Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity
Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity
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DOI：
10.1101/gad.1673408
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发表时间：
2008-12-01
影响因子：
10.5
通讯作者：
Lindquist, Susan
中科院分区：
文献类型：
--
作者：
Duennwald, Martin L.;Lindquist, Susan
蛋白质错误折叠，无论是由衰老、环境因素还是基因突变引起的，都是神经退行性疾病的共同基础。具有异常长的多聚谷氨酰胺（polyQ）扩增的蛋白质的错误折叠导致几种神经退行性疾病，例如亨廷顿病（HD）。虽然许多细胞通路已被证明在HD中受损，但polyQ毒性的主要触发因素仍然难以捉摸。我们报告，酵母细胞和神经元样PC 12细胞表达polyQ-扩增亨廷顿蛋白（htt）片段显示出令人惊讶的具体，立即，和激烈的缺陷内质网（ER）相关的降解（ERAD）。我们进一步破译ERAD中这种缺陷的机制基础：polyQ扩增的htt片段对必需ERAD蛋白Np 14、Ufd 1和p97的截留。在酵母和哺乳动物神经元样细胞中，Npl 4和Ufd 1的过表达改善了polyQ毒性。我们的研究结果表明，受损的ER蛋白稳态是一个广泛的和高度保守的贡献者polyQ在酵母中的毒性，在PC 12细胞，重要的是，在纹状体细胞表达全长polyQ-扩大亨廷顿。
Protein misfolding, whether caused by aging, environmental factors, or genetic mutations, is a common basis for neurodegenerative diseases. The misfolding of proteins with abnormally long polyglutamine (polyQ) expansions causes several neurodegenerative disorders, such as Huntington's disease (HD). Although many cellular pathways have been documented to be impaired in HD, the primary triggers of polyQ toxicity remain elusive. We report that yeast cells and neuron-like PC12 cells expressing polyQ-expanded huntingtin (htt) fragments display a surprisingly specific, immediate, and drastic defect in endoplasmic reticulum (ER)-associated degradation (ERAD). We further decipher the mechanistic basis for this defect in ERAD: the entrapment of the essential ERAD proteins Npl4, Ufd1, and p97 by polyQ-expanded htt fragments. In both yeast and mammalian neuron-like cells, overexpression of Npl4 and Ufd1 ameliorates polyQ toxicity. Our results establish that impaired ER protein homeostasis is a broad and highly conserved contributor to polyQ toxicity in yeast, in PC12 cells, and, importantly, in striatal cells expressing full-length polyQ-expanded huntingtin.