Molecular Mechanism of Toxin-Induced Protein Misfolding

描述(申请人提供)：小分子毒素已被发现与许多蛋白质错误折叠疾病有关。以亚砷酸盐(As(111))为模型体系，分析环境毒素在体内改变全球蛋白质折叠的潜在作用。As(111)诱导蛋白质错误折叠的机制将通过比较在As(111)处理的细胞中被发现错误折叠的蛋白质和被发现在原位结合As(111)的蛋白质来评估。As(111)诱导的错误折叠将通过比较As(111)处理细胞中的错误折叠蛋白质和其他应激诱导剂处理的细胞中的错误折叠蛋白质来进一步表征，从而阐明As(111)诱导错误折叠的机制。使用本提案中概述的方法，还将研究综合应激反应和AIRAP在保护细胞免受As(111)毒性中的作用。这项工作不仅将为暴露于As(111)的众多易患人类疾病的人类群体确定潜在的治疗靶点，而且还将允许更好地了解环境毒素在使人们易患蛋白质错误折叠的衰老和神经退行性疾病中所起的作用。

DESCRIPTION (provided by applicant): Small molecule toxins have been found to be epidemiologically linked to a number of protein misfolding diseases. Using arsenite (As(lll)) as a model system, the potential role of environmental toxins on altering the global protein fold in vivo will be analyzed. The mechanism of As(lll)-induced protein misfolding will be evaluated by comparing the proteins found to be misfolded in As(lll)-treated cells and proteins that are found to bind As(lll) in situ. As(lll)-induced misfolding will be further characterized by comparisons between the misfolded proteins in As(lll) treated cells and misfolded proteins in cells treated with other stress- inducing agents, allowing the mechanism of As(lll)-induced misfolding to be elucidated. Using the methods outlined in this proposal, the role of the Integrated Stress Response and AIRAP in protecting cells against As(lll) toxicity will be also be examined. This work will not only identify potential therapeutic targets for the numerous human populations predisposed to human disease by As(lll) exposure, but it will also allow for a better understanding of the role environmental toxins play in predisposing populations to protein misfolding diseases of aging and neurodegeneration.