Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Brain / cytology
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Brain / drug effects
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Brain / metabolism
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Caspase 3 / analysis
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Caspase 3 / metabolism
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Caspase 9 / analysis
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Caspase 9 / metabolism
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Cell Death / drug effects
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Cell Death / genetics
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Cells, Cultured
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Disease Models, Animal
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Embryo, Mammalian
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Female
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Green Fluorescent Proteins / genetics
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Humans
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Huntingtin Protein
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Huntington Disease / drug therapy
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Huntington Disease / metabolism*
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Huntington Disease / pathology
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Hydrogen Peroxide / toxicity
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Male
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Melatonin / pharmacology*
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Melatonin / therapeutic use
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Mice
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Mice, Mutant Strains
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Middle Aged
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mutation / genetics*
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism
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Neurons / drug effects*
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Neurons / ultrastructure
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Neuroprotective Agents / pharmacology*
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Postmortem Changes
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Rats
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Receptor, Melatonin, MT1 / genetics
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Receptor, Melatonin, MT1 / metabolism*
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Receptor, Melatonin, MT2 / genetics
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Receptor, Melatonin, MT2 / metabolism
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Statistics, Nonparametric
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Time Factors
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Transfection / methods
Substances
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HTT protein, human
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Huntingtin Protein
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Nerve Tissue Proteins
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Neuroprotective Agents
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Nuclear Proteins
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RNA, Messenger
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RNA, Small Interfering
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Receptor, Melatonin, MT1
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Receptor, Melatonin, MT2
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Green Fluorescent Proteins
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Hydrogen Peroxide
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Caspase 3
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Caspase 9
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Melatonin