Protein fate in neurodegeneration: Investigations of novel regulatory mechanisms

描述（由申请人提供）：大多数神经退行性疾病的一个标志是有毒的、错误折叠的蛋白质的积累。更好地了解蛋白质命运决定如何发生可能揭示退行性脑疾病的新治疗靶点。虽然关于神经元的蛋白质质量控制系统如何处理异常蛋白质已经了解了很多，但一个主要的未解决的问题仍然存在：伴侣蛋白和泛素系统如何决定折叠或降解这些蛋白质？拟议的研究将测试一个整体假设，即特定的E2酶Ube2w通过快速单泛素化错误折叠的蛋白质来调节蛋白质的命运。目的1将使用Ube2w基因敲除小鼠和小鼠损伤模型来研究Ube2w在体内预测的神经保护作用。目的2将定义Ube2w快速将泛素附着在底物上的新机制。目的3将寻求建立底物蛋白的展开性与Ube2w和其他E2s对泛素的附着之间的直接关系。总之，这些目标将有助于阐明Ube2w在降解蛋白毒性蛋白中的作用，并可能为其在对抗神经毒性中的作用提供见解。

DESCRIPTION (provided by applicant): A hallmark of most neurodegenerative diseases is the accumulation of toxic, misfolded proteins. A better understanding of how protein fate determination occurs may reveal novel therapeutic targets for degenerative brain diseases. While much has been learned about how the protein quality control system of neurons handles abnormal proteins, a major unresolved question remains: How is the determination to fold or degrade such proteins made by the chaperone and ubiquitin systems? The proposed studies will test the overall hypothesis that a specific E2 enzyme, Ube2w, regulates protein fate by rapidly monoubiquitinating misfolded proteins. Aim 1 will employ Ube2w knockout mice and a mouse model of tauopathy to investigate Ube2w's predicted neuroprotective role in vivo. Aim 2 will define the novel mechanism by which Ube2w rapidly attaches ubiquitin to substrates. Aim 3 will seek to establish a direct correlation between the unfoldedness of a substrate protein and the attachment of ubiquitin by Ube2w and other E2s. Together these aims will help elucidate the role of Ube2w in degrading proteotoxic proteins and may provide insight into its role in countering neurotoxicity. PUBLIC HEALTH RELEVANCE: The work proposed here will advance our understanding of how the ubiquitin and the chaperone systems collaborate to determine the fate of misfolded proteins. The work performed here may lead to novel drug targets and increase our understanding of how basic cellular pathways function to protect neurons from proteotoxic species.