多聚谷氨酰胺延伸蛋白募集细胞内正常蛋白质或RNA的分子机制

多聚谷氨酰胺(PolyQ)疾病,是一类由编码蛋白质的基因中CAG三核苷酸重复序列的异常延伸所引发的神经退行性疾病.CAG三核苷酸重复序列导致所编码蛋白质的PolyQ序列的异常延伸,使蛋白质发生错误折叠和积聚,并在细胞内形成包涵体.包涵体的形成是神经退行性疾病的一个重要特征.PolyQ蛋白在积聚过程中,可以将细胞内与其特异相互作用的蛋白质或RNA募集到包涵体中.被募集的其他蛋白质或RNA不仅自身的可溶性组分减少,而且由于被"挟持"到包涵体中其在细胞内的有效组分也相应地减少,从而影响其正常的生物功能.根据特异相互作用的模式,我们将募集作用分为以下几种类型:蛋白质(含Poly Q蛋白)的共积聚;特定结构域或模体介导的募集作用(包括泛素等修饰介导的募集作用);RNA介导的募集作用;以及对分子伴侣蛋白的募集作用.PolyQ延伸蛋白的积聚和对其他组分的募集可能是引发细胞毒性和神经退行性病变的重要原因.

Sequestration of Cellular Essential Proteins or RNA by Polyglutamine-Expanded Protein Aggregates

Polyglutamine (polyQ) diseases are a group of neurodegenerative disorders caused by aberrant expansion of CAG trinucleotide in the coding sequence of different disease proteins. This CAG trinucleotide repeats lead to the abnormal polyQ expansion in the translated proteins, which may cause protein misfolding and aggregation. Protein aggregation or inclusion formation is a common feature shared by diverse neurodegenerative diseases. Aggregation of polyQ-expanded proteins can sequester other interacting proteins or RNA into the insoluble aggregates or inclusions, which may result in decrease in the soluble pools of both polyQ proteins and other sequestered proteins or RNA, leading to the loss of biological function. According to the interaction modes, we classified the sequestration effects of protein aggregates into four distinct types: protein (including polyQ protein) co-aggregation; specific domain/motif-mediated sequestration (including modified ubiquitin and others); RNA-mediated sequestration; and sequestration of molecular chaperones. Thus, aggregation of the polyQ-expanded proteins and sequestration of cellular essential proteins may be the major causes for cytotoxicity and neurodegeneration.