帕金森病相关α-突触核蛋白的纤维状聚集形成和降解机制

帕金森病的主要病理学依据是大脑中黑质区多巴胺能神经元的缺失和大脑各区域出现路易氏小体。路易氏小体是细胞内的包涵体，混杂了大量的高度纤维化的α-突触核蛋白以及其它一些蛋白如泛素等。在分子水平，α-突触核蛋白的基因突变和多拷贝表达是造成细胞毒性并引起帕金森病的常见原因，而这又通常与自噬-溶酶体途径的失调密切相关。这些提示在机体老化的过程中，由于细胞内蛋白质质量控制体系逐步失活，造成毒性蛋白在细胞中的逐年累积，最终形成不可逆的细胞死亡。但是，对α-突触核蛋白如何形成病态构像及如何清除体内的病态聚集却还未可知。本项目将通过以α-突触核蛋白作为模式底物，来研究 1)如何利用蛋白质质量控制体系修复和清除致病α-突触核蛋白? 2)α-突触核蛋白如何由正常状态转变为细胞毒性状态? 3)路易氏小体到底是细胞毒性还是一种保护机制? 我们希望通过对上述问题的系统研究，为帕金森症的治疗找到分子依据。

Parkinson's disease (PD) is a long-term degenerative disorder of central nervous system that mainly affects the motor system, diagnosed by dopaminergic cells loss within the substantia nigra pars compacta in association with the development of intracytoplasmic, protein rich inclusions termed Lewy's body in other brain area. The classic Lewy’s body is spherical and contains fibrillar α-synuclein as well as its associated proteins such as ubiquitin. At the genetic level, Parkinson disease is correlated with α-synuclein mutation and gene dosage variations, as well as the disturbance in the autophagy-lysosome pathway. The collapse of protein quality control with age results in the accumulation of misfolded proteins, which disrupt the cellular homeostasis and eventually lead to cell death. However, it is still unknown the pathogenesis of α-synuclein aggregates as well as the aggregates degradation mechanism. In this proposal, we will mainly focus on the study of α-synuclein to dissect 1) What the mechanism is underlying the clearance of toxic α-synuclein by the protein quality control system? 2) How α-synuclein is transformed from the functional protein to fibrillar aggregates? 3) whether Lewy's body is toxic to cell or a protective mechanism? Only by answering these questions, can we harness the information to develop new therapeutics for Parkinson disease.