PGC-1alpha and GABAergic Dysfunction in Huntington Disease

描述(申请人提供)：亨廷顿病(HD)是一种衰弱的遗传性疾病，在一段时间内精神和运动功能逐渐恶化，导致死亡。研究表明，HD患者纹状体和肌肉组织中转录共激活因子PGC-1的表达减少，突变的Huntingtin(MHTT)干扰PGC-1的正常表达和活性。此外，PGC-1基因的多态影响运动症状的发病年龄。根据PGC-1在代谢调节中的作用，科学家们假设PGC-1的缺陷导致了HD的神经元脆弱性和线粒体缺陷。PGC-1在大脑中的作用还不是很清楚。PGC-1特异性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是适当表达钙缓冲小白蛋白所必需的。此外，PGC-1缺失的动物表现出GABA能信号、长时程增强和运动功能的异常。初步研究表明，在HD的细胞培养模型中，PGC-1的表达持续下调，在小鼠模型中，PGC-1及其靶标小白蛋白和葡萄糖转运蛋白4在纹状体、海马区和皮质的表达减少。这些数据很有趣，因为在HD小鼠模型中，小白蛋白阳性(PV)中间神经元功能在HD小鼠出现运动症状之前就已经受损。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，即使是轻微的PV神经元功能障碍也会对纹状体/皮质输出和运动功能产生深远的影响。我们认为，PGC-1的缺陷使PV神经元在HD中容易受到伤害，并损害了它们适当地抑制局部投射神经元和协调运动输出的能力。本应用中提议的实验将通过确定1)纹状体PV神经元间存活、形态、信号、钙稳态和运动功能对PGC-1的需求，2)PGC-1消融对纹状体其他脆弱神经元群体的影响，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，以及4)PGC-1过表达对HD小鼠细胞生存和运动功能的影响。为了确定PGC-1功能障碍对神经元活性和功能的影响，以确定PGC-1是否是治疗HD的合适靶点，拟议的实验对于确定PGC-1功能障碍对神经元存活和功能的影响是必要的。 与公共卫生相关：亨廷顿病(HD)是一种毁灭性的神经疾病，每10万人中就有7人发生这种疾病。虽然HD的遗传基础是已知的，但目前还没有有效的治疗方法。这些研究将测试控制线粒体功能和中间神经元钙稳态的转录途径是否有可能作为HD患者的治疗靶点。

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. PUBLIC HEALTH RELEVANCE: Huntington Disease (HD) is a devastating neurological disorder that occurs in as many as 7 in every 100,000 people. While the genetic basis for HD is known, there are no effective therapies available. These studies will test whether transcriptional pathways that control mitochondrial function and calcium homeostasis in interneurons have potential as targets for treatment of patients with HD.