PLD1介导的线粒体功能异常在PD发病机制中的作用

表观遗传调控在介导慢性环境暴露对PD基因表达改变的影响中发挥重要作用。本研究小组前期研究发现，PD患者尸检脑组织黑质中有DNA羟甲基化改变的区域在PLD信号通路显著富集；PD患者黑质中PLD1蛋白表达显著下降；进一步在果蝇模型中证明，多巴胺能细胞中过表达PLD1可以部分挽救α-synuclein果蝇的运动障碍。这些结果提示，PLD1可能参与了PD的发病过程。本研究拟在前期研究的基础上，在细胞水平和动物水平，通过药物和基因工程的方法改变PLD1活性/表达，应用一系列分子生物学技术，明确PLD1缺陷对线粒体形态、分裂/融合平衡、线粒体功能、mtDNA及细胞存活等的影响；过表达野生型/酶缺陷型PLD1能否挽救其相关表型；探讨PLD1致病的可能机制；明确外周血PLD1表达改变能否作为PD的生物学标记物。本项目的开展有望为探索PD发病机制拓展新的思路，为寻找PD新的诊断标记物和治疗靶点提供线索。

Epigenetics plays an important role in mediating the effect of chronic environmental exposure on Parkinson’s disease (PD) gene expression. In our previous study, we found differentially hydroxymethylated regions (DhMRs) in PD postmortem brain, substantia nigra, were enriched in PLD signaling pathway. Moreover, we proved that PLD1 expression was significantly decreased in substantia nigra of PD patients with respect to controls. In drosophila, the decreased climbing ability induced by overexpressing α-synuclein could be rescued by overexpression of PLD in dopaminergic cells. These results indicate that PLD1 may play a role in the pathogenesis of PD. In this study, to explore whether PLD1 mediates mitochondrial dynamic imbalance and dysfunction and then participates in the pathogenesis of PD and its possible mechanism, we would analysis the effect of genetic or pharmacological PLD1 inhibition on mitochondrial morphology, fission and fusion balance, function, mtDNA and cell survival in vivo and in vitro using a series of molecular biology techniques. In addition, we would determine whether overexpression of PLD1 wt or mutant can rescue aboved phenotypes and whether the change of PLD1 expression in peripheral blood can be used as a biomarker of PD. This project is expected to expand our understanding of molecular mechanisms of PD, and provide clues for the search of new diagnostic markers and therapeutic targets for PD.