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, since melatonin-mediated protection is dependent upon 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.

Melatonin Reduces Projection Neuronal Injury Induced by 3-Nitropropionic Acid in the Rat Striatum

“…Furthermore, MT also pharmacologically reduces the ability of amyloid β protein to form β sheets and amyloid fibrils in the AD model [51]. Besides AD and PD, there is growing evidence that its antioxidative effects play an important role in HD [52]. MT was found to prevent the morphological changes in the pyramidal neurons of the hippocampus when quinolinic acid was given as an intrahippocampal injection 5 days earlier [53].…”

Mitochondrial Hormone Receptors - an Emerging Field of Signaling in the Cell’s Powerhouse

“…These findings on the effects mitochondrial CB 1 were also important for interpreting the mitochondrial action of the melatonin receptor MT 1 . This receptor subtype was shown to be located in mitochondria, contrary to MT 2 [32]. Under basal, non compromised conditions, melatonin regulates respiration and Complex 1 activity in a similar way as cannabinoids via CB 1 .…”

Promising Role of Melatonin as Neuroprotectant in Neurodegenerative Pathology

“…Furthermore, melatonin prevents cell death of primary cortical neurons that have been challenged with proapoptotic inducer [139]. Melatonin treatment counteracted the mitochondrial cell death pathways through the inhibition of the release of Smac (small mitochondria-derived activator of caspases) and the activation of caspase-9 in apoptotic mutanthtt ST14A striatal cells [30,140]. Mitochondrial complex II inhibitor, 3-nitropropionic acid can closely replicate the neurochemical, histological, and clinical features of HD and hence used in an experimental model of HD [141,142].…”

“…So far, the antioxidant melatonin has been suggested to defer the signs of HD in a 3-nitropropionic acid-induced rat animal model of HD [141] and to reduce lipid per oxidation induced by quinolinic acid (a causative agent in HD) [143]. Moreover, it has been demonstrated that melatonin treatment inhibits the mutant htt-induced caspase activation and preserves MT1 receptor expression [30].…”

“…The altered levels of melatonin receptors have been reported in aging and neurological disorders [22][23][24][25][26]. Specific role of MT1/MT2 has been suggested in Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis [23,[27][28][29][30][31].…”