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（由申请人提供）：亨廷顿氏病（HD）是由以常染色体显性方式传播的基因突变引起的神经退行性痛苦。突变的继承是致命的。高清症状在中年出现，包括非自愿运动，精神障碍和认知障碍。大脑中受影响最严重的区域是脑皮质和基底神经节的皮质下核，尤其是尾状/鬼蛋白酶。目前，该疾病还没有令人满意的疗法，尽管在HD中受影响的基因和突变的性质已知近15年，但治愈的希望仍然很遥远。该疾病是由基因1中CAG重复膨胀区域扩展区域的遗传所引起的，该基因编码为无处理的蛋白质编码的功能较差，称为亨廷顿蛋白。亨廷顿蛋白N末端附近的膨胀的聚谷氨酰胺伸展由HD突变引起。尽管介导突变的神经毒性的分子机制仍然未知，但谷氨酰胺重复重复的数量与HD的发作年龄和HD的严重程度相关。在过去的十年中，对HD的分子遗传学的了解导致了创建HD转基因小鼠模型的令人兴奋的进步。我们建议利用这些模型中的两个（R6/2，YAC128）来进行系统级分析，以分析HD突变对体内基底神经节功能的影响，并特别强调变化的时间顺序。这种关注神经退行性基底神经节疾病功能的电路级变化的一部分是由类似推理（即开发有效的帕金森氏病症状治疗的发展），在这种症状上是尼古拉氏菌多巴胺（DA）细胞损失的主要病理，但已知神经毒性的分子依据仍然存在。在HD的人类和小鼠模型研究中，基底神经节途径的功能障碍也表明。我们将使用生化，解剖学和电生理方法在体内分析小鼠HD模型中黑性HD模型中的质纹状体和皮质DA系统的状态。对基底神经节（Globus Pallidus，丘脑核）的其他部位的生理研究将揭示电路中潜在的“下游”改变。我们假设这样的系统级别的理解（以前缺乏）将加快为这种毁灭性疾病的有症状治疗。公共卫生相关性：亨廷顿氏病（HD）是由于大脑选择性区域中脑细胞的遗传编程变性而引起的。这种退化会导致不受控制的运动，智力能力的丧失和情感障碍。 HD的频率为每100,000人4至7人，是一种家族疾病，通过正常基因的突变从父母到儿童传递。既然该基因已找到，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。