长型PTEN调控PINK1/Parkin介导的线粒体自噬在帕金森病中的作用和机制研究

帕金森病 (PD) 是一种最常见的神经退行性疾病。PINK1/Parkin介导的线粒体自噬功能异常是导致多巴胺能神经元死亡等PD病理改变的核心发病机制之一。申请人在前期工作中首次报道了长型PTEN（PTEN-Long/PTEN-L）是一种新型的线粒体自噬抑制蛋白，其表达量的不同直接影响PINK1/Parkin介导的线粒体自噬水平，但其在PD发病机制中的作用迄今未见报道。申请人预实验发现，高表达PTEN-L可以降低Parkin磷酸化，加剧Parkin聚集小体的形成，抑制神经细胞线粒体自噬，明显增加可导致PD的多种神经毒素引起的神经细胞死亡，提示PTEN-L可能参与了PD的病理过程。为此，本项目将利用神经细胞、果蝇和小鼠等模式生物作为研究体系，采用多种方法深入系统地阐明PTEN-L调控线粒体自噬在PD中的作用。本研究不仅将完善线粒体自噬的分子调控网络，而且将为PD的治疗提供新的靶点和思路。

Parkinson’s disease (PD) is one of the most common neurodegenerative disorder. The dysfunction of PINK1-Parkin-mediated mitophagy is one of the key mechanisms, leading to the death of dopaminergic neurons. Our recent study firstly provided convincing evidence that PTEN-Long (PTEN-L) is a novel negative regulator of mitophagy; different expression level of PTEN-L directly affects PINK1-Parkin-mediated mitophagy. However, it remains elusive up to date that whether PTEN-L is involved in the pathogenesis of PD. Our preliminary results revealed that overexpression of PTEN-L reduced the phosphorylation level of Parkin, promoted Parkin aggresome formation, inhibited mitophagy in neurons, and significantly increased neuron cell death caused by several neurotoxic agents, suggesting that PTEN-L is possibly involved in the pathogenesis of PD. Therefore, in this proposal, we will use neurons, Drosophila melanogaster and mice as the experimental model system to determine the implication of the regulation of PINK1-Parkin-mediated mitophagy by PTEN-L in the pathogenesis of PD. Our study will not only provide deeper understanding of the molecular mechanisms of mitophagy but also suggest that PTEN-L may serve as a molecular target in developing novel therapeutic approaches for PD.