申请人对囊泡分泌调控机制和神经退行性病变的研究（Nat Commun, 2018; PNAS, 2014; Nat Commun, 2014）中发现：多巴胺神经元的胞吞与囊泡循环异常是导致帕金森病（PD）的重要机制。本申请在此基础上研究细胞周期蛋白G相关激酶（GAK）在PD病理过程中的作用与机制。GAK是网格蛋白介导胞吞作用的重要调节蛋白，主要调控包被小泡的脱壳作用，进而参与囊泡循环调控。遗传证据表明GAK是重要的PD致病基因，敲低GAK表达可导致果蝇产生PD相关行为，但GAK对多巴胺神经元囊泡循环和多巴胺分泌的调节作用仍不清楚，GAK失活在哺乳动物中是否导致PD及其病理机制尚缺少直接的在体证据。本申请将结合脑片电化学、行为学实验、confocal和TIRF成像等，系统研究GAK对多巴胺神经元囊泡循环和多巴胺分泌的调节及其在PD中的重要意义，以期为PD治疗找到新的药物靶点。

In the study of vesicle recycling and neurodegenerative diseases (Nat Commun, 2018; Front Mol Neurosci,2017; PNAS, 2014; Nat Commun, 2014), we found that the inhibition of endocytosis and vesicle recycling plays a critical role in the pathology of Parkinson’s disease (PD). Here, we study the function of endocytosis-related protein—cyclin-G associated kinase (GAK)—in the pathogenesis of PD. GAK functions as an important co-chaperon in the Hsc70 dependent uncoating of clathrin-coated vesicles. It is genetically associated with PD and GAK dysfunction leads to the PD-like syndromes in Drosophila. However, whether and how GAK dysfunction leads to PD pathogenesis in mammalian hasn’t been validated yet. Whether and how the impaired vesicle recycling and dopamine transmission are involved in the GAK-linked PD remains unknown. By using virus infection in vivo, electrochemistry in brain slices, confocal and TIRF imaging, behavior, and biochemistry experiments, we plan to study the mechanisms of vesicle recycling and DA release in DA neurons and the role of GAK in PD by technologies. This will uncover the mechanisms of GAK-associated PD, shed new light on the genetic causes of PD, and provide the novel therapeutic targets for the treatment of PD.