Ataxin-3对阿尔茨海默病Cdk5信号通路的调控及机理研究

项目名称： Ataxin-3对阿尔茨海默病Cdk5信号通路的调控及机理研究

项目编号： No.31300880

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 刘红美

作者单位： 中国科学院动物研究所

项目金额： 23万元

中文摘要： 阿尔茨海默病(AD)是老年人中最常见的神经系统退行性疾病。研究显示Cdk5在Aβ非依赖的AD发病机制中起关键作用，其活性调控异常与AD主要病理特征, 包括老年斑的形成、tau蛋白高度磷酸化以及神经突触丢失都密切相关，但目前Cdk5自身调控机制尚不明确。我们前期的工作首次发现Cdk5是去泛素化酶ataxin-3的结合伙伴，并且证实二者之间存在直接相互作用，提示它们可能在功能上相互调节。本项目拟采用生化、分子和细胞技术着重分析ataxin-3对Cdk5及其下游底物的调控及可能的分子机理，研究ataxin-3是否影响由Cdk5激活介导的神经细胞凋亡，从而参与AD的病理发生，同时还将探讨Cdk5对ataxin-3的调控作用。鉴于去泛素化酶在泛素酶解通路中具有细胞种类和底物特异性，更适宜作为治疗靶标，因此，本研究将为AD药物的设计提供新靶点，并对探讨去泛素化酶在AD病理发生中的作用具有重要意义。

中文关键词： 去泛素化酶；ataxin-3；Cdk5信号通路；阿尔茨海默病；

英文摘要： Alzheimer's disease (AD) is the most common neurodegenerative disorder among old people. Recent studies show that the dysregulation of cyclin-dependent kinase 5 (Cdk5) is a linking event between the major AD neuropathological markers: amyloid plaques, tau hyperphosphorylation and synaptic and neuronal loss, thus contributing significantly to AD pathogenesis by amyloid-independent mechanism. However, how exactly Cdk5 is regulated needs further study. Recently, for the first time we identify Cdk5 as a novel binding partner of ataxin-3, a specific deubiquitinating enzyme (DUB). Moreover, a direct interaction between ataxin-3 and Cdk5 is observed, indicating that they may interact functionally. Our present study focuses on the role of ataxin-3 in the regulation of Cdk5 and its downstream substrates and the underlying molecular mechanisms by using interdisciplinary approaches combining biochemistry, molecular and cell biology. In the meantime, we will investigate whether ataxin-3 can affect the neuronal apoptosis mediated by activated Cdk5, thus being involved in the development of AD. The effect of Cdk5 on ataxin-3 will be determined as well. Given that deubiquitinating enzymes offer significant advantages as therapeutic targets within the ubiquitin enzymatic pathway because of their cell-type and substrate-specific

英文关键词： deubiquitinating enzyme；ataxin-3；Cdk5 signaling pathway；Alzheimer's disease；