Whittaker Daniel S, Tamai T Katherine, Bains Raj S, Villanueva Sophia Anne Marie, Luk Shu Hon Christopher, Dell'Angelica Derek, Block Gene D, Ghiani Cristina A, Colwell Christopher S
Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
Front Nutr. 2022 Nov 3;9:1034743. doi: 10.3389/fnut.2022.1034743. eCollection 2022.
Disturbances in sleep/wake cycles are common among patients with neurodegenerative diseases including Huntington's disease (HD) and represent an appealing target for chrono-nutrition-based interventions. In the present work, we sought to determine whether a low-carbohydrate, high-fat diet would ameliorate the symptoms and delay disease progression in the BACHD mouse model of HD. Adult WT and BACHD male mice were fed a normal or a ketogenic diet (KD) for 3 months. The KD evoked a robust rhythm in serum levels of β-hydroxybutyrate and dramatic changes in the microbiome of male WT and BACHD mice. NanoString analysis revealed transcriptional changes driven by the KD in the striatum of both WT and BACHD mice. Disturbances in sleep/wake cycles have been reported in mouse models of HD and are common among HD patients. Having established that the KD had effects on both the WT and mutant mice, we examined its impact on sleep/wake cycles. KD increased daytime sleep and improved the timing of sleep onset, while other sleep parameters were not altered. In addition, KD improved activity rhythms, including rhythmic power, and reduced inappropriate daytime activity and onset variability. Importantly, KD improved motor performance on the rotarod and challenging beam tests. It is worth emphasizing that HD is a genetically caused disease with no known cure. Life-style changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed. Our study demonstrates the therapeutic potential of diet-based treatment strategies in a pre-clinical model of HD.
睡眠/觉醒周期紊乱在包括亨廷顿舞蹈症（HD）在内的神经退行性疾病患者中很常见，是基于时间营养学的干预措施的一个有吸引力的靶点。在本研究中，我们试图确定低碳水化合物、高脂肪饮食是否能改善HD的BACHD小鼠模型的症状并延缓疾病进展。成年野生型（WT）和BACHD雄性小鼠分别喂食正常饮食或生酮饮食（KD）3个月。KD引起了雄性WT和BACHD小鼠血清β-羟基丁酸水平的强烈节律变化以及微生物群的显著变化。NanoString分析揭示了KD在WT和BACHD小鼠纹状体中驱动的转录变化。HD小鼠模型中已报道存在睡眠/觉醒周期紊乱，且在HD患者中很常见。在确定KD对野生型和突变型小鼠均有影响后，我们研究了其对睡眠/觉醒周期的影响。KD增加了白天的睡眠时间并改善了睡眠开始时间，而其他睡眠参数未改变。此外，KD改善了活动节律，包括节律功率，并减少了不适当的白天活动和开始变异性。重要的是，KD在转棒试验和挑战性横梁试验中改善了运动表现。值得强调的是，HD是一种由基因引起的疾病，尚无已知的治愈方法。非常需要不仅能改善HD患者生活质量而且能延缓疾病进展的生活方式改变。我们的研究证明了基于饮食的治疗策略在HD临床前模型中的治疗潜力。
