review series). Caspase-12 is activated by ER stress, but apparently not by death receptor-mediated or mitochondriatargeted apoptotic signals.…”

Traffic Jams II: An Update of Diseases of Intracellular Transport

“…ataxias disease Inhibition of the proteasome degradative system (45) leads to activation of ER stress signaling through activation of the IRE1 receptor. IRE1 recruits the TRAF2-ASK1 complex leading to JNK activation and induction of apoptosis.…”