Abnormal Energy Homeostasis in ALS

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DESCRIPTION (provided by applicant): The longterm of objective of these studies is to determine if correcting the metabolic abnormalities in ALS will slow the progression of the neurodegeneration process. Specific aim - Previous studies of patients with ALS and mouse models of motor neuron disease have demonstrated an imbalance between energy intake and expenditure. The key abnormality is increased basal metabolic rate a problem evident in all tissue, most significantly in muscle. This imbalance of energy intake and expenditure is pathophysiologically significant, since it's partial correction by providing mutant mice with a high fat, high calorie diet slows disease progression. Specific aim: Is the motor neuron disease of mutant SOD mice prevented or slowed by genetically reducing basal metabolic rate? The Leptin-ObR signaling system controls food intake and basal metabolic rate. We will generate mice that express G93A mutant human SOD in the ob/ob background. The ob locus encodes the protein leptin and ob/ob mice are hypometabolic (among other metabolic derangements). We will monitor, over time, strength, endurance, survival, motor neuron number and metabolic parameters. Two dietary regimens will be studied: 1) Animals will be given ad libitum access to food and this leads to marked obesity in the ob/ob mice. The extent to which this will occur in mice expressing mutant in the ob/ob background can only be determined empirically as is the extent to which this influences motor neuron disease, 2) Animals will be pair-fed. The hypometabolic phenotype of the ob/ob leads to weight gain in pair fed animals, but less than occurs in animals with ad libitum access to food. This feeding paradigm isolates systemic hypometabolic alterations engendered by the ob/ob from the hyperphagia incurred by defective leptin-ObR signaling. Primary methodology/principle organism. We will use the G93A SOD mouse and the ob/ob mouse. Behavioral, anatomical, biochemical and metabolic studies will be undertaken. Relationship to neuromuscular disease. These studies are directly relevant to all motor neuron disease. PUBLIC HEALTH RELEVANCE: This project aims to link metabolism of the organism with susceptibility to neurodegenerative diseases. If food consumption and metabolic rate are related to neurodegenerative disease then new forms of intervention (i.e., diet, exercise, pharmacology) may prove useful therapeutically.