帕金森病相关蛋白parkin对突触核蛋白降解的调控作用及其致病机制

In dementia with Lewy bodies (DLB) and Parkinson's disease (PD) alpha-synuclein is the main component of inclusion bodies in neurons and glial cells. Beta-synuclein WT protects against alpha-synuclein-induced neurodegeneration. Beta-syn P123H mutant is prone to aggregation and causes mitochondrial damage and cell death. As E3 ubiquitin protein ligase, Parkinsons related protein parkin is involved in the process of beta-syn P123H synucleinopathies and autophagy, although it is not clear the mechanisms, roles and pathogenesis of parkin on beta-syn P123H degradation by autophagy-lysosome pathway (ALP)...This project will focus on the mechanisms and regulation of parkin on synuclein degradation in synucleinopathies of beta-syn P123H stable cells and transgenic mice model. In the experiment we explore the effects of autophagy on beta-syn degradation and neurodegeneration, investigate the direct or indirect interactions of parkin, synuclein and potential ubiquitinated protein in synucleinopathies, in which probing the new posible target sites. We also determine the cause of beta-syn degradation mediated by pakin, analyze the relations among parkin, synuclein and UPS...In brief through the project it will provide us the new theory and stratagy of medical therapy for DLB and Parkinson's disease.

在路易小体痴呆和帕金森病患者，α-syn是神经元和胶质细胞包涵体主要成分。Beta-syn WT对α-syn诱导的神经元退化有保护作用，而突变体P123H易于聚集并导致线粒体损伤和细胞死亡。PD相关分子Parkin参与beta-synP123H突触核蛋白病理学和细胞自噬过程，但其机理和对syn蛋白降解的作用尚不清楚。本研究将在稳定表达beta-syn P123H细胞系和转基因小鼠上进行。实验将探讨parkin在突变beta-syn蛋白病理变化过程中的作用、机制及影响因素，研究parkin参与的细胞自噬对蛋白降解和神经细胞退化的影响，分析在synucleinopathies病理变化过程中parkin和synuclein的相互作用，明晰parkin介导的synuclein蛋白降解机理，确定parkin、synuclein降解与UPS的关系，从而为LB痴呆及PD病人的药物治疗提供理论基础和靶点。

在路易小体痴呆和帕金森病患者，α-syn是神经元和胶质细胞包涵体主要成分。Beta-syn WT对α-syn诱导的神经元退化有保护作用，而突变体P123H易于聚集并导致线粒体损伤和细胞死亡。PD相关分子Parkin参与beta-synP123H突触核蛋白病理学和细胞自噬过程，但其机理和对syn蛋白降解的作用尚不清楚。本研究将在稳定表达beta-syn P123H细胞系和转基因小鼠上进行。实验将探讨parkin在突变beta-syn蛋白病理变化过程中的作用、机制及影响因素，研究parkin参与的细胞自噬对蛋白降解和神经细胞退化的影响，分析在突触核蛋白病理变化过程中parkin和synuclein相互作用，明晰parkin介导的synuclein蛋白降解机理。研究结果显示野生型和突变型Parkin在细胞内分布特征不同。Parkin突变体在细胞内聚集，使线粒体膜电位降低以及片段化，且不能募集到去极化线粒体上。 Parkin与PINK1一起参与线粒体质量控制。Parkin调控mTOR通路调节自噬，促使突触核蛋白β-syn P123H进入自噬体和溶酶体降解，而Parkin突变抑制突触核蛋白降解，促进蛋白胞浆内累积，增强路易体痴呆相关的神经退化。提示Parkin在帕金森病蛋白降解调控中起重要作用，其为LB痴呆及PD病人的药物治疗提供理论基础和靶点。