PGC-1alpha and GABAergic Dysfunction in Huntington Disease

描述（由申请人提供）：亨廷顿舞蹈病（HD）是一种使人衰弱的遗传性疾病，涉及多年的精神和运动功能进行性恶化，导致死亡。研究表明，在HD患者的纹状体和肌肉组织中，转录共激活物过氧化物酶体增殖物激活受体共激活物1 （PGC-1）的表达降低，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的发病年龄。鉴于PGC-1在代谢调节中的作用，科学家们假设PGC-1的缺乏导致了HD的神经元易损性和线粒体缺陷。PGC-1在大脑中的作用尚不明确。PGC-1特异地集中在表达谷氨酸脱羧酶67 （GAD67）的神经元中，来自Cowell实验室的新数据表明PGC-1是钙缓冲蛋白小白蛋白的适当表达所必需的。此外，PGC-1缺失的动物表现出gaba能信号、长期增强和运动功能的异常。初步研究表明，PGC-1在HD细胞培养模型中持续下调，在小鼠模型中纹状体、海马和皮质中PGC-1及其靶点小白蛋白和葡萄糖转运蛋白4的表达降低。这些数据很有趣，因为在HD小鼠模型中，小蛋白阳性（PV+）中间神经元功能在运动症状出现之前在皮层受损。此外，由于PV+神经元对中棘神经元和皮质锥体神经元具有很强的前馈抑制作用，因此即使PV+神经元功能的轻微紊乱也会深刻影响纹状体/皮质输出和运动功能。我们认为PGC-1的缺失会使PV+神经元在HD中易感，并损害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、形态学、信号传导、钙稳态和运动功能对PGC-1的需求，2)PGC-1消融对纹状体中其他易感神经元群体的影响，3)PGC-1和PGC-1靶基因表达变化的区域和细胞特异性来验证这一假设。4) PGC-1过表达对HD小鼠模型细胞存活和运动功能的影响。为了确定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影响，以确定PGC-1是否是治疗HD的合适靶点，本实验是必要的。

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.