Energy Balance and Neurodegenerative Disease

描述（由申请人提供）：线粒体功能障碍存在于所有神经退行性疾病中。功能失调的线粒体填充中枢神经系统（CNS）细胞和非中枢神经系统组织。这会导致机体层面的生物能量异常。肌萎缩性侧索硬化症（ALS）和亨廷顿病的几种小鼠模型显示出高代谢表型-有过多的静息能量消耗。燃料输入和利用之间的不匹配导致体重减轻和低体脂。这不能归因于营养不良，甲状腺功能亢进，发烧，过度的运动活动或过度的棕色脂肪活动。有一些证据（已发表的以及在本提案的初步数据部分中描述的）表明，改善燃料输入和利用之间的不匹配在寿命和弱点方面是有益的。在本提案中，我们的目的是严格检验假设，高代谢在ALS小鼠模型有助于病理生理事件。如果钝化或纠正突变SOD小鼠的高代谢缺陷是有益的，它将为神经退行性疾病的治疗开辟新的治疗选择。由于线粒体功能障碍是神经退行性疾病的普遍病理，因此益处可能非常广泛。

DESCRIPTION (provided by applicant): Mitochondrial dysfunction is found in all neurodegenerative diseases. Dysfunctional mitochondria populate central nervous system (CNS) cells as well as non-CNS tissues. This can lead to organism level bioenergetic abnormalities. Several mouse models of Amyotrophic Lateral Sclerosis (ALS) and Huntington Disease display a hypermetabolic phenotype - there is excessive resting energy expenditure. The mismatch between fuel input and utilization leads to weigh loss and low body fat. This can not be attributed to poor nutrition, hyperthyroidism, fever, excessive motor activity or excessive brown fat activity. There is some evidence (published as well as described in a preliminary data section of this proposal) that ameliorating the mismatch between fuel input and utilization is beneficial in terms of life span and weakness. In this proposal we aim to rigorously test the hypothesis that hypermetabolism in a mouse model of ALS contributes to the pathophysiological events. If blunting or correcting the hypermetabolic defect in the mutant SOD mouse is beneficial it will open new therapeutic options for the treatment of neurodegenerative diseases. Since mitochondrial dysfunction is a universal pathology in neurodegenerative diseases, the benefits may be very broad. PUBLIC HEALTH RELEVANCE: Mitochondria are the power plants of cells and defective operation of mitochondria is seen in all neurodegenerative diseases. To compensate, mitochondria can work overtime and this leads to increase consumption of fuel (i.e., sugars, fats and oxygen). This proposal will test the idea that restraining the mitochondria from overworking will benefit a mouse model of a neurodegenerative disease.