Rac1香叶酰香叶酰化修饰在帕金森病发生中的作用与分子机理研究

氧化应激致神经元焦亡与帕金森病（PD）的发生密切关联。氧化应激状态下，NADPH氧化酶复合物各调节亚基Rac1、p67phox和p47phox等先后募集于细胞膜上，进行动态组装进而活化产生过量H2O2诱导神经元焦亡。已有研究表明，Rac1香叶酰香叶酰化修饰后从胞浆易位于细胞膜发挥生物学作用。我们前期工作发现Rac1香叶酰香叶酰化修饰对NADPH氧化酶的活化，H2O2的过量产生，以及神经元的焦亡起重要调节作用，但其在PD中的作用机理尚待探究。本项目拟通过PD模型，综合研究Rac1香叶酰香叶酰化修饰动态调控NADPH氧化酶组装活化的分子机制，及其在过量H2O2产生介导神经元焦亡中的调节作用机理，深入探索Rac1香叶酰香叶酰化修饰在PD发生中的生物学功能，并评估相关药物及抑制剂在PD防治中可能的临床应用价值。我们的工作将为防治氧化应激诱导的PD发生提供新思路和新的潜在治疗靶点。

Oxidative stress induces neuronal pyroptosis which is closely related to Parkinson's disease (PD). Under oxidative stress, NADPH oxidase complex subunits Rac1, p67phox and p47phox recruit on the cell membrane to assemble and activate dynamically, resulting in excessive H2O2 which would induce neuronal pyroptosis. Recent studies have shown that Rac1 geranylgeranylation could locate on the cell membrane from the cytoplasm to perform biological functions. Our previous work has found that Rac1 geranylgeranylation played an important role in regulating the activation of NADPH oxidase, excessive production of H2O2 and neuronal pyroptosis, but its mechanism in PD remained to be explored. This project intends to study the molecular mechanism of Rac1 geranylgeranylation in the dynamic regulation of NADPH oxidase assembly and activation through PD models comprehensively, and its specific function in inducing excessive H2O2 which has mediated neuronal pyroptosis. It also explores the biological function of Rac1 geranylgeranylation in PD, and evaluates the potential clinical application value of drugs and inhibitors in the prevention and treatment of PD. Our work will provide a new approach and a potential therapeutic target for the prevention and treatment of PD which is induced by oxidative stress.