Basal Ganglia Functions in Huntington's Disease: Genetic Mouse Models

描述（由申请人提供）：亨廷顿氏病（HD）是一种神经退行性疾病，由常染色体显性遗传方式的基因突变引起。这种突变的遗传是致命的。HD的症状出现在中年，包括不自主运动、精神障碍和认知障碍。大脑中受影响最严重的区域是大脑皮层和基底神经节的皮质下核，特别是尾状核/壳核。目前还没有令人满意的治疗方法，治愈的希望仍然遥远，尽管事实上，HD的基因和突变的性质已经知道了近15年。这种疾病是由基因外显子1中CAG重复序列扩展区域的遗传引起的，该基因编码一种普遍存在的蛋白质，其功能尚不清楚，称为亨廷顿蛋白。亨廷顿蛋白N端附近的聚谷氨酰胺延伸是由HD突变引起的。谷氨酰胺重复序列的数量与HD的发病年龄和严重程度相关，但介导突变神经毒性的分子机制尚不清楚。在过去的十年中，对HD分子遗传学的了解已经导致HD基因修饰小鼠模型的创建取得了令人兴奋的进展。我们建议利用其中两种模型（R6/2, YAC128）在体内对HD突变对基底神经节功能的影响进行系统水平的分析，特别强调变化的时间过程。这种对神经退行性基底神经节疾病回路水平功能改变的关注部分受到类似推理的启发，即帕金森病有效对症治疗的发展，其中黑质纹状体多巴胺（DA）细胞损失的主要病理是已知的，但神经毒性的分子基础仍然不清楚。在人类和小鼠HD模型研究中也发现了基底神经节DA通路的功能障碍。我们将使用生化、解剖和电生理方法分析小鼠HD模型中黑质纹状体和中皮层DA系统的体内状态。对基底节区其他部位（白球、丘脑底核）的生理研究将揭示该回路中潜在的“下游”改变。我们假设，这种系统层面的理解，以前缺乏，将加速发展对症治疗这种毁灭性的疾病。公共卫生相关性：亨廷顿氏病（HD）是由大脑选择性区域的脑细胞遗传程序性变性引起的。这种退化导致不受控制的运动，智力丧失和情绪紊乱。HD的发病率为每10万人中有4到7人，是一种家族性疾病，通过正常基因的突变从父母传给孩子。现在这个基因已经被定位，研究人员正在继续研究HD基因，目的是了解这种突变是如何导致这种毁灭性的致命疾病的。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a neurodegenerative affliction caused by a genetic mutation that is transmitted in an autosomal dominant manner. Inheritance of the mutation is fatal. The symptoms of HD emerge in mid-life and include involuntary movement, psychiatric disturbance and cognitive impairment. The most severely affected areas of the brain are the cerebral cortex and the subcortical nuclei of the basal ganglia, in particular the caudate/putamen. There currently is no satisfactory therapy for the disease and the hope for a cure remains distant despite the fact that the gene affected in HD and the nature of the mutation have been known for nearly 15 years. The disease is caused by inheritance of an expanded region of CAG repeats in exon 1 of the gene coding for a ubiquitous protein of poorly understood function known as huntingtin. An expanded polyglutamine stretch near the N- terminus of the huntingtin protein results from the HD mutation. The number of glutamine repeats correlates with the age of onset and severity of HD although the molecular mechanisms mediating the neurotoxicity of the mutation remain unknown. During the past decade, knowledge of the molecular genetics of HD has led to exciting advances in the creation of genetically modified mouse models of HD. We propose to utilize two of these models (R6/2, YAC128) to conduct a systems-level analysis of the impact of the HD mutation on basal ganglia function in vivo with particular emphasis on the time-course of changes. This focus on circuit-level alterations of function in a neurodegenerative basal ganglia disease is inspired in part by analogous reasoning, i.e. the development of effective symptomatic treatments for Parkinson's disease, in which the primary pathology of nigrostriatal dopamine (DA) cell loss is known but the molecular basis of the neurotoxicity remains obscure. Dysfunction in basal ganglia DA pathways is also indicated in both human and mouse model studies of HD. We will analyze, in vivo, the status of the nigrostriatal and mesocortical DA systems in mouse HD models using biochemical, anatomical and electrophysiological approaches. Physiological studies of other sites in the basal ganglia (globus pallidus, subthalamic nucleus) will reveal potential "downstream" alterations in the circuitry. We hypothesize that such a systems-level understanding, previously lacking, will hasten development of symptomatic treatments for this devastating disease. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) results from genetically programmed degeneration of brain cells in selective areas of the brain. This degeneration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance. HD has a frequency of 4 to 7 per 100,000 persons and is a familial disease, passed from parent to child through a mutation in the normal gene. Now that the gene has been located, investigators are continuing to study the HD gene with the goal of understanding how the mutation causes this devastating fatal disorder.