Dopamine Toxicity in Models of Huntington's Disease

描述(改编自申请人的摘要)：这项工作的总体目标 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]。亨廷顿氏病是一种 进行性神经退行性疾病，其发病机制[不] 完全理解。在亨廷顿病患者中，有一种 编码亨廷顿蛋白的基因突变，导致一种 扩增的聚谷氨酰胺序列导致基底节变性。 越来越多的证据表明，递质多巴胺的新陈代谢 单胺氧化酶，在细胞中存在潜在的代谢缺陷 存在，可能导致一系列事件，导致神经元功能障碍和 死亡。具体目标1。将决定多巴胺增强的程度， MAO抑制剂减弱氧化应激参数，线粒体 神经元培养中的功能和神经元死亡及用药的小鼠 线粒体抑制剂3-硝基丙酸。的优势 3-硝基丙酸为亨廷顿病提供了一种模型 这是由于能源生产中相对“纯粹”的缺陷造成的。具体目标2， 将研究多巴胺和MAO抑制剂对这些同样的影响 全长突变型亨廷顿蛋白和亨廷顿蛋白基因在PC6细胞中的表达 用不同长度的聚谷氨酰胺扩增的细胞。它的用途 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及特异性的关系 突变的亨廷顿蛋白--对DA的易感性有待确定。最后， 具体目标3将确定多巴胺是否增强，MAO抑制剂 减轻/延迟，生化和神经病理以及行为学 第一外显子转基因小鼠的畸形和存活 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氏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来治疗 这种紊乱。

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.