PLA2G6基因突变对线粒体自噬的影响及其在帕金森病发病机制中的作用研究

In our previous work, we found that the mutation of PLA2G6 can cause autosomal recessive early-onset Parkinsonism and also sporadic early-onset Parkinsonism. The PLA2G6 gene encodes a protein called iPLA2β. In vitro, we demonstrated that the PLA2G6 mutation may cause mitochondrial dysfunction and mitophagy deficiency. As mitochondrial dysfunction induced by mitophagy deficiency has been demonstrated to play an important role in PD pathogenesis, we hypothesize that PLA2G6 mutation may cause mitochondrial dysfunction by mitophagy inhibition. In this study, we will verify whether PLA2G6 mutation, knockdown or overexpression will change the morphology, number and function of mitochondria as well as mitophagy in SH-SY5Y cells/ mouse primary DA neurons. And then we will further explore whether Parkin, PINK1 is involved in PLA2G6 mediated mitophagy pathway. The main objective of this study is to further explore PLA2G6 mutation’s effect on mitophagy pathway and PD pathogenesis.

前期工作中，我们发现PLA2G6基因突变可导致常染色体隐性遗传早发性帕金森综合征及散发早发性帕金森综合征。PLA2G6基因位于22q13.1，编码iPLA2β蛋白。预实验中，我们初步证实了PLA2G6基因变异可能导致线粒体功能障碍、线粒体自噬障碍。已知线粒体自噬障碍所致线粒体功能障碍在帕金森病发病过程中起重要作用，因此我们推测PLA2G6突变将导致线粒体自噬障碍，受损线粒体无法及时通过线粒体自噬清除，进而表现为线粒体功能障碍。我们拟利用PLA2G6敲除、突变或过表达的SH－SY5Y细胞/小鼠原代多巴胺能神经元模型观察线粒体形态、数量和功能的改变，明确线粒体自噬是否改变，进一步探讨PINK1、Parkin是否参与了PLA2G6 介导的线粒体自噬通路，深入探讨PLA2G6突变对线粒体自噬的影响及其在帕金森病发病机制中的作用。

前期工作中，我们发现PLA2G6基因突变可导致常染色体隐性遗传早发性帕金森综合征及散发早发性帕金森综合征。PLA2G6基因位于22q13.1，编码iPLA2β蛋白。预实验中，我们初步证实了PLA2G6基因变异可能导致线粒体功能障碍、线粒体自噬障碍。已知线粒体自噬障碍所致线粒体功能障碍在帕金森病发病过程中起重要作用，因此我们推测PLA2G6突变将导致线粒体自噬障碍，受损线粒体无法及时通过线粒体自噬清除，进而表现为线粒体功能障碍。我们利用PLA2G6敲除、突变或过表达的SH－SY5Y细胞/小鼠原代多巴胺能神经元模型观察线粒体形态、数量和功能的改变，明确线粒体自噬存在改变，并进一步发现PINK1、Parkin可能参与了PLA2G6 介导的线粒体自噬通路，提示PLA2G6突变对线粒体自噬的影响可能在帕金森病发病机制中发挥作用。