PARK16位点内SLC41A1基因变异对多巴胺神经元离子稳态和功能的影响

项目名称： PARK16位点内SLC41A1基因变异对多巴胺神经元离子稳态和功能的影响

项目编号： No.81200984

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： 严雅萍

作者单位： 浙江大学

项目金额： 23万元

中文摘要： 帕金森病(parkinson's disease, PD)是第二大神经变性疾病，为一遗传因素和环境因素共同起作用的复杂疾病，其致病机制尚未阐明。目前已定位了18个帕金森病遗传位点，其中PARK3、PARK10、PARK12和PARK16位点的致病基因尚未克隆。PARK16位点包括NUCKS1，RAB7L1，SLC41A1和PM20D1四个基因，其中SLC41A1基因表达的蛋白是一相对较广谱的离子通道，而金属离子铁、镁等被报道与PD发病相关。为了更深入地研究PARK16位点与PD发病的相关性，我们的前期工作对其相关基因在PD患者中行突变检测，发现了3个SLC41A1基因的新变异(p. Lys146Glu, p. Pro480Pro和一个内含子区域的变异)。因此，我们拟在细胞和动物模型中研究SLC41A1基因及其变异是否通过影响金属离子稳态而影响神经元的存活，及其作用机制。

中文关键词： 自噬；α-synuclein；细胞凋亡；离子转运；SLC41A1敲除

英文摘要： Parkinson's disease (PD) is the second most common neurodegenerative disease. Although it is generally accepted that the disease is caused by both genetic and enviromental factors, its exact pathogenesis remains unclear. To date, researchers have identified 18 loci, of which genes for PARK3, PARK10, PARK12 and PARK16 have not be cloned yet. The PARK16 locus contains four genes of NUCKS1，RAB7L1，SLC41A1and PM20D1. SLC41A1 protein is a relatively universal ion channel, and ions like magnesium, copper, zinc, iron are associated with the pathogenesis of PD. To further explore the role of PARK16 locus in PD, we previously identified three new variants (p. Lys146Glu, p. Pro480Pro and a new intron variant) in SLC41A1 gene after screening Chinese PD patients for mutations in PD-associated genes. Whether the unusual expression of SLC41A1 gene and its variants break the cellular ionic homeostasis? Whether it's the way by which the gene affects the survival of neuron? And the inherent mechanism remains to be studied.

英文关键词： autophagy；α-synuclein；cell apoptosis；ion exchange；SLC41A1 knockout