中脑黑质纹状体中多巴胺能神经细胞凋亡导致多巴胺分泌不足是帕金森病（PD）的主要病理基础。目前研究表明，动力相关蛋白1（Drp1）诱导的线粒体异常分裂在多巴胺能神经细胞凋亡中发挥了重要作用，但其上游调控机制尚不清楚。在我们前期构建的PD细胞和动物模型中，证实了Drp1调控的线粒体异常分裂参与了PD发生，并发现PD中ROCK1被激活，而ROCK1活化抑制剂（Y-27632）可通过抑制CaN介导的Drp1去磷酸化激活抑制线粒体异常分裂和神经细胞凋亡，改善模型小鼠的PD症状。我们前期实验结果提示：ROCK1可能是通过CaN去磷酸化激活Drp1，从而参与PD的发生。本项目拟通过体内外研究，阐明ROCK1激活Drp1诱导的神经细胞线粒体异常分裂在PD发病中的作用机制，同时明确ROCK1抑制剂对PD的治疗作用。本项目将加深对PD发病机制的理论认识，为推动ROCK1抑制剂成为PD治疗药物提供实验依据。

Dopamine deficiency caused by midbrain nigra striatum dopaminergic nerve cell apoptosis is the main pathological basis of Parkinson's disease (PD). The Current study has shown that dynamin-related protein 1 (Drp1)-induced mitochondrial aberrant fission plays an important role in dopaminergic neural cell apoptosis. However, the upstream regulatory mechanism of its action remains unclear. Previously we have successfully established cell and animal models of PD and confirmed that the mitochondrial aberrant fission regulated by Drp1 was involved in the process of PD, in which ROCK1 was activated and the specific ROCK1 inhibitor Y-27632 could inhibit mitochondrial aberrant fission through suppressing CaN-induced Drp1 dephosphorylation/activation, decrease dopaminergic nerve cell apoptosis and significantly improve symptoms of PD in mice. Our preliminary experiments revealed that ROCK1 could dephosphorylate/activate Drp1 through CaN, resulting in mitochondria aberrant fission, and eventually leading to PD. In this proposal, we aim to elucidate the molecular mechanism of ROCK1 via activation of Drp1-mediated neural cell mitochondrial aberrant fission in PD in vitro and in vivo, and confirm the therapeutic effect of ROCK1 inhibitor on PD. Our study will strengthen the understanding of the pathogenesis of PD and provide experimental evidence for the application of ROCK1 inhibitor in treating PD.