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标志是有毒的错误折叠蛋白质的积累。更好地了解蛋白质命运决定如何发生，可能会揭示退行性脑疾病的新治疗靶点。虽然已经了解了很多关于神经元的蛋白质质量控制系统如何处理异常蛋白质，一个主要的未解决的问题仍然是：如何决定折叠或降解这些蛋白质的伴侣和泛素系统？拟议的研究将测试一个特定的E2酶，Ube2w，通过快速monoubiquitinating错误折叠的蛋白质调节蛋白质命运的总体假设。目的1将使用Ube2w敲除小鼠和tau蛋白病小鼠模型来研究Ube2w的预测的体内神经保护作用。目标2将定义Ube2w快速连接泛素底物的新机制。目的3将寻求建立底物蛋白的未折叠性与Ube2w和其他E2的泛素附着之间的直接相关性。这些目标将有助于阐明Ube2w在降解蛋白毒性蛋白质中的作用，并可能深入了解其在对抗神经毒性中的作用。

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.