The melatonin MT1 receptor axis modulates mutant Huntingtin-Mediated Toxicity

Xin Wang, Ana Sirianni, Zhijuan Pei, Kerry Cormier, Karen Smith, Jiying Jiang, Shuanhu Zhou, Hui Wang, Rong Zhao, Hiroko Yano, Jeong Eun Kim, Wei Li, Bruce S. Kristal, Robert J. Ferrante, Robert M. Friedlander

Research output: Contribution to journalArticlepeer-review

151 Scopus citations


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.

Original languageEnglish
Pages (from-to)14496-14507
Number of pages12
JournalJournal of Neuroscience
Issue number41
StatePublished - Oct 12 2011


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