Oxidation-dependent mutant huntingtin oligomers and Huntington's disease pathogen

氧化依赖性突变亨廷顿寡聚物和亨廷顿病病原体

• 批准号: 8023446
• 负责人: Jonathan H Fox
• 金额: $ 21.62万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8023446
• 关键词: Address; Alzheimer' s Disease; Anatomy; Automobile Driving; Behavioral; Biochemical; Biological Assay; Brain; C-terminal; Cell Culture System; Cells; Cleaved cell; Corpus striatum structure; Cysteine; Data; Dimerization; Disease; Disease Outcome; Disease Progression; Drug Delivery Systems; Enzymes; Exons; Foundations; Genes; Glutamine; Human; Huntington Disease; Intervention; Lead; Length; Light; Mediator of activation protein; Mus; N-terminal; Neocortex; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; Oxidoreductase; Pathogenesis; Point Mutation; Post-Translational Protein Processing; Process; Proteins; Research; Research Design; Resistance; Role; Site; Structure; Sulfhydryl Compounds; System; Toxic effect; Transferase; Wild Type Mouse; Work; behavior measurement; dimer; drug discovery; effective therapy; human Huntingtin protein; in vivo; monomer; mutant; new therapeutic target; novel; oxidation; pathogen; polyglutamine; protein aggregate; protein oligomer; public health relevance; research study

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a progressive and ultimately fatal neurodegenerative disease that afflicts about 30000 people in the USA and has no effective treatment. HD is caused by a CAG expansion within the huntingtin gene. Pathological hallmarks of HD are neuronal accumulation of soluble and aggregated misfolded huntingtin protein and neuronal degeneration primarily involving striatum and neocortex. There is accumulating evidence that soluble oligomers of mutant huntingtin protein (mhtt) are important mediators of HD pathogenesis. Our long-term objective is to define the role of mhtt oligomers in HD and to determine if interventions that decrease oligomer levels are neuroprotective in HD mice and provide an effective target for treating human HD. We have preliminary data demonstrating that some oligomers of mutant huntingtin form via site-specific oxidation of cysteine residues. These findings have led us to hypothesize that oxidation-dependent mhtt oligomers are important mediators of HD. In this proposal we plan to address the role of these oligomeric species in the pathogenesis of HD. In Aim 1 we will determine how HD progression is modified by blocking or accelerating mutant huntingtin dimerization in mouse striatum. Our hypothesis is that dimerization of mutant huntingtin promotes HD progression. We will use a lentiviral system to generate mice expressing forms of mutant N171-82Q huntingtin that dimerize or are dimerization resistant and evaluate behavioral, biochemical and anatomic disease outcomes. In Aim 2 we will screen using a cell culture system for a thiol transferase enzyme(s) that promotes conversion of soluble oligomeric huntingtin to monomer. We hypothesize that a thiol transferase that promotes this conversion will also secondarily result in decreased mutant huntingtin levels. The proposed studies will advance our understanding of the mechanisms underlying neurodegeneration in HD and could lead to the identification of new therapeutic targets. Because protein oligomers have been implicated in mechanisms underlying several neurodegenerative disorders, the proposed research could also shed light on these diseases.

描述（由申请人提供）：亨廷顿舞蹈症 (HD) 是一种进行性且最终致命的神经退行性疾病，在美国约有 30,000 人患有这种疾病，并且没有有效的治疗方法。 HD 是由亨廷顿基因内的 CAG 扩增引起的。 HD 的病理特征是可溶性和聚集的错误折叠亨廷顿蛋白的神经元积累以及主要涉及纹状体和新皮质的神经元变性。越来越多的证据表明，突变型亨廷顿蛋白 (mhtt) 的可溶性寡聚体是 HD 发病机制的重要介质。我们的长期目标是确定 mhtt 寡聚物在 HD 中的作用，并确定降低寡聚物水平的干预措施是否对 HD 小鼠具有神经保护作用，并为治疗人类 HD 提供有效靶标。我们的初步数据表明，突变亨廷顿蛋白的一些寡聚物是通过半胱氨酸残基的位点特异性氧化形成的。这些发现使我们推测氧化依赖性 mhtt 寡聚物是 HD 的重要介质。在本提案中，我们计划解决这些寡聚物种在 HD 发病机制中的作用。在目标 1 中，我们将确定如何通过阻断或加速小鼠纹状体中突变亨廷顿二聚化来改变 HD 进展。我们的假设是突变亨廷顿蛋白的二聚化促进 HD 进展。我们将使用慢病毒系统来生成表达突变型 N171-82Q 亨廷顿蛋白的小鼠，这些突变型 N171-82Q 亨廷顿蛋白可二聚化或具有二聚化抗性，并评估行为、生化和解剖疾病结果。在目标 2 中，我们将使用细胞培养系统筛选硫醇转移酶，该酶可促进可溶性寡聚亨廷顿蛋白转化为单体。我们假设促进这种转化的硫醇转移酶也会继而导致突变亨廷顿蛋白水平降低。拟议的研究将增进我们对 HD 神经变性机制的理解，并可能导致新治疗靶点的确定。由于蛋白质寡聚物与多种神经退行性疾病的机制有关，因此拟议的研究也可以揭示这些疾病。