帕金森病相关基因PINK1和α-Synuclein调控PP2A影响神经细胞存活的分子机制

PINK1 and alpha-synuclein(α-Syn) are PD-related disease genes, both of which exist in Lewy's body of PD patients. Our finished the National Natural Science Foundation of China in 2012 found that PINK1 and α-Syn could regulate protein phosphatase 2A (PP2A) respectively, and had an opposite role. Many studies have been reported that PP2A activity changes obviously in neurodegenerative diseases, which suggests that PP2A as a key molecular participates in PD pathogenesis. However, the molecular mechanism of PINK1 and α-Syn regulating PP2A activity is still unclear. Our studies use PINK1, α-Syn overexpression/siRNA cell and mice model to investigate whether PINK1 and α-Syn regulate PP2A activity through Ca2+/Calmodulin/Src pathway; further clarify whether PINK1 can reverse PP2A activity by α-Syn-mediated; ultimately determine whether PINK1 can resist α-Syn-induced nerve cell injury through regulating PP2A activity. This study will search new targets for PD nerve cell protection and intervention and provide new clues for PD pathogenic mechanism and therapeutic approaches.

PINK1和α-突触核蛋白（α-Syn）是帕金森病（PD）相关致病基因，两者都存在于PD患者路易体中。2012年结题国自然研究发现，PINK1与α-Syn可分别调节蛋白磷酸酶2A（PP2A）活力，且作用相反。文献报道在神经退行性疾病中PP2A活力明显变化，提示PP2A可能是二基因参与PD致病机制的作用环节。但是PINK1与α-Syn调控PP2A活力的分子机制目前尚不清楚。本课题将运用PINK1和α-Syn敲减/过表达的细胞及小鼠模型，明确PINK1是否通过Ca2+/Calmodulin/Src信号通路调节PP2A活力；确定α-Syn是否也通过上述途径调节PP2A活力；进一步明确PINK1是否可以逆转α-Syn对PP2A活力的调节；最终明确PINK1是否可以通过调控PP2A活力抵抗α-Syn所致的神经细胞损伤，寻找PD神经细胞保护及干预的新靶位，为明确PD的致病机制探讨新的治疗途径提供线索。

帕金森病(Parkinson's disease，PD)是一种常见于中老年人的神经退行性疾病，其病理特征是中脑黑质多巴胺能神经元进行性的丢失以及残存神经元胞体中特征性“Lewy 体”（ Lewy bodies , LBs）的形成。PTEN-induced kinase 1 (PINK1) 和α-突触核蛋白 （α-Synuclein, α-Syn）的异常改变均与PD的发生密切相关。本课题组2012年结题的国自然研究发现，PINK1和α-Syn可分别正向或反向调节蛋白磷酸酶2A（PP2A）的活力，且在PD发病过程中也存在PP2A活力的异常改变，提示PP2A可能是上述两种蛋白参与PD发病的一个重要环节。本课题在前期研究基础上，研究发现：①α-Syn过表达可通过促进Calmodulin-Src复合物形成而激活Src激酶，使PP2A酪氨酸307位点磷酸化增高，从而抑制PP2A活力；而PINK1通过促进Calmodulin-Src复合物解离而抑制Src活力，使Src磷酸化PP2A水平降低(PP2A激活)，最终通过提高PP2A活力缓解过表达α-Syn致神经细胞损伤; ② α-Syn主要通过其N端结构域发挥细胞毒性，而PINK1可以通过其激酶区与α-Syn N端发生直接相互作用，从而抵抗后者诱导的线粒体功能障碍及细胞凋亡。本实验对α-Syn和PINK1参与PD发生发展的相关机制进行了初步探讨，为PD发病机制及潜在药物作用靶点提供新思路。