DIETARY RESTRICTION NORMALIZES GLUCOSE METABOLISM AND BRAIN DERIVED NEUROTROPHIC FACTOR LEVELS, SLOWS DISEASE PROGRESSION AND INCREASES SURVIVAL IN HUNTINGTIN MUTANT MICE
W. Duan, Z Guo, H Jiang, X. M Ware, J Li, M.P. Mattson
Laboratory of Neurosciences, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224
Huntingtons disease (HD) is a progressive neurodegenerative disorder
characterized by uncontrolled body movements, psychiatric disturbances,
and dementia resulting from degeneration of neurons in the striatum and
cerebral cortex - it is caused by polyglutamine repeat expansions in
the huntingtin protein. In addition to neurological deficits, HD
patients exhibit abnormalities in glucose metabolism suggestive of a
hypermetabolic state. We now report that the progression of
neuropathological (formation of huntingtin inclusions and apoptotic
protease activation), behavioral and metabolic (glucose intolerance)
abnormalities in huntingtin mutant mice, an animal model of HD, are
retarded when the mice are fasted every other day resulting in an
extension of lifespan. Dietary restriction increases levels of
brain-derived neurotrophic factor (BDNF) and the protein chaperone
HSP-70, which are depleted in HD mice fed a normal diet. These
findings establish links between food intake, brain BDNF levels and
glucose metabolism in a mouse model of HD, and suggest that mutant
huntingtin promotes neuronal degeneration by impairing cellular stress
resistance.
Key words:
Dietary restriction, Huntington's disease, Brain derived neurotrophic factor, striatum.
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