Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans
Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans
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DOI：
10.1073/pnas.100107297
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发表时间：
2000-05-23
影响因子：
11.1
通讯作者：
Morimoto, RI
中科院分区：
文献类型：
--
作者：
Satyal, SH;Schmidt, E;Morimoto, RI
几种不相关蛋白质中多聚谷氨酰胺重复序列的扩增会导致具有不同但相关病理学的神经退行性疾病。为了提供研究常见致病特征的模型系统，我们检查了秀丽隐杆线虫中表达的多谷氨酰胺重复序列的行为。体壁肌肉细胞中多聚谷氨酰胺重复序列作为绿色荧光蛋白（CFP）融合蛋白的表达导致离散的细胞质聚集体，这些聚集体出现在胚胎发生早期，并与幼虫到成体发育的延迟相关。热休克反应在单个细胞中以聚谷氨酰胺长度依赖性方式被特殊激活。多聚谷氨酰胺表达和聚集体形成的毒性作用可以通过酵母伴侣 Hsp104 的共表达来逆转。与多聚谷氨酰胺聚集体相关的稳态改变会导致具有较短谷氨酰胺重复序列的可溶性蛋白质的隔离，以及富含谷氨酰胺的核蛋白的重新定位。这些诱导聚集和重新定位的观察结果对涉及蛋白质聚集的疾病具有影响。
Expansion of polyglutamine repeats in several unrelated proteins causes neurodegenerative diseases with distinct but related pathologies, To provide a model system for investigating common pathogenic features, we have examined the behavior of polyglutamine expansions expressed in Caenorhabditis elegans, The expression of polyglutamine repeats as green fluorescent protein (CFP)-fusion proteins in body wall muscle cells causes discrete cytoplasmic aggregates that appear early in embryogenesis and correlates with a delay in larval to adult development. The heat shock response is activated idiosyncratically in individual cells in a polyglutamine length-dependent fashion. The toxic effect of polyglutamine expression and the formation of aggregates can be reversed by coexpression of the yeast chaperone Hsp104, The altered homeostasis associated with polyglutamine aggregates causes both the sequestration of an otherwise soluble protein with shorter arrays of glutamine repeats and the relocalization of a nuclear glutamine-rich protein. These observations of induced aggregation and relocalization have implications for disorders involving protein aggregation.