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

基本信息

批准号：
8537521
负责人：
Carlos T Cepeda
金额：
$ 18.58万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8537521
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

项目摘要

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.

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，其特征是舞蹈症、认知缺陷和精神障碍。主要的神经病理学是纹状体中中等大小的棘神经元（MSN）的损失，但细胞损失也发生在大脑皮层、下丘脑以及其他大脑区域。神经元损失之前会出现白质体积减少，这表明髓磷脂分解和突触连接改变。使用电生理学方法，我们之前证明了突触活动的显着变化，特别是皮层和纹状体之间的渐进性断开以及纹状体抑制活动的增加，这两者都显着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 治疗主要集中于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，因为该突变广泛表达于多个大脑区域和外周器官。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并最终退化。此外，大脑胆固醇生物合成途径的破坏很早就发生，这可以部分解释突触功能障碍和髓磷脂分解。本申请中的实验旨在检查脂质代谢改变的作用，特别是脑胆固醇，作为 HD 遗传小鼠模型运动和突触紊乱的主要病因，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（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 的行为和电生理学的影响。这种饮食对于其他神经系统疾病有效，对于亨廷顿舞蹈症，它可以提供必要的替代能量来源来缓解症状。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。利用这种全局策略，我们希望提供一种拯救突触和行为表型的新方法。