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

描述(申请人提供)：亨廷顿病(HD)是一种神经退行性疾病，由常染色体显性遗传的基因突变引起。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。大脑受影响最严重的区域是大脑皮层和基底节的皮质下核，特别是尾状核/壳核。目前，这种疾病还没有令人满意的治疗方法，尽管受HD影响的基因和突变的性质已经知道了近15年，但治愈的希望仍然遥远。这种疾病是由基因第一外显子中CAG重复序列的扩展区域遗传引起的，该基因编码了一种功能鲜为人知的普遍存在的蛋白质，称为亨廷顿蛋白。HD突变导致亨廷顿蛋白N端附近延伸出一条扩张的聚谷氨酰胺。谷氨酰胺重复的数量与HD的发病年龄和严重程度相关，尽管介导该突变神经毒性的分子机制尚不清楚。在过去的十年中，HD的分子遗传学知识在创建HD的转基因小鼠模型方面取得了令人兴奋的进展。我们建议利用其中的两个模型(R6/2，YAC128)在体内对HD突变对基底节功能的影响进行系统水平的分析，并特别强调变化的时间过程。这种对神经退行性基底节疾病电路水平功能改变的关注在一定程度上是受到类比推理的启发，即开发出有效的帕金森病对症治疗方法，其中黑质纹状体多巴胺(DA)细胞丢失的主要病理已知，但神经毒性的分子基础仍不清楚。在人类和小鼠的HD模型研究中，也表明基底神经节DA通路功能障碍。我们将使用生化、解剖学和电生理学的方法，在体内分析小鼠HD模型中黑质纹状体和中皮质DA系统的状态。对基底节其他部位(苍白球、丘脑底核)的生理学研究将揭示回路中潜在的“下游”变化。我们假设，以前缺乏的这种系统水平的理解将加速这种毁灭性疾病的对症治疗的发展。与公共卫生相关：亨廷顿病(HD)是由大脑选择性区域的脑细胞遗传程序性退化引起的。这种退化会导致不受控制的运动、智力丧失和情绪障碍。HD的发病率为每10万人中有4至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。现在基因已经定位，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.