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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS077909-01A1
Application #
8371374
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Gubitz, Amelie
Project Start
2012-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$209,375
Indirect Cost
$84,375
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104