PGC-1alpha and GABAergic Dysfunction in Huntington Disease

描述（由申请人提供）：亨廷顿舞蹈症 (HD) 是一种使人衰弱的遗传性疾病，涉及多年来精神和运动功能的逐渐恶化，最终导致死亡。研究表明，HD 患者纹状体和肌肉组织中转录共激活因子过氧化物酶体增殖物激活受体共激活因子 1 (PGC-1) 的表达降低，并且突变型亨廷顿蛋白 (mHtt) 会干扰 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出现年龄。鉴于 PGC-1 在代谢调节中的作用，科学家推测 PGC-1 的缺陷会导致 HD 中的神经元脆弱性和线粒体缺陷。 PGC-1 在大脑中的作用尚不明确。 PGC-1 特别集中在表达谷氨酸脱羧酶 67 (GAD67) 的神经元中，Cowell 实验室的新数据表明，PGC-1 是钙缓冲小清蛋白适当表达所必需的。此外，PGC-1缺失的动物在GABA能信号传导、长时程增强和运动功能方面表现出异常。初步研究表明，HD 细胞培养模型中 PGC-1 持续下调，小鼠模型纹状体、海马和皮质中 PGC-1 及其靶标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，在出现运动症状之前，皮质中的小白蛋白阳性 (PV ) 中间神经元功能就受到损害。此外，由于PV神经元对中型棘神经元和皮质锥体神经元具有强烈的前馈抑制作用，即使PV神经元功能的轻微干扰也会深刻影响纹状体/皮质输出和运动功能。我们认为 PGC-1 的缺陷使 PV 神经元在 HD 中容易受到伤害，并损害其正确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) PGC-1 在纹状体 PV 中间神经元存活、形态、信号传导、钙稳态和运动功能中的需求，2) PGC-1 消融对纹状体中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 小鼠模型中的细胞存活和运动功能。所提出的实验对于确定 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是必要的，目的是确定 PGC-1 是否是治疗 HD 的合适靶点。 公共卫生相关性：亨廷顿病 (HD) 是一种毁灭性的神经系统疾病，每 10 万人中就有多达 7 人患有这种疾病。虽然 HD 的遗传基础已知，但尚无有效的治疗方法。这些研究将测试控制中间神经元线粒体功能和钙稳态的转录途径是否有潜力作为 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.