RT Journal Article
SR Electronic
T1 The Melatonin MT1 Receptor Axis Modulates Mutant Huntingtin-Mediated Toxicity
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 14496
OP 14507
DO 10.1523/JNEUROSCI.3059-11.2011
VO 31
IS 41
A1 Wang, Xin
A1 Sirianni, Ana
A1 Pei, Zhijuan
A1 Cormier, Kerry
A1 Smith, Karen
A1 Jiang, Jiying
A1 Zhou, Shuanhu
A1 Wang, Hui
A1 Zhao, Rong
A1 Yano, Hiroko
A1 Kim, Jeong Eun
A1 Li, Wei
A1 Kristal, Bruce S.
A1 Ferrante, Robert J.
A1 Friedlander, Robert M.
YR 2011
UL http://www.jneurosci.org/content/31/41/14496.abstract
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.