Neuroapoptosis Laboratory and Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Neurosci. 2011 Oct 12;31(41):14496-507. doi: 10.1523/JNEUROSCI.3059-11.2011.
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.
褪黑素在几种神经退行性变的实验模型中具有神经保护作用。然而，褪黑素是否在亨廷顿病（HD）的遗传模型中提供神经保护作用尚不清楚。我们报告称，褪黑素可延迟 HD 转基因小鼠模型的疾病发作和死亡。此外，突变的亨廷顿蛋白（htt）介导的细胞、小鼠和人类中的毒性与 1 型褪黑素受体（MT1）的丧失有关。我们观察到来自野生型小鼠大脑的线粒体中存在高水平的 MT1 受体，但来自 HD 小鼠大脑的 MT1 受体则少得多。此外，我们证明褪黑素可抑制突变 htt 诱导的半胱天冬酶激活并维持 MT1 受体的表达。这一观察结果至关重要，因为褪黑素介导的保护作用取决于 MT1 受体的存在和激活。总之，我们描述了一种病理过程，即突变 htt 诱导的线粒体 MT1 受体丧失增强了神经元的脆弱性，并可能加速了神经退行性过程。
