帕金森病基因VPS35突变致内体溶酶体DAT转运障碍的机制研究

Dopamine has a central role in Parkinson’s disease (PD) and endo-lysosome dysfunction is a major pathophysiological pathway of PD. The direct link between Dopamine disturbances and endo-lysosome dysfunction is a key to understanding the role of endo-lysosome dysfunction in PD. DAT is responsible for dopamine homeostasis. The membrane stability of DAT is maintained via e endolysosomal system. VPS35 is a key protein of endo-lysosomal system and responsible for redistribution of molecules. Our preliminary data suggests that VPS35 can directly interact with DAT whereas VPS35 D620N mutation reduces membrane DAT, leading to dopamine neuron degeneration. Endo-lysosomal PD gene α-synuclein and LRRK2 have direct interaction with DAT and VPS35, respectively. Therefore, we propose to study the molecular mechanism underlying VPS35 D620N-induced loss of membrane DAT and the potential role of α-synuclein and LRRK2 in cell, elegans and animal models. We believe that our proposed study is likely to provide insight in pathogenesis of VPS35-related PD as well as other forms of PD, which may identify new PD therapeutic targets.

多巴胺系统在帕金森病（PD）中处于核心地位。内体溶酶体紊乱是PD的重要机制。内体溶酶体紊乱如何直接影响多巴胺系统是理解PD发病的关键问题。神经元间多巴胺的稳态有赖于膜上多巴胺转运体（DAT）的功能，而内体溶酶体负责DAT的代谢与转运。VPS35是内体溶酶体中的分选蛋白，其D620N突变导致典型的PD。我们发现VPS35可以直接与DAT结合，D620N突变导致膜上DAT减少及多巴胺能神经元退变。PD基因α-synuclein和LRRK2是内体溶酶体相关基因，前者可直接结合DAT而后者与VPS35直接关联。我们认为VPS35-DAT通路是内体溶酶体与PD之间的重要桥梁，而α-synuclein和LRRK2可能参与其中。本课题以细胞、线虫及动物为平台，研究VPS35致DAT膜上减少的机制，探索α-synuclein和LRRK2的在其中的作用，为确定VPS35靶点及PD内体溶酶体机制提供新的思路。