线粒体障碍是运动障碍病帕金森病（PD）神经元变性的重要机制。LRRK2基因突变是目前PD最常见的遗传性病因。LRRK2突变导致线粒体动态平衡紊乱，包括形态异常及转运障碍。LRRK2不同变异位点产生紊乱类型不同，提示可能累及不同的信号通路。Parkin和KIF5A是我们发现的LRRK2相关结合蛋白，两者都是参与维持动态平衡的重要分子，其中Parkin负责形态维持而KIF5A负责转运。两者病变都可导致神经元变性。我们前期工作发现LRRK2抑制Parkin功能，初步研究表明增强KIF5A可改善线粒体动态平衡紊乱。本课题拟以细胞及转基因果蝇为模型，采用基因转染、RNA干拢、生化及病理技术，观察线粒体的动态变化及神经变性。研究Parkin和KIF5A相关通路在LRRK2线粒体动态平衡紊乱中的作用，为探讨LRRK2致病机制及携带不同LRRK2变异位点的PD病人的个体化治疗研究提供一种新思路。

Mitochondria dysfunction plays an major role in the neurodegeneration in parkinson's disease (PD). Mutations in Leucine-rich-repeat-kinase 2 (LRRK2), are the most common genetic causes in both familial and sporadic PD. LRRK2 is partially localized in mitochondria. LRRK2 has kinase and GTPase activities and scaffolding functions. RRK2 mutants can induce mitochondrial dynamic dyshomeostasis. Among our previously identified LRRK2 interactors, Parkin and KIF5A are mainly involved in mitochondria dynamic homeostasis. Parkin participates in mitochondria dynamics through the mitochondrial quality control mechanism. KIF5A, a neuronal kinesin of kinensin-1 family, is responsible for transportation of mitochondria from cell body to distal areas. In our preliminary studies, we demonstrated that different mutations/variants caused different mitochondria dynamic dyshomeostasis, suggesting that LRRK2 induced mitochondria dynamic problem through a complex multiple pathway mechanism. We further found that overexpression of KIF5A attenuated LRRK2-induced mitochondria dynamic dyshomeostasis. Therefore, we propose to study the role of Parkin and KIF5A in LRRK2-induced mitochondria dynamic dyshomestasis in cell and fly models. We believe that our proposed study is likely to provide insight in pathogenesis of LRRK2-related PD as well as other forms of PD and may identify new therapeutic targets.