Molecular Mechanism of Toxin-Induced Protein Misfolding

描述（由申请人提供）：小分子毒素已被发现在流行病学上与许多蛋白质错误折叠疾病有关。本文将以亚砷酸盐（As(ll)）为模型系统，分析环境毒素对体内整体蛋白折叠改变的潜在作用。通过比较在As（ll）处理的细胞中发现的错误折叠的蛋白质和在原位结合As（ll）的蛋白质，将评估As（ll）诱导的蛋白质错误折叠的机制。As（lll）诱导的错误折叠将通过比较As（lll）处理的细胞中的错误折叠蛋白和其他应激诱导剂处理的细胞中的错误折叠蛋白来进一步表征，从而阐明As（lll）诱导的错误折叠机制。使用本提案中概述的方法，综合应激反应和AIRAP在保护细胞免受As（ll）毒性中的作用也将被检查。这项工作不仅将确定潜在的治疗靶点，为众多人群易感的人类疾病的暴露，但它也将允许更好地理解环境毒素在易感人群的蛋白质错误折叠的老化和神经退行性疾病的作用。

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.