ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats
ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats
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DOI：
10.1101/gad.992302
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发表时间：
2002-06-01
影响因子：
10.5
通讯作者：
Ichijo, H
中科院分区：
文献类型：
--
作者：
Nishitoh, H;Matsuzawa, A;Ichijo, H
编码多聚谷氨酰胺的CAG三核苷酸重复序列的扩增是至少九种人类遗传性神经退行性疾病的根本病因，其中包括亨廷顿病和脊髓小脑性共济失调。多聚谷氨酰胺片段以聚集体的形式在细胞质和/或细胞核中积累，并诱导神经元细胞死亡。然而，多聚谷氨酰胺诱导细胞死亡的分子机制存在争议。在此，我们展示以下内容：（1）具有致病重复长度的多聚谷氨酰胺通过蛋白酶体功能障碍引发内质网应激；（2）内质网应激通过形成IRE1 - TRAF2 - ASK1复合物激活ASK1；（3）ASK1基因敲除（ASK1(-/-) ）的原代神经元在多聚谷氨酰胺、蛋白酶体抑制剂以及内质网应激诱导的JNK激活和细胞死亡方面存在缺陷。这些研究结果表明，ASK1是内质网应激诱导细胞死亡过程中的关键因素，在多聚谷氨酰胺疾病的神经病理改变中发挥重要作用。
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.