Posttranslational Modification of Deubiquitinating Enzymes in Neurodegeneration

神经变性中去泛素化酶的翻译后修饰

• 批准号: 7738174
• 负责人: Sokol Todi
• 金额: $ 8.56万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7738174
• 关键词: Affect; Alzheimer' s Disease; American; Animals; Behavioral; Binding Sites; Biochemistry; Biological Models; Biology; Brain; Catalytic Domain; Cell model; Cell physiology; Cells; Cellular Stress; Cellular biology; Cessation of life; Deubiquitinating Enzyme; Deubiquitination; Development; Disease; Disease model; Drosophila genus; Enzymes; Eye; Family; Foundations; Future; Genetic; Graduate Education; Health; Human; Human Genome; Huntington Disease; Impairment; In Vitro; Investigation; Knowledge; Laboratories; Link; Lysine; MJD1 protein; Machado-Joseph Disease; Manuscripts; Mentors; Mentorship; Michigan; Modeling; Modification; Mutate; Mutation; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurosciences; Parkinson Disease; Pathology; Pathway interactions; Phase; Physiological; Play; Positioning Attribute; Post-Translational Protein Processing; Preparation; Principal Investigator; Process; Protein Biochemistry; Proteins; Quality Control; Regulation; Reporting; Research; Role; Scientist; Site; Spinocerebellar Ataxias; Stress; Students; System; Techniques; Tissues; Training; Ubiquitin; Ubiquitination; Work; age related; base; enzyme activity; fly; in vivo; insight; meetings; mouse model; neurotoxic; offspring; polyglutamine; protein degradation; protein misfolding; public health relevance; response; skills; ubiquitin ligase

DESCRIPTION (provided by applicant): Neurodegeneration is closely linked to perturbations in protein quality control (PQC). Ubiquitin pathways are central to PQC through their role in protein degradation. Here, I will investigate how deubiquitinatng enzymes (DUBs), integral components of ubiquitin pathways, are regulated by ubiquitination and how ubiquitination in turn affects their roles in PQC. These studies focus initially on a unique DUB and polyglutamine disease protein, ataxin-3 (ATS), and later will be extended to other brain-expressed DUBs. Mentored Phase (Dr. Henry Paulson; Univ. of Michigan): ATS is a deubiquitinating enzyme that functions in PQC. Mutations in ATS cause Spinocerebellar Ataxia Type S. I have collected evidence that ATS is ubiquitinated and its ubiquitinaion increases in proteotoxic stress. Importantly, ubiquitination directly enhances ATS activity. Here, I will determine where ATS is ubiquitinated, how ubiquitination activates it, and examine changes in ATS ubiquitination in neurodegeneration. As ubiquitination may regulate DUBs generally, I will also study ubiquitination of other brain-expressed DUBs (JosDI & 2, USP25, 28 & S7), strong contenders for this type of regulation. Together with training in neurodegeneration and biochemistry, student mentorship, presentation of my work at various meetings, and manuscript preparation, these studies will prepare me for an independent academic position. Independent Phase: Catalytically active ATS is neuroprotective in fly models of neurodegeneration. I will generate Drosophila lines expressing wild type or non-ubiquitinatable forms of ATS throughout the nervous system or in the eye. Through structural, behavioral and physiological studies I will examine whether ATS ubiquitination is important to its neuroprotective role in intact animals. I will also extend findings from the Mentored Phase to determine if ubiquitination of other DUBs regulates their activity and their relation to PQC. Indeed, very little is known about DUB function and regulation in neurons. Together with continued development of my knowledge and skills as an independent scientist and mentor, this research will provide strong foundations for a lab that studies a family of enzymes that is important to all ubiquitin pathways. PUBLIC HEALTH RELEVANCE: Age-dependent neurodegeneration affects millions of Americans. Here, I propose to investigate mechanisms important in protecting neurons against toxic proteinaceous agents that accumulate in the brain.

描述(由申请人提供)： 神经变性与蛋白质质量控制(PQC)中的扰动密切相关。泛素途径通过其在蛋白质降解中的作用而对PQC起着中心作用。在这里，我将研究去泛素化酶(DUBS)是如何受泛素化调节的，以及泛素化如何反过来影响它们在PQC中的作用。这些研究最初集中在一种独特的Dub和多谷氨酰胺疾病蛋白ataxin-3(ATS)上，后来将扩展到其他大脑表达的Dub。指导阶段(亨利·保尔森博士；大学：ATS是一种脱泛素酶，在PQC中发挥作用。ATS的突变导致脊髓小脑性共济失调S型。我收集的证据表明，ATS是泛素化的，它的泛素化在蛋白毒性应激中增加。重要的是，泛素化直接增强ATS活性。在这里，我将确定ATS在哪里泛素化，泛素化如何激活它，并检查神经退行性变中ATS泛素化的变化。由于泛素化一般可以调节Dub，我也将研究其他大脑表达的Dub的泛素化(JosDI&2，USP25，28&S7)，这是这种类型调节的有力竞争者。再加上神经退行性变和生物化学方面的培训，学生指导，在各种会议上展示我的工作，以及手稿准备，这些研究将为我成为一个独立的学术职位做好准备。独立期：在神经变性的果蝇模型中，催化活性ATS具有神经保护作用。我将产生在整个神经系统或眼睛中表达野生型或非无处不在形式的ATS的果蝇株。通过结构、行为和生理学研究，我将检验ATS泛素化是否对其在完整动物中的神经保护作用重要。我还将扩展指导阶段的研究结果，以确定其他DUB的泛素化是否调节它们的活性以及它们与PQC的关系。事实上，人们对神经元的Dub功能和调控知之甚少。随着我作为一名独立科学家和导师的知识和技能的不断发展，这项研究将为研究一系列对所有泛素途径都很重要的酶的实验室提供坚实的基础。公共卫生相关性：影响数百万美国人的年龄依赖性神经退行性变。在这里，我建议研究在保护神经元免受大脑中积累的有毒蛋白质类物质的影响方面的重要机制。