锰（Mn）既是环境中比较常见的重金属污染物，又是帕金森病的环境致病因素之一。在锰诱导α-突触核蛋白（α-Syn）寡聚化过程中，神经细胞内的蛋白质量控制系统发挥了重要作用，但具体机制尚不清楚。本项目拟在申请人既往研究的基础上，进一步提出推断：锰诱导α-Syn蛋白过表达的早期，在未折叠蛋白反应和相关分子伴侣信号的作用下，泛素-蛋白酶体系统和自噬-溶酶体途径对异常α-Syn蛋白进行清除，以达到保护的作用；在锰的长期作用下，蛋白酶体活性被抑制；锰诱导的亚硝基化作用和α-Syn通过结合高迁移率族蛋白1（HMGB1）干扰自噬对异常蛋白的清除，导致α-Syn蛋白寡聚体出现。本项目将活细胞成像与双分子荧光互补（BiFC）技术相结合，通过对蛋白质量控制系统相关的蛋白分子及其相互作用的研究，揭示蛋白质量控制系统对锰诱导α-Syn蛋白寡聚化过程的调控作用，为锰神经毒作用机理的研究和治疗靶点提供科学的理论依据。

Manganese (Mn) is one of the common heavy metal pollutants in the environment and one of the environmental pathogenic factors of Parkinson's disease. The protein quality control system plays an important role in Mn-induced oligomerization of α-Synuclein (α-Syn) protein. But, the specific mechanisms are not clear. This project aims to, based on our previous research, further put forward inference: In the early stage of Mn-induced α-Syn protein overexpression, ubiquitin-proteasome system and autophagic-lysosomal pathway were activated by the action of unfolded protein response and related molecular chaperones in order to eliminating the abnormal α-Syn protein in the nerve cells; Under the action of Mn for a long time, the proteasome activity was inhibited; In addition, Mn-induced S-nitrosylation and the combination of the α-Syn protein and HMGB1 protein disturbed the ability of autophagy to the removal of abnormal proteins resulting in the emergence of α-Syn protein oligomers. Through the study of proteins associated with protein quality control systems and their interactions using live cell imaging and bimolecular fluorescence complementation technologies, this project will reveal that the protein quality control system play an important role in Mn-induced oligomerization of α-Syn protein. This project will provide a scientific theoretical basis for the mechanism study and therapeutic targets of Mn neurotoxicity.