突变型α-synuclein在小胶质细胞内或细胞间隙间的异常积聚可导致小胶质细胞的异常激活，由此介导的炎性损伤与PD的发生密切相关，但突变型α-synuclein发生异常积聚的机制尚未明确。小胶质细胞内正常的内体运输是保证α-synuclein降解，避免α-synuclein异常积聚的关键，我们前期研究发现小胶质细胞内突变型α-synuclein不能被有效地运输至晚期内体，且控制早期内体形态及功能的Rab5活性异常增高，提示突变型α-synuclein可能通过影响Rab及上游调节因子导致内体运输的障碍、蛋白降解的异常。本课题将在我们前期发现基础上，进一步探讨（1）导致小胶质细胞内突变型α-synuclein内体运输障碍的具体途径和相关分子机制；（2）上述相关内体运输调控因素的异常与小胶质细胞异常激活和PD发生的关系。课题的开展将帮助完善PD的炎性发病机制，为PD治疗新途径的探索提供帮助。

Both accumulation of mutant α-synuclein in or outside of microglial can lead to the abnormal activation of microglia and the subsequent inflammatory injury is closely related to the occurrence of PD. However, the mechanism underlying the abnormal accumulation has not yet been elucidated. As we know, regular endosomal transportation can guarantee the degradation of α-synuclein without abnormal accumulation. Our previous study found that mutant α-synuclein in microglia cannot be efficiently transported to the late endosomes and the activity of Rab5, a protein controlling the structure and function of the early endosomes, increased abnormally. These results suggested that mutant α-synuclein may affect some Rabs, along with its upstream regulatory factors, resulting in endosomal transportation obstacles and abnormal protein degradation. Base on our preliminary results, we propose in this project that we are going to further explore the following: (1) the specific pathways which lead to the blockage of the transportation of mutant α-synuclein in endosome of microglia and the related molecular mechanism; (2) the relationship between the abnormal regulation factors of the transport and the exceptional activation of microglia and PD pathogenesis. This project will replenish to the PD inflammatory pathogenesis and provide help to explore new avenues for the treatment of PD.