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

基底神经节在亨廷顿病中的功能：遗传小鼠模型

• 批准号: 8096619
• 负责人: ELIZABETH D. ABERCROMBIE
• 金额: $ 33.12万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8096619
• 关键词: Affect; Age; Age of Onset; Area; Basal Ganglia; Basal Ganglia Diseases; Biochemical; Biochemistry; Brain; CAG repeat; Cell Nucleus; Cells; Cerebral cortex; Child; Code; Corpus striatum structure; Development; Disease; Disease model; Distant; Dopamine; Electrophysiology (science); Emotional Disturbance; Exons; Faculty; Familial disease; Frequencies; Functional disorder; Gene Mutation; Genes; Genetic; Globus Pallidus; Glutamine; Goals; Health; Human; Huntington Disease; Impaired cognition; Involuntary Movements; Knowledge; Mediating; Modeling; Molecular; Molecular Genetics; Movement; Mus; Mutation; Nature; Nerve Degeneration; Neurons; Parents; Parkinson Disease; Pathology; Pathway interactions; Persons; Pharmaceutical Preparations; Physiological; Property; Proteins; Research Personnel; Severities; Site; Staining method; Stains; Stretching; Structure of subthalamic nucleus; Substantia nigra structure; Symptoms; Synapses; Synaptic Transmission; System; Testing; Tetrabenazine; Therapeutic Effect; Time; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; base; brain cell; dopamine system; dopaminergic neuron; extracellular; frontal lobe; human Huntingtin protein; in vivo; middle age; monoamine; mouse model; neurochemistry; neurotoxicity; pars compacta; polyglutamine; programs; putamen; response; transport inhibitor

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.

描述（申请人提供）：亨廷顿病（HD）是一种由常染色体显性遗传方式遗传的基因突变引起的神经退行性疾病。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层下核，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中受影响的基因和突变的性质已经知道了近15年。这种疾病是由编码一种普遍存在的功能知之甚少的蛋白质（称为亨廷顿蛋白）的基因的外显子1中CAG重复序列的扩展区域遗传引起的。亨廷顿蛋白的N-末端附近的扩展的多聚谷氨酰胺延伸由HD突变产生。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仍不清楚。在过去的十年中，知识的分子遗传学的HD导致了令人兴奋的进展，在创建转基因小鼠模型的HD。我们建议利用其中两个模型（R6/2，YAC 128）进行HD突变对基底神经节功能在体内的影响，特别强调变化的时间过程的系统水平的分析。这种对神经退行性基底神经节疾病中的回路水平的功能改变的关注部分受到类似推理的启发，即帕金森病的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学是已知的，但神经毒性的分子基础仍然不清楚。在HD的人类和小鼠模型研究中也表明基底神经节DA通路的功能障碍。我们将分析，在体内，黑质纹状体和中皮层DA系统在小鼠HD模型的生化，解剖和电生理方法的状态。对基底神经节其他部位（苍白球、丘脑底核）的生理学研究将揭示回路中潜在的“下游”改变。我们假设，这种系统水平的理解，以前缺乏，将加快发展对症治疗这种毁灭性的疾病。公共卫生相关性：亨廷顿病（HD）是由大脑特定区域的脑细胞遗传程序性变性引起的。这种退化会导致不受控制的运动，智力丧失和情绪困扰。HD的发病率为每10万人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。现在基因已经被定位，研究人员正在继续研究HD基因，目的是了解突变如何导致这种毁灭性的致命疾病。