2002年6月1日 · In the present study, we investigated the role of ASK1 in the pathogenesis of polyQ diseases. PolyQ fragments with pathogenic repeat length inhibited proteasomal activity and thereby induced ER stress. Activated IRE1 by polyQ induced the TRAF2–ASK1 complex formation that led to JNK activation.

2017年9月21日 · IRE1 plays an essential role in ER stress-mediated aggregation of mutant huntingtin via the inhibition of autophagy flux

2002年6月1日 · 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.

The mutation responsible for HD leads to an abnormally long polyglutamine (polyQ) expansion in the huntingtin (Htt) protein, which confers one or more toxic functions to mutant Htt leading to neuronal loss in the striatum .

2010年7月20日 · The ER-resident transmembrane kinase-endoribonuclease inositol-requiring enzyme 1 (IRE1) is the best characterized UPR signal transduction molecule. In yeast, Ire1 oligomerizes upon activation in response to an accumulation of misfolded proteins in the ER.

This study began a new concept that linked ER stress and HD pathology. A subsequent study investigating the cause of cell death in PC12 and related neuronal cell lines harboring PolyQ found that IRE1 activated TRAF2-ASK1 complex formation and activation of c-Jun N-terminal kinase (JNK) signaling plays an important role in striatal neuronal death.

In mammals, the UPR signaling pathway is initiated by three ER membrane-associated sensors: activating transcription factor-6 (ATF6), inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), and double-stranded RNA-dependent protein kinase (PKR)-like eukaryotic initiation factor 2α (eIF2α) kinase (PERK) . If the survival signal is ...

2022年12月1日 · Expanded polyglutamine (PolyQ) induces ER stress in neurons and activates IRE1α, which forms a protein complex with TRAF2 and ASK1 (IRE1α-TRAF2-ASK1) and activates the JNK pathway, thus inducing apoptosis (Nishitoh et al., 2002).

Activated IRE1 by polyQ induced the TRAF2–ASK1 complex formation that led to JNK activation. We show that primary neu-rons derived from ASK1−/− mice were resistant to ER stress-, proteasome dysfunction-, and polyQ-induced JNK activation and cell death.

2020年12月30日 · We showed that expansion of the polyQ sequence causes ER stress via proteasome dysfunction, accompanying ASK1 activation via formation of the IRE1–TRAF2–ASK1 complex, resulting in polyQ protein-induced cell death .