酿酒酵母中α-synuclein蛋白聚集诱导的细胞毒性的研究

Characterization of Aggregation-induced Toxicity by α-synuclein in Yeast

帕金森症(Parkinson's Disease,PD)是当今最为广泛的神经退行性疾病之一。研究显示,α-synuclein蛋白在帕金森症的发生过程中有着非常重要的作用。以酿酒酵母为模式系统,通过调控α-synuclein蛋白在胞内的表达量或改变其它一些可能影响α-synuclein聚集状态的因素,对α-synuclein蛋白在帕金森症的发生过程中可能的细胞毒性机制进行了研究。结果表明,α-synuclein蛋白的高水平表达会明显增强该蛋白因聚集所诱导的细胞毒性,而且这种细胞毒性与细胞代谢状态明显相关;超表达酿酒酵母分子伴侣YDR533C可以明显缓解α-synuclein蛋白异源表达对酵母生长的抑制。上述结果表明,蛋白折叠与折叠过程中的质量控制在α-synuclein蛋白聚集过程中有着非常重要的作用。

Parkinson＇s disease （PD） is the most common neurodegenerative movement disorder and α-synuclein plays an important role in its development. Using the genetically tractable Saccharomyces cere- visiae as a model system, the phenotypic repercussions and potential mechanisms of α-synuclein-induced cytotoxicity are characterized through modulating its expression level and other cellular factors. Aggregα- tion-induced toxicity is more dramatic upon elevated expression of α-synuclein than than induced at moder- ate levels of expression. The induced toxicity is also enhanced by reagents such as dimethyl sulfoxide, which increase intracellular levels of phospholipid and membrane, as well as ferrous ions and hydrogen peroxide, both of which cause oxidative stresses in yeast cells. In contrast, over-expression of yeast homologue of human chaperone DJ-1, YDR533C, markedly alleviate the inhibition of growth afflicted by exogenous expression of α-synuclein. Taken together, the data presented suggest a role for protein folding machinery together with quality control system in dealing with the aggregation of α-synuclein.