Department of Zoology, University of Delhi , Delhi, India.
Chronobiol Int. 2021 Jan;38(1):61-78. doi: 10.1080/07420528.2020.1842752. Epub 2020 Dec 17.
Deficit in locomotion (motor) ability and disturbance of the circadian behavior and sleep-wake pattern characterize Huntington's disease (HD). Here, we examined the disturbance of circadian timing with the progression of HD pathogenesis, and tested the efficacy of melatonin and curcumin in preventing the motor deficit and disturbed eclosion behavior in the model of HD. To examine circadian timing, we assayed mRNA expression of genes of the transcriptional feedback (TF) loop that generates the near 24-h rhythmicity. We performed qPCR of the , and genes in transgenic fly heads from elav-Gal4 (pan neuronal) and PDF-Gal4 (PDF-specific neurons) driver lines through the progression of HD disease post-eclosion, from day 1 to its terminal stage on day 13. was arrhythmic from day 1, but and became arrhythmic on day 13 of the HD pathogenesis in elav, but not PDF, neurons. Twenty-four-hour mRNA rhythms showed alteration in the waveform properties (mesor and amplitude, not acrophase), but not in the persistence, in both elav-Gal4 and PDF-Gal4 HD flies; however, disturbance of the clock gene rhythm was delayed in PDF-Gal4 flies. To assess the preventive effects on HD pathogenesis, flies of both driver lines were provided with melatonin (50, 100, or 150 μg) or curcumin (10 μM) in the diet commencing from the larval stage. Both melatonin (100 μg) and curcumin reestablished the 24-h pattern in mRNA expression of and to normal (control) levels, and significantly improved both locomotion ability and eclosion behavior of HD flies. We suggest that the disturbance of circadian timekeeping progressively accelerated HD pathogenesis, possibly via modulation of the transcriptional state that resulted in the modification of the Huntington gene. These findings suggest melatonin and curcumin might be potential therapeutic agents for the treatment of HD in humans, although this needs specific investigation.
运动（运动）能力缺陷和昼夜行为和睡眠-觉醒模式紊乱是亨廷顿病（HD）的特征。在这里，我们研究了随着 HD 发病机制的进展，昼夜节律时间的干扰，并测试了褪黑素和姜黄素在预防模型中运动缺陷和扰乱羽化行为的功效。为了检查昼夜计时，我们检测了产生近 24 小时节律的转录反馈（TF）环的基因的 mRNA 表达。我们通过羽化后 HD 疾病的进展，从第 1 天到第 13 天的终末期，在 elav-Gal4（全神经元）和 PDF-Gal4（PDF 特异性神经元）驱动线的转基因蝇头中进行 qPCR，对 ， 和 基因进行了 qPCR。从第 1 天开始， 就失去了节律性，但 在 elav 神经元中，而不是在 PDF 神经元中，HD 发病的第 13 天， 和 变得失去了节律性。24 小时的 mRNA 节律在波形特性（中值和振幅，而不是峰相位）发生改变，但在 elav-Gal4 和 PDF-Gal4 HD 蝇中没有改变，但是时钟基因节律的干扰在 PDF-Gal4 蝇中延迟。为了评估对 HD 发病机制的预防作用，从幼虫阶段开始，两种驱动线的蝇都在饮食中提供褪黑素（50、100 或 150μg）或姜黄素（10μM）。褪黑素（100μg）和姜黄素都将 和 的 24 小时 mRNA 表达模式恢复到正常（对照）水平，并显著改善了 HD 蝇的运动能力和羽化行为。我们认为，昼夜计时的干扰逐渐加速了 HD 发病机制，可能通过调节转录状态，从而改变亨廷顿基因。这些发现表明，褪黑素和姜黄素可能是治疗人类 HD 的潜在治疗剂，尽管这需要专门的研究。
