帕金森病（PD）发生、发展的重要原因是多巴胺能(DA)神经元内α-突触核蛋白(α-syn)发生磷酸化修饰作用，但其详细分子机制尚未阐明，Dyrk1a是α-syn残基磷酸化的主要激酶。其SNPs分布与不同种族PD罹患风险相关，但我们仍不清楚该基因变异介导的α-syn磷酸化修饰在疾病发展过程中的作用机制。本课题在前期基础上，收集1000名PD患者，通过捕获测序+高通量测序，确定该基因20个SNPs和散发性PD的关系；同时检测病例的血清/脑脊液中α-syn等分子及其磷酸化水平，从临床角度验证磷酸化修饰影响DA神经元变性的生物学证据；并针对鉴定的Dyrk1a突变位点，以基因缺陷模型细胞为基础，PD模型动物为验证，观察该基因功能、表达对α-syn等分子磷酸化修饰的影响及相关信号分子的调控规律，揭示Dyrk1a介导的α-syn磷酸化修饰在DA神经元凋亡过程中的分子信号通路。

Phosphation of alpha-synuclein (a-syn) in dopaminergic (DA) neurons takes part in the occurrence and development of Parkinson's disease (PD), but little is known about the molecular mechanism. Dyrk1a is a main kinase of phosphating at the residues of a-syn. It has been reported that SNPs distribution of Dyrkla gene is associated with the risk of PD in different races. However, it is still unclear how a-syn phosphation modification mediated by the gene and its mutations affects the progression of the disease. Based on previous study, we plan to confirm the relationship between 20 SNPs and sporadic PD by capture sequencing and high-throughput sequencing from 1000 cases of PD, to detect the molecules such as a-syn and their phosphating levels in the serum/cerebrospinal fluid and to observe the effect of expression and function of Dyrkla mutation on a-syn phosphating modification and the regulation law of related signal molecules by genetic defect cell model and PD animal model, and attempt to verify the effects of phosphating modification on DA neuron degeneration from a clinical point of view and to reveal the molecular signal pathway of a-syn phosphating modification mediated by Dyrkla in the process of DA neurons apoptosis.