人类新基因MAFIP在帕金森病发生过程中的机制研究

项目名称： 人类新基因MAFIP在帕金森病发生过程中的机制研究

项目编号： No.81200975

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 神经系统疾病、精神疾病

项目作者： 李洋

作者单位： 安徽医科大学

项目金额： 23万元

中文摘要： 帕金森病是一种当今临床常见且难以治愈的神经功能障碍疾病，其发病率还在逐年增高。研究发现在大脑黑质神经元内a-Synuclein与E3泛素连接酶CHIP，分子伴侣HSP70和BAG5等蛋白形成不溶的Lewy小体，是帕金森病的典型病理变化。同时a-Synuclein还会在细胞内自发形成可溶性的寡聚体，对细胞造成毒性。在此过程中CHIP的泛素连接酶酶活性受BAG5和HSP70的调控，对a-Synuclein进行泛素化修饰起了关键性作用。我们的前期研究发现人类新基因MAFIP可以在细胞内与CHIP，HSP70和BAG5形成复合体，故而推测其很可能影响CHIP的酶活而参与影响帕金森病的发生过程。本研究试图鉴定MAFIP与以上蛋白成员在体内和体外的具体相互作用，并确认其对CHIP酶活的影响机制，探索此蛋白在细胞内是否参与调控了a-Synuclein的寡聚化作用，最终对神经细胞的细胞学效应产生何种影响。

中文关键词： miR-193a-3p；化疗耐受；DNA甲基化；；

英文摘要： Parkinson's disease (PD) is one of the most common neurodegenerative disease nowadays and the incidence is still increasing.The most typical pathological marks of PD is the presence of intracellular protein aggregates, known as Lewy bodies within the surviving nigral neurons. a-Synuclein (a-syn), E3 ubuquitin ligase CHIP, molecular chaperon HSP70 and BAG5 are major components of these protein inclusions.a-syn monomers can also self associate into soluble higher-order structures such as oligomers and confer significant toxicity to cells which may be modulated by chaperones and co-chaperones such as HSP70 and BAG5. In this process the ubiquitylation of a-syn by CHIP plays a crucial role. Our previous study found that the transcriptional product of human novel gene MAFIP can form a complex in the cell with CHIP, HSP70 and BAG5, which raised the possibility that MAFIP may affect the activity of E3 ligase CHIP involved in the process of Parkinson's disease. This study attempts to identify the interaction between MAFIP and CHIP, HSP70, BAG5 etc. in vitro and in vivo, explore if MAFIP is involved in the regulation of a-synuclein oligomerization in the cell, and cause what kinds of the cytological effects on the nerve cells.

英文关键词： miR-193a-3p；chemoresistance；DNA methylation；；