Modulation of Lipid Metabolism to Rescue Aberrant Synaptic Transmission in HD

调节脂质代谢以挽救 HD 中的异常突触传递

• 批准号: 8425533
• 负责人: Carlos T Cepeda
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425533
• 关键词: Adipose tissue; Affect; Agonist; Animals; Area; Basal Ganglia; Behavior; Behavioral; Body Weight decreased; Brain; Brain region; Carbohydrates; Cells; Cellular Morphology; Cellular Stress; Cerebral cortex; Cholesterol; Chorea; Clinical; Clinical Research; Cognitive; Cognitive deficits; Corpus striatum structure; Cyclodextrins; Diet; Electrophysiology (science); Energy Intake; Energy Metabolism; Energy Supply; Energy-Generating Resources; Etiology; Fatty acid glycerol esters; Functional disorder; Genes; Genetic; Global Change; Gluconeogenesis; Glucose; Gold; Human; Huntington Disease; Hydroxycholesterols; Hypothalamic structure; In Vitro; Individual; Inherited; Insulin; Investigation; Knock-in Mouse; Late-Onset Huntington Disease; Lead; Length; Leptin; Liver; Maintenance; Membrane; Membrane Microdomains; Metabolic; Metabolism; Methods; Modeling; Molecular; Mood Disorders; Motor; Movement; Mus; Mutation; Myelin; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Oligodendroglia; Organ; Output; Palliative Care; Pathology; Pathway interactions; Patients; Peripheral; Phenotype; Property; Proteins; Risk; Role; Signal Transduction; Signaling Molecule; Simvastatin; Slice; Supplementation; Symptoms; Synapses; Synaptic Membranes; Synaptic Transmission; Synaptic Vesicles; Therapy Clinical Trials; Transgenic Organisms; Trinucleotide Repeats; Vertebral column; Work; abstracting; base; design; effective therapy; glucose metabolism; gray matter; human Huntingtin protein; hypocretin; in vivo; insulin secretion; insulin sensitivity; ketogenic diet; lipid metabolism; mouse model; nervous system disorder; neuron loss; neuropathology; neurotransmission; novel; preclinical study; prevent; receptor; research study; therapeutic target; trafficking; white matter

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.

描述（由申请人提供）：摘要亨廷顿病（HD）是一种致命的遗传性神经退行性疾病，其特征是舞蹈病、认知缺陷和精神障碍。主要的神经病理学是纹状体中中型多刺神经元（MSN）的损失，但细胞损失也发生在大脑皮层、下丘脑以及其他脑区域。神经元损失之前是白色物质体积的减少，表明髓鞘破坏和突触连接改变。使用电生理学方法，我们先前证明了突触活动的显著改变，特别是皮质和纹状体之间的进行性断开，以及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传导并导致运动症状。HD治疗主要集中在预防纹状体的神经退行性变化。然而，有效的治疗必须考虑全局变化，因为突变在多个脑区和外周器官中广泛表达。人们越来越认识到，HD的主要特征之一是伴随神经系统症状的代谢紊乱。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分解。本申请中的实验旨在检查脂质代谢（特别是脑胆固醇）改变作为HD遗传小鼠模型中运动和突触紊乱的主要病因因素的作用，并通过操纵胆固醇水平来挽救这些改变。在目标1中，我们将研究生酮饮食（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。这种饮食对其他神经系统疾病有效，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研究潜在的机制。使用这种全局策略，我们希望提供一种新的方法来拯救突触和行为表型。 公共卫生相关性：亨廷顿氏病（HD）是一种致命的遗传性神经退行性疾病，其特征在于无法控制的运动和认知缺陷。HD的主要特征之一是导致细胞应激和最终退化的代谢紊乱。本申请中的实验检查了脂质代谢作为小鼠模型中运动和突触改变的病原体的作用，并通过操纵脂质代谢，特别是脑胆固醇水平来挽救这些变化。