Modulation of Lipid Metabolism to Rescue Aberrant Synaptic Transmission in HD

描述(申请人提供)：亨廷顿病(HD)是一种以舞蹈症、认知障碍和精神障碍为特征的致命性遗传性神经退行性疾病。主要的神经病理是纹状体中中等大小的棘神经元(MSN)的丢失，但大脑皮层、下丘脑和其他脑区也会发生细胞丢失。在神经元丢失之前，脑白质体积减少，这表明髓鞘破裂和突触连接改变。使用电生理方法，我们以前发现突触活动发生了显著的变化，特别是皮质和纹状体之间的渐进性分离，纹状体抑制活性的增加，这两者都显著改变了基底神经节输出区域的信号，并导致了运动症状。HD治疗主要集中在防止纹状体的神经退行性变化。然而，有效的治疗必须考虑到全球变化，因为突变广泛表达在多个大脑区域和外围器官。越来越多的人认识到HD的主要特征之一是伴随着神经症状的代谢障碍。葡萄糖代谢受损和能量供应不足会导致细胞应激和最终退化。此外，大脑胆固醇生物合成途径的中断发生在早期，这可以部分解释突触功能障碍和髓鞘破坏。本应用中的实验旨在检查脂代谢变化，特别是脑胆固醇的变化，作为遗传性HD小鼠模型中运动和突触障碍的主要病因因素的作用，并通过控制胆固醇水平来挽救这些变化。在目标1中，我们将研究生酮饮食(一种富含脂肪、低碳水化合物和正常蛋白质水平的饮食)对MSN行为和电生理的影响。这种饮食在其他神经疾病中有效，在HD中，它可以提供必要的替代能源来缓解症状。在目标2中，我们将通过调节切片中的胆固醇水平来检查潜在的机制。利用这一全球策略，我们希望提供一种新的方法来挽救突触和行为表型。 公共卫生相关性：亨廷顿病(HD)是一种致命的遗传性神经退行性疾病，其特征是无法控制的运动和认知缺陷。HD的主要特征之一是代谢紊乱，导致细胞应激和最终退化。这项应用中的实验检验了脂代谢作为小鼠模型中运动和突触变化的致病因素的作用，并通过操纵脂代谢，特别是脑胆固醇水平来挽救这些变化。

DESCRIPTION (provided by applicant): Abstract Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder characterized by chorea, cognitive deficits and psychiatric disturbances. The main neuropathology is the loss of medium-sized spiny neurons (MSNs) in the striatum, but cell loss also occurs in cerebral cortex, hypothalamus, as well as other brain regions. Neuronal loss is preceded by reductions in white matter volume, suggesting myelin breakdown and altered synaptic connectivity. Using electrophysiological methods, we previously demonstrated significant alterations in synaptic activity, in particular a progressive disconnectio between cortex and striatum, and an increase in striatal inhibitory activity, both of which markedly alter signaling to output regions of the basal ganglia and contribute to motor symptoms. HD treatments have primarily focused on preventing neurodegenerative changes in the striatum. However, an effective therapy has to consider global changes as the mutation is widely expressed in multiple brain areas and peripheral organs. It is becoming increasingly recognized that one of the main features of HD is a metabolic disturbance that accompanies neurological symptoms. Impaired glucose metabolism and inadequate energy supply can lead to cell stress and eventual degeneration. In addition, a disruption in the brain cholesterol biosynthetic pathway occurs early, which could partially explain synaptic dysfunction and myelin breakdown. The experiments in this application are designed to examine the role of alterations in lipid metabolism, in particular brain cholesterol, as a primary etiologic factor in motor and synaptic disturbances in genetic mouse models of HD and to rescue these alterations by manipulating cholesterol levels. In Aim 1, we will examine the effects of a Ketogenic Diet (a diet rich in fat, low in carbohydrates and normal in protein levels) on behavior and electrophysiology of MSNs. This diet is effective in other neurological disorders and in HD it could provide essential alternative sources of energy to alleviate symptoms. In Aim 2 we will examine potential mechanisms by modulating cholesterol levels in slices. Using this global strategy, we hope to provide a novel method to rescue the synaptic and behavioral phenotype. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder characterized by uncontrollable movements and cognitive deficits. One of the main features of HD is a metabolic disturbance leading to cell stress and eventual degeneration. The experiments in this application examine the role of lipid metabolism as a causative agent of motor and synaptic alterations in mouse models and to rescue these changes by manipulating lipid metabolism, in particular brain cholesterol levels.