Dopamine Toxicity in Models of Huntington's Disease

亨廷顿病模型中的多巴胺毒性

基本信息

批准号：
6761866
负责人：
William F Maragos
金额：
$ 28.96万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2006-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (Adapted from applicant's abstract): The overall goal of this application is to elucidate the roles of dopamine and the enzyme monoamine oxidase in models of Huntington's disease [HD]. Huntington's disease is a progressive neurodegenerative disorder, the pathogenesis of which is [not] completely understood. In patients with Huntington's disease, there is a mutation in the gene encoding the protein huntingtin, which results in an expanded polyglutamine sequence leading to degeneration of the basal ganglia. There is mounting evidence that metabolism of the transmitter dopamine by the enzyme monoamine oxidase, in cells in which an underlying metabolic defect exists, may lead to a cascade of events resulting in neuronal dysfunction and death. Specific Aim 1. Will determine the degree to which dopamine enhances, and MAO inhibitors attenuate, parameters of oxidative stress, mitochondrial function and neuron death in neuronal culture and mice treated with the mitochondrial inhibitor 3-nitropropionic acid. The advantage of 3-nitropropionic acid is that it provides a model of Huntington's disease resulting from relatively "pure" defect in energy production. Specific Aim 2, will examine the effects of dopamine and MAO inhibitors on these same parameters in PC6 cells transfected with full- length mutant huntingtin and cells transfected with differing lengths of polyglutamine expansions. The use of these different constructs will allow the "dose-response" relationship between polyglutamine length and toxicity to be determined and the specificity of mutant huntingtin-conferred susceptibility to DA to be established. Lastly, Specific Aim 3 will determine whether dopamine enhances, and MAO inhibitors attenuate/delay, the biochemical and neuropathological as well as behavioral abnormalities and survive in transgenic mice transfected with the first exon of the huntingtin gene. The results of these studies will demonstrate the critical role that metabolism of dopamine plays in striatal neuron death in Huntington's disease and offer a potentially novel therapeutic approach for the treatment of this disorder.

描述（改编自申请人的摘要）：此的总体目标应用是阐明多巴胺和单胺的作用亨廷顿氏病模型中的氧化酶[HD]。亨廷顿氏病是进行性神经退行性疾病，其发病机理是[非] 完全理解。在亨廷顿氏病的患者中，有一个编码蛋白质狩猎蛋白的基因突变，这导致了扩展的聚谷氨酰胺序列导致基底神经节变性。有越来越多的证据表明发射机多巴胺的代谢酶单胺氧化酶，在细胞中，潜在的代谢缺陷存在，可能导致一系列事件导致神经元功能障碍和死亡。特定目标1。将确定多巴胺增强的程度， MAO抑制剂减弱，氧化应激的参数，线粒体神经元培养的功能和神经元死亡和用线粒体抑制剂3-硝基离子酸。优势 3-亚硝基离子酸是它提供了亨廷顿氏病的模型由于能源生产中相对“纯”缺陷而产生的。具体目标2，将检查多巴胺和MAO抑制剂对这些的影响 PC6细胞中的参数，用全长突变体亨廷顿蛋白和用不同长度的聚谷氨酰胺膨胀转染的细胞。使用在这些不同的构造中，将允许“剂量反应”关系在多谷氨酰胺长度和要确定的毒性和特异性之间建立对DA的突变亨特蛋白限制的敏感性。最后，特定的目标3将确定多巴胺是否增强和MAO抑制剂衰减/延迟，生化和神经病理学以及行为异常和在转染的第一个外显子转染的转基因小鼠中生存亨廷顿基因。这些研究的结果将证明关键多巴胺代谢在亨廷顿的纹状体神经元死亡中起作用的作用疾病并提供一种潜在的新型治疗方法来治疗这个疾病。