Protein fate in neurodegeneration: Investigations of novel regulatory mechanisms

摘要 大多数神经退行性疾病的一个特点是有毒的、折叠错误的堆积 蛋白质。更好地理解蛋白质命运的决定机制可能会揭示 退行性脑疾病的新治疗靶点。虽然我们已经学到了很多 关于神经元的蛋白质质量控制系统如何处理异常蛋白质，a 重大悬而未决的问题仍然是：如何下决心放弃或降低这种 由伴侣和泛素系统产生的蛋白质？拟议中的研究将检验 一种特定的E2酶Ube2w通过以下方式调节蛋白质命运的总体假设 快速单核苷酸错误折叠的蛋白质。目标1将使用Ube2w基因敲除小鼠 以及一种牵张症的小鼠模型，以研究Ube2w预测的神经保护作用 在活体内。目标2将定义Ube2w快速连接的新机制 泛素到底物。目标3将寻求建立两者之间的直接关联 底物蛋白的去折叠和Ube2w等分子对泛素的吸附 E2S。这些目标将有助于阐明Ube2w在降解蛋白毒素中的作用。 蛋白质，并可能提供对其在对抗神经毒性方面的作用的洞察。

Abstract 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.