Dopamine Toxicity in Models of Huntington's Disease

亨廷顿病模型中的多巴胺毒性

• 批准号: 6361950
• 负责人: William F Maragos
• 金额: $ 21.72万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6361950
• 关键词: Huntington's disease; amine oxidase (flavin); brain metabolism; corpus striatum; dihydroxyphenylalanine; disease /disorder model; dopamine; enzyme activity; enzyme inhibitors; free radical oxygen; gene targeting; genetically modified animals; glia; laboratory mouse; mitochondria; nerve /myelin protein; neurons; neuropharmacology; oxidative stress; tissue /cell culture

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（改编自申请人摘要）：本研究的总体目标 应用是阐明多巴胺和单胺酶的作用， 亨廷顿病模型中的氧化酶[HD]。亨廷顿病是一种 进行性神经退行性疾病，其发病机制[不是] 完全理解在患有亨廷顿病的患者中， 编码亨廷顿蛋白的基因发生突变，导致 扩展的多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，多巴胺的代谢递质由 单胺氧化酶，在细胞中，其中潜在的代谢缺陷 存在，可能导致级联事件，导致神经元功能障碍， 死亡具体目标1.会决定多巴胺增强的程度， 和单胺氧化酶抑制剂减弱，氧化应激参数，线粒体 在神经元培养物和用所述化合物处理的小鼠中， 线粒体抑制剂3-硝基丙酸。的优点 3-硝基丙酸的另一个优点是它提供了一个亨廷顿病的模型 这是由能量产生中相对“纯”的缺陷造成的。具体目标2， 将研究多巴胺和单胺氧化酶抑制剂对这些相同的影响， 转染全长突变亨廷顿蛋白的PC6细胞中的参数， 用不同长度的多聚谷氨酰胺扩增转染的细胞。使用 这些不同的结构将允许“剂量-反应”关系 多聚谷氨酰胺长度与待测毒性之间的关系以及特异性 突变亨廷顿基因对多巴胺的易感性。最后， 具体目标3将确定多巴胺是否增强，而MAO抑制剂 减弱/延迟，生物化学和神经病理学以及行为 第一外显子转染的转基因小鼠中， 亨廷顿基因这些研究的结果将证明关键的 多巴胺代谢在亨廷顿舞蹈症纹状体神经元死亡中的作用 并提供了一种潜在的新的治疗方法，用于治疗 这种混乱。