Journal
JOURNAL OF NEUROSCIENCE
Volume 31, Issue 41, Pages 14496-14507Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3059-11.2011
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Funding
- National Institutes of Health/National Institute of Neurological Disorders and Stroke
- Muscular Dystrophy Association
- Huntington's Disease Society of America
- Veterans Administration
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Melatonin mediates neuroprotection in several experimental models of neurodegeneration. It is not yet known, however, whether melatonin provides neuroprotection in genetic models of Huntington's disease (HD). We report that melatonin delays disease onset and mortality in a transgenic mouse model of HD. Moreover, mutant huntingtin (htt)-mediated toxicity in cells, mice, and humans is associated with loss of the type 1 melatonin receptor (MT1). We observe high levels of MT1 receptor in mitochondria from the brains of wild-type mice but much less in brains from HD mice. Moreover, we demonstrate that melatonin inhibits mutant htt-induced caspase activation and preserves MT1 receptor expression. This observation is critical, because melatonin-mediated protection is dependent on the presence and activation of the MT1 receptor. In summary, we delineate a pathologic process whereby mutant htt-induced loss of the mitochondrial MT1 receptor enhances neuronal vulnerability and potentially accelerates the neurodegenerative process.
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