Protein fate in neurodegeneration: Investigations of novel regulatory mechanisms

神经变性中的蛋白质命运：新型调节机制的研究

基本信息

批准号：
8382975
负责人：
Kenneth Matthew Scaglione
金额：
$ 9.87万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8382975
关键词：
Active Sites Affect Biochemical Biological Biological Assay Brain Brain Diseases Cells Cellular Stress Client Complex Cultured Cells Defect Development Disease Pathway Drug Delivery Systems Enzymes Event Half-Life Heat-Shock Proteins 70 Histologic In Vitro Investigation Kinetics Knock-out Knockout Mice Knowledge Laboratories LacZ Genes Lead Learning Luciferases Lysine Measures Mediating Mentors Messenger RNA Molecular Molecular Chaperones Monitor Mus Nerve Degeneration Neurodegenerative Disorders Neurons Pathway interactions Phase Play Prevention Proteins Quality Control Reporter Genes Research Research Personnel Role Stress System Tauopathies Testing Time To specify Toxic effect Training Transgenic Mice Ubiquitin Ubiquitin-Conjugating Enzymes Ubiquitination Wild Type Mouse Work aged deprotonation in vivo insight mouse model multicatalytic endopeptidase complex mutant neurotoxicity new therapeutic target novel pH gradient polypeptide programs protein degradation protein misfolding response tau Proteins therapy development ubiquitin ligase ubiquitin-protein ligase

项目摘要

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.

描述（由申请人提供）：大多数神经退行性疾病的标志是有毒，错误折叠蛋白的积累。更好地理解蛋白质命运如何确定可能揭示出新型的脑疾病治疗靶标。尽管关于神经元的蛋白质质量控制系统如何处理异常蛋白质的蛋白质质量控制系统已经了解了很多，但仍有一个未解决的问题仍然存在：如何折叠或降解由伴侣和泛素系统产生的这种蛋白质的决心？拟议的研究将检验总体假设，即特定的E2酶UBE2W通过迅速单液化错误折叠的蛋白质来调节蛋白质命运。 AIM 1将采用UBE2W敲除小鼠和Tauopathy的小鼠模型来研究UBE2W在体内预测的神经保护作用。 AIM 2将定义UBE2W迅速将泛素连接到底物的新型机制。 AIM 3将寻求建立底物蛋白的展开性与UBE2W和其他E2S的泛素附着之间的直接相关性。这些目的共同有助于阐明ube2W在降解蛋白质蛋白质中的作用，并可以洞悉其在对抗神经毒性中的作用。公共卫生相关性：这里提出的工作将促进我们对泛素和伴侣系统如何合作以确定错误折叠蛋白的命运的理解。这里进行的工作可能导致新的药物靶标，并增加我们对基本细胞途径如何保护神经元免受蛋白质毒性物种的理解。