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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

基本信息

批准号：
8134748
负责人：
Jonathan H Fox
金额：
$ 14.01万
依托单位：
UNIVERSITY OF WYOMING
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8134748
关键词：
Address Alzheimer&apos 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 HDAC1 gene HDAC4 gene Health 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 research study

项目摘要

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）：亨廷顿氏病（HD）是一种进行性和最终致命的神经退行性疾病，在美国约有30000人患病，目前尚无有效的治疗方法。HD是由亨廷顿基因内的CAG扩增引起的。HD的病理学标志是可溶性和聚集性错误折叠亨廷顿蛋白的神经元积聚和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寡聚体在HD中的作用，并确定降低寡聚体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提供有效靶点。我们有初步的数据表明，一些寡聚体的突变亨廷顿形式通过位点特异性氧化的半胱氨酸残基。这些发现使我们假设氧化依赖性mhtt寡聚体是HD的重要介质。在这项提案中，我们计划解决的作用，这些寡聚体的物种在发病机制的HD。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蛋白二聚化来改变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产生表达突变型N171- 82 Q亨廷顿蛋白形式的小鼠，所述突变型N171- 82 Q亨廷顿蛋白二聚化或二聚化抗性，并评估行为、生化和解剖学疾病结果。在目的2中，我们将使用细胞培养系统筛选促进可溶性寡聚亨廷顿蛋白转化为单体的巯基转移酶。我们推测，巯基转移酶，促进这种转换也将其次导致减少突变亨廷顿蛋白水平。拟议的研究将推进我们对HD神经变性机制的理解，并可能导致新的治疗靶点的确定。由于蛋白质寡聚体与几种神经退行性疾病的潜在机制有关，因此拟议的研究也可以揭示这些疾病。