Cdc42介导的神经元树突重塑在帕金森病发生中的作用

项目名称： Cdc42介导的神经元树突重塑在帕金森病发生中的作用

项目编号： No.81472166

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘怒云

作者单位： 南方医科大学

项目金额： 61万元

中文摘要： 神经元树突重塑异常在多种疾病发生发展中起重要作用。帕金森病(PD)核心问题是中脑多巴胺能神经元进行性变性。神经递质多巴胺匮乏导致PD患者纹状体区呈现异常树突重塑，表现为神经元树突棘密度显著下降等。小GTP酶Cdc42是Rho家族最受关注的分子之一。我们近期研究提示Cdc42在PD纹状体神经元树突重塑中发挥作用，但具体分子机制不清楚。为进一步探讨Cdc42在PD神经元树突重塑中的作用，本研究应用Cdc42功能获得性突变小鼠与纹状体特异性Cdc42基因敲除小鼠，集中探讨PD发生中，Cdc42是否调控神经元树突重塑及相关行为学变化；进一步，Cdc42通过何种下游效应分子发挥生物学效应。我们提出假说：PD发生中，多巴胺匮乏通过抑制Cdc42表达及活性，进一步影响Cdc42相关下游分子而诱导神经元树突重塑。上述问题的回答为进一步阐明Cdc42通路在PD中的作用，寻找新的治疗PD靶点和药物奠定基础。

中文关键词： 帕金森病；树突棘；重塑；Cdc42；效应分子

英文摘要： Parkinson's disease (PD) is a debilitating neurological disorder marked by progressive slowing of movements and difficulty in initiating them, and is caused by the degeneration of dopamine neurons in the midbrain and their axonal projections to the striatum. A key alteration that has been reported in various rodent models and PD patients is a significant reduction in striatal spine density. The striatal spine loss is an early pathological feature of PD, tightly linked with the degree of stratal DA deneration. Importantly,mainining normal strital pine density improves the therapeutic benefit induced by graftedDA neurons. The Rho family of small GTPases, including Rac, RhoA and Cdc42, are important regulators of the actin rearrangement which play key roles in dendritic morphogenesis. Althrough many investigations illustrate the importance of Rho family GTPase in dendritic morphogenesis, it remains unclear whether they also function to regulate the dendritic reorganization in PD. Our recent findings indicate that the induction of Cdc42 and Rac1 in the Cpu is important for cocaine exposure-induced remodeling of dendritic spines and behavioral plasticity. Meanwhile we found that activation of Cdc42 GTPase may restore the spine loss in PD mouse model. However, the precise molecular mechanisms leading to these morphological changes have yet to be fully investigated. These preliminary results lead us to hypothesize that Cdc42 plays key role in dendritic remodeling in PD. By using a complex methods, including the construction of striatum specific Rac1 knockout mice and the gain of function Cdc42 GAP gene targeted mice, we aimed at answer the following questions: whether Cdc42 GTPase signaling is involved in the structural plasticity in PD? And by what downstream effectors, the Cdc42 GTPase signaling regulate dendritic remodeling? The answers to these questions will provide further insight into the molecular and cellular mechanism of PD and may provide new leads to the development of novel therapeutics targeting Cdc42 GTPase signaling.

英文关键词： Parkinson's disease;spine;remodeling;Cdc42;effector molecular