title: The melatonin MT1 receptor axis modulates mutant Huntingtin-mediated toxicity.
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.
authors: Neuroapoptosis Laboratory and Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. xwang@rics.bwh.harvard.edu
authors: Xin
authors: X
authors: Wang
authors: Ana
authors: A
authors: Sirianni
authors: Zhijuan
authors: Z
authors: Pei
authors: Kerry
authors: K
authors: Cormier
authors: Karen
authors: K
authors: Smith
authors: Jiying
authors: J
authors: Jiang
authors: Shuanhu
authors: S
authors: Zhou
authors: Hui
authors: H
authors: Wang
authors: Rong
authors: R
authors: Zhao
authors: Hiroko
authors: H
authors: Yano
authors: Jeong Eun
authors: JE
authors: Kim
authors: Wei
authors: W
authors: Li
authors: Bruce S
authors: BS
authors: Kristal
authors: Robert J
authors: RJ
authors: Ferrante
authors: Robert M
authors: RM
authors: Friedlander
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism; D053453:Caspase 9 / Q000032:analysis / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006861:Hydrogen Peroxide / Q000633:toxicity; D008297:Male; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011180:Postmortem Changes; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D044122:Receptor, Melatonin, MT1 / Q000235:genetics / Q000378:metabolism*; D044123:Receptor, Melatonin, MT2 / Q000235:genetics / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D049452:Green Fluorescent Proteins; D006861:Hydrogen Peroxide; D053148:Caspase 3; D053453:Caspase 9; D008550:Melatonin