PGC-1alpha and GABAergic Dysfunction in Huntington Disease

亨廷顿病中的 PGC-1α 和 GABA 能障碍

• 批准号: 8451477
• 负责人: Rita Marie Cowell
• 金额: $ 30.31万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8451477
• 关键词: Ablation; Affect; Age; Age of Onset; Animals; Antioxidants; Behavior; Behavioral; Brain; Buffers; Calcium; Calcium Signaling; Cell Culture Techniques; Cells; Cessation of life; Corpus striatum structure; Data; Defect; Deterioration; Disease; Enzymes; Exons; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Glucose Transporter; Glutamate Decarboxylase; Goals; Hereditary Disease; Hippocampus (Brain); Homeostasis; Huntington Disease; Interneuron function; Interneurons; Knockout Mice; Light; Long-Term Potentiation; Measures; Mediating; Metabolic; Mitochondria; Modeling; Morphology; Motor; Motor output; Mus; Muscle; Neurons; Parvalbumins; Pathway interactions; Patients; Pattern; Peroxisome Proliferator-Activated Receptors; Population; Property; Regulation; Research Personnel; Respiration; Role; Scientist; Severities; Signal Transduction; Specificity; Staging; Structure; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Up-Regulation; base; effective therapy; feeding; hippocampal pyramidal neuron; human Huntingtin protein; immunoreactivity; interest; motor control; motor deficit; mouse model; mutant; nervous system disorder; nestin protein; overexpression; promoter; public health relevance; putamen; reconstitution; research study

DESCRIPTION (provided by applicant): Huntington's Disease (HD) is a debilitating genetic disorder involving progressive deterioration of psychiatric and motor function over a period of years, leading to death. Studies indicate that the expression of the transcriptional co-activator peroxisome proliferator activated receptor co-activator 1 (PGC-1) is decreased in striatum and muscle tissue from patients with HD and that mutant huntingtin (mHtt) interferes with normal expression and activity of PGC-1. Furthermore, polymorphisms in the PGC-1 gene influence the age of onset of motor symptoms. In light of the proposed role for PGC-1 in metabolic regulation, scientists have hypothesized that deficiencies in PGC-1 contribute to neuronal vulnerability and mitochondrial defects in HD. The roles of PGC-1 in the brain are not well-defined. PGC-1 is concentrated specifically in neurons that express the enzyme glutamic acid decarboxylase 67 (GAD67), and new data from the Cowell lab indicate that PGC-1 is required for the appropriate expression of the calcium buffer parvalbumin. Furthermore, PGC-1 null animals show abnormalities in GABAergic signaling, long-term potentiation, and motor function. Preliminary studies show that PGC-1 is consistently downregulated in cell culture models of HD, and the expression of PGC-1 and its targets parvalbumin and glucose transporter 4 are decreased in the striatum, hippocampus, and cortex in a mouse model. These data are interesting, considering that parvalbumin-positive (PV+) interneuron function is compromised in the cortex prior to the onset of motor symptoms in mouse models of HD. In addition, because of the strong feed-forward inhibitory effect PV+ neurons exert on medium spiny neurons and cortical pyramidal neurons, even slight disturbances in PV+ neuron function could profoundly influence striatal/cortical output and motor function. We propose that a deficiency in PGC-1 predisposes PV+ neurons to vulnerability in HD and compromises their ability to properly inhibit local projection neurons and coordinate motor output. The experiments proposed in this application will test this hypothesis by determining 1) the requirement for PGC-1 in striatal PV+ interneuron survival, morphology, signaling, calcium homeostasis, and motor function, 2) the effects of PGC-1 ablation on other vulnerable neuronal populations in the striatum, 3) the regional and cellular specificity of changes in PGC-1 and PGC-1-target gene expression in mouse models of HD, and 4) the impact of PGC-1 overexpression on cellular survival and motor function in a mouse model of HD. The proposed experiments are necessary to determine the cell autonomous and non-cell autonomous effects of PGC-1 dysfunction on neuronal viability and function with the goal of determining whether PGC-1 is an appropriate target for the treatment of HD.

描述（由申请人提供）：亨廷顿氏病（HD）是一种使人衰弱的遗传性疾病，涉及精神和运动功能在数年内进行性恶化，导致死亡。研究表明转录共激活因子过氧化物酶体增殖物激活受体共激活因子1（PGC-1）的表达在HD患者的纹状体和肌肉组织中降低，突变型亨廷顿蛋白（mHtt）干扰PGC-1的正常表达和活性。此外，PGC-1基因的多态性影响运动症状发作的年龄。鉴于PGC-1在代谢调节中的作用，科学家们假设PGC-1的缺陷导致HD中的神经元脆弱性和线粒体缺陷。 PGC-1在大脑中的作用尚未明确。PGC-1特别集中在表达谷氨酸脱羧酶67（GAD 67）的神经元中，来自Cowell实验室的新数据表明，PGC-1是钙缓冲剂小清蛋白适当表达所必需的。此外，PGC-1缺失动物显示GABA能信号传导、长时程增强和运动功能异常。初步研究表明，在HD的细胞培养模型中，PGC-1始终下调，并且在小鼠模型中，纹状体、海马和皮质中PGC-1及其靶标小清蛋白和葡萄糖转运蛋白4的表达降低。这些数据是有趣的，考虑到小清蛋白阳性（PV+）中间神经元功能受损之前，在HD小鼠模型的运动症状发作的皮质。此外，由于PV+神经元对中等棘神经元和皮质锥体神经元施加的强前馈抑制作用，即使PV+神经元功能的轻微干扰也会深刻地影响纹状体/皮质输出和运动功能。我们认为，PGC-1的缺陷使PV+神经元易受HD的影响，并损害了它们适当抑制局部投射神经元和协调运动输出的能力。 本申请中提出的实验将通过确定1）纹状体PV+中间神经元存活、形态、信号传导、钙稳态和运动功能对PGC-1的需求，2）PGC-1消融对其他脆弱神经元的影响来测试这一假设。在纹状体中，3）HD小鼠模型中PGC-1和PGC-1靶基因表达变化的区域和细胞特异性，和4）PGC-1过表达对HD小鼠模型中细胞存活和运动功能的影响。所提出的实验是必要的，以确定PGC-1功能障碍对神经元活力和功能的细胞自主和非细胞自主的影响，目的是确定PGC-1是否是治疗HD的适当靶标。