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Updated: Sep 14, 2025
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Circadian Entrainment of Drosophila Melanogaster
Published on: June 3, 2020
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在马查多-约瑟夫病患者和临床前模型中,循环节律受到干扰
Rodrigo F N Ribeiro1,2,3,4, Dina Pereira1,2,4, Sara M Lopes1,2,4
1Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra, Coimbra 3004-504, Portugal.
Brain : a journal of neurology
|July 22, 2025
概括
马查多-约瑟夫病 (MJD) 患者和小鼠表现出中断的昼夜节律和受损的时钟基因表达. 突变的ATAXIN-3蛋白损害了关键时钟基因的调节,这表明了新的治疗点.
科学领域:
- 神经科学是一个神经科学.
- 时间生物学 时间生物学
- 遗传学 是一个遗传学.
背景情况:
- 马查多-约瑟夫病 (MJD) 是一种脊髓小脑缩症,源于ATXN3基因中扩展的CAG重复,导致突变的ATAXIN-3 (mutATXN3) 蛋白.
- 循环节律障碍越来越被认为是神经退行性疾病的早期指标和潜在驱动因素.
- 昼夜时钟失调在MJD病理生理学中的作用仍然在很大程度上未被探索.
研究的目的:
- 为了研究MJD患者的昼夜节律障碍和YAC-MJD转基因小鼠模型.
- 描述MJD时钟失调背后的机制.
- 探索基于昼夜时间的干预措施对MJD和其他脊髓小脑动症的潜力.
主要方法:
- 在MJD患者中进行动图,以评估两个星期的昼夜活动.
- 车轮运行实验,核心体温遥测,免疫组织化学 (SCN/PVN中的AVP,VIP),以及YAC-MJD小鼠大脑中的时钟基因的qPCR.
- 使用 luciferase 记者对 Bmal1/Per2 钟基因促进体的 mutATXN3 影响的研究.
主要成果:
- 患有MJD的患者表现出昼夜节律强度的逐渐下降,与临床严重程度相关.
- YAC-MJD小鼠表现出活动减少,碎片化增加,在时差后延迟重新训练,并扰乱了核心体温节奏.
- 转基因小鼠的VIP/AVP水平降低,小脑钟基因表达减少;突变ATXN3失去了驱动Per2的能力,与野生型ATXN3.3不同.
结论:
- 中央时钟功能障碍,表现为时钟基因表达受损和活动/温度节律受损,在MJD中显而易见.
- 这项研究提供了第一个关于昼夜节律失调及其在MJD中的机制的强有力的证据.
- 研究结果表明,对于MJD和相关的脊髓小脑动症,有潜在的新生物标志物和基于昼夜的治疗策略.
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