多聚谷氨酰胺蛋白募集正常蛋白质的细胞效应及分子机制

项目名称： 多聚谷氨酰胺蛋白募集正常蛋白质的细胞效应及分子机制

项目编号： No.31470758

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 胡红雨

作者单位： 中国科学院上海生命科学研究院

项目金额： 85万元

中文摘要： 蛋白质的错误折叠会引起淀粉样积聚和包涵体的形成，与神经退行性疾病的发生密切相关。多聚谷氨酰胺（PolyQ）序列是由特定基因的CAG三核苷酸重复延伸所引起的; PolyQ延伸蛋白易发生积聚并在细胞内形成包涵体。本申请项目以两个PolyQ蛋白Ataxin-3和Ataxin-7 为对象和模型，研究PolyQ蛋白募集正常蛋白质的细胞效应及分子机制。我们将重点研究PolyQ蛋白的积聚包涵体对与之特异相互作用的关键蛋白质的募集作用，这些蛋白质包括泛素链、P97/VCP、USP22等。通过分子和细胞水平的研究，将澄清一些基本观点或假设：如PolyQ延伸是否影响其周围序列的结构和蛋白质相互作用；PolyQ包涵体募集其它蛋白质是否通过特异的相互作用；PolyQ包涵体的细胞毒性是否由于募集其它关键蛋白质所产生的。该项目的研究成果将为神经退行性疾病发病机理和预防治疗提供理论依据。

中文关键词： 蛋白质积聚；多聚谷氨酰胺蛋白；募集作用；蛋白质相互作用；包涵体

英文摘要： Misfolding of proteins may cause their amyloidogenic aggregation and inclusion formation, which strongly associates with the pathogenesis of some neurodegenerative diseases. Polyglutamine (PolyQ) sequences are originated by expansion of the CAG tri-nucleotide repeat in particular genes, while PolyQ-expanded proteins readily undergo misfolding and thus form inclusions. In this project, we will take two PolyQ proteins, Ataxin-3 and Ataxin-7, as model proteins to investigate the cellular effects and molecular mechanism underlying the sequestration of normal cellular proteins by PolyQ-expanded protein aggregates and inclusions. We will focus on the PolyQ proteins that sequester some cellular key proteins including ubiquitin chains, P97/VCP, USP22, and so on. By using molecular and cellular approaches, we will clarify some controversial viewpoints or hypotheses: whether PolyQ expansion affects the structures of local sequences and interactions with other proteins; whether a PolyQ protein sequesters cellular proteins through specific interactions; and whether the cytotoxicity of PolyQ inclusions is resulted from sequestration of the cellular key proteins. The research will provide fundamental information for deciphering pathologies of the neurodegenerative diseases and discovering pharmaceutical therapy.

英文关键词： Protien Aggregation;PolyQ Protein;Sequestration;Protein Interaction;Inclusion