Energy Balance and Neurodegenerative Disease

描述(申请人提供)：线粒体功能障碍见于所有神经退行性疾病。功能障碍的线粒体存在于中枢神经系统(CNS)细胞和非中枢神经系统组织中。这可能会导致生物体水平的生物能量异常。肌萎缩侧索硬化症(ALS)和亨廷顿病的几个小鼠模型显示出高代谢表型--存在过度的静息能量消耗。燃料输入和利用之间的不匹配导致体重减轻和身体脂肪减少。这不能归因于营养不良、甲状腺机能亢进、发烧、过度运动或过量的棕色脂肪活动。有一些证据(已公布并在本提案的初步数据部分中描述)表明，改善燃料投入和利用之间的不匹配在寿命和弱点方面是有益的。在这项建议中，我们的目标是严格检验ALS小鼠模型中的高代谢对病理生理事件的贡献这一假设。如果钝化或纠正突变的SOD小鼠的高代谢缺陷是有益的，它将为治疗神经退行性疾病打开新的治疗选择。由于线粒体功能障碍是神经退行性疾病的普遍病理，其益处可能非常广泛。

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.