Energy Balance and Neurodegenerative Disease

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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.