调控线粒体PINK1积聚的激酶筛选及其对多巴胺能神经元的保护机制

线粒体损伤是帕金森病（PD）的重要病理特征和核心机制之一。PINK1突变可致家族遗传性PD，在线粒体损伤时，野生型PINK1可积聚于线粒体外膜，介导线粒体自噬以清除受损线粒体，而突变的PINK1丧失该功能，使线粒体自噬发生障碍，诱导多巴胺能（DA）神经元死亡。因此，探索PINK1在线粒体上的积聚机制有助于理解PINK1在PD中的病理意义和致病机制。我们预实验发现，PD模型药物不能引起PINK1在线粒体积聚，因而不能有效诱导线粒体自噬。我们通过活性化合物高通量筛选发现，酪氨酸激酶受体VEGFR拮抗剂和PLK1激酶抑制剂等化合物可以调节PINK1在线粒体的积聚。我们推测，PINK1的线粒体积聚受到某些特定的信号通路调节，我们拟运用细胞、分子及生化技术，并通过在体MPTP和PINK1敲除小鼠模型，结合药理学干预，阐明PINK1在线粒体上积聚的信号通路调控机制及其对PD中DA神经元的保护效应。

Mitochondrial damage is an important pathological feature of Parkinson's disease (PD). Mutations in PINK1 gene lead to familial PD. Upon mitochondrial damage, wild-type PINK1 is accumulated on the outer mitochondrial membrane (OMM), inducing mitophagy to remove the damaged mitochondria, while the mutant PINK1 can not be accumulated on OMM, so that the damaged mitochondria is unable to be cleared, leading to dopaminergic (DA) neuronal death. Therefore, it is of help for understanding PINK1 pathological significance in PD and PD pathogenesis by exploring the mechanism of PINK1 accumulation on mitochondria. Our preliminary data showed that in PD models, PINK1 can not be accumulated on OMM, which could not effectively induce mitophagy. By high-throughput screening a kinase inhibitor compound library, we found that VEGFR receptor antagonists and PLK1 inhibitors, etc., could promote PINK1 accumulation on mitochondria. We speculate that the accumulation of PINK1 on mitochondria is regulated by the some specific signaling pathways. We are planning to use cell, molecular biological and biochemical methods, and in vivo MPTP and PINK1 knockout mice, in combination with pharmacological intervention, to explore PINK1 accumulation mechanisms and signal pathways on mitochondria, thus identify the protective effects of PINK1 accumulation as well as the related kinase signals on dopaminergic neurons in PD.