Progressive disruption of cellular protein folding in models of polyglutamine diseases
Progressive disruption of cellular protein folding in models of polyglutamine diseases
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DOI：
10.1126/science.1124514
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发表时间：
2006-03-10
期刊：
影响因子：
56.9
通讯作者：
Morimoto, RI
中科院分区：
文献类型：
--
作者：
Gidalevitz, T;Ben-Zvi, A;Morimoto, RI
许多人类疾病与错误折叠和易于聚集的蛋白质的慢性表达有关。多聚谷氨酰胺残基在无关蛋白质中的扩张与神经退行性疾病的早期发病有关。为了了解错误折叠蛋白的存在如何导致细胞功能障碍，我们采用了线虫纤毛虫谷氨酰胺聚集模型。在这里，我们发现多谷氨酰胺的扩张破坏了蛋白质折叠质量控制的全球平衡，导致具有不稳定的温度敏感突变的各种亚稳态蛋白质的功能丧失。反过来，这些蛋白质，虽然在正常生理条件下是无害的，但增强了聚谷氨酰胺蛋白的聚集。因此，整个基因组中的弱折叠突变可以作为多谷氨酰胺表型和毒性的修饰物。
Numerous human diseases are associated with the chronic expression of misfolded and aggregation-prone proteins. The expansion of polyglutamine residues in unrelated proteins is associated with the early onset of neurodegenerative disease. To understand how the presence of misfolded proteins leads to cellular dysfunction, we employedCaenorhabditis eleganspolyglutamine aggregation models. Here, we find that polyglutamine expansions disrupted the global balance of protein folding quality control, resulting in the loss of function of diverse metastable proteins with destabilizing temperature-sensitive mutations. In turn, these proteins, although innocuous under normal physiological conditions, enhanced the aggregation of polyglutamine proteins. Thus, weak folding mutations throughout the genome can function as modifiers of polyglutamine phenotypes and toxicity.