Protein fate in neurodegeneration: Investigations of novel regulatory mechanisms

描述(申请人提供)：大多数神经退行性疾病的一个特点是有毒的、错误折叠的蛋白质积累。更好地理解蛋白质命运决定是如何发生的，可能会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，但一个主要的悬而未决的问题仍然是：如何决定折叠或降解由伴侣和泛素系统产生的这些蛋白质？这项拟议的研究将检验一个总体假设，即一种特定的E2酶Ube2w通过快速使错误折叠的蛋白质单素化来调节蛋白质的命运。目的1将使用Ube2w基因敲除小鼠和牵张症小鼠模型来研究Ube2w在体内预测的神经保护作用。目标2将定义Ube2w快速将泛素附着到底物上的新机制。目标3将寻求建立底物蛋白的展开与Ube2w和其他E2结合泛素之间的直接关联。总之，这些目的将有助于阐明Ube2w在降解蛋白毒性蛋白方面的作用，并可能为了解其在对抗神经毒性方面的作用提供依据。

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.