PT  - JOURNAL ARTICLE
AU  - Wang, Xin
AU  - Sirianni, Ana
AU  - Pei, Zhijuan
AU  - Cormier, Kerry
AU  - Smith, Karen
AU  - Jiang, Jiying
AU  - Zhou, Shuanhu
AU  - Wang, Hui
AU  - Zhao, Rong
AU  - Yano, Hiroko
AU  - Kim, Jeong Eun
AU  - Li, Wei
AU  - Kristal, Bruce S.
AU  - Ferrante, Robert J.
AU  - Friedlander, Robert M.
TI  - The Melatonin MT1 Receptor Axis Modulates Mutant Huntingtin-Mediated Toxicity
AID  - 10.1523/JNEUROSCI.3059-11.2011
DP  - 2011 Oct 12
TA  - The Journal of Neuroscience
PG  - 14496--14507
VI  - 31
IP  - 41
4099  - http://www.jneurosci.org/content/31/41/14496.short
4100  - http://www.jneurosci.org/content/31/41/14496.full
SO  - J. Neurosci.2011 Oct 12; 31
AB  - 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.