REV-ERB-alpha和-beta协调调节天体细胞的反应性和蛋白质静止功能
Collin J Nadarajah1, Michelle Y Li1, Elsa I Quillin1
1Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110.
概括
这项研究表明,REV-ERB核受体调节星细胞功能和大脑健康. 在星球细胞中REV-ERB-α和REV-ERB-β的双重删除可以减轻帕金森氏症.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 时间生物学 时间生物学
背景情况:
- 分子昼夜钟调节中枢神经系统 (CNS) 功能,包括质反应和神经退行性病理.
- 核受体REV-ERB-α (Nr1d1) 和REV-ERB-β (Nr1d2) 是影响新陈代谢,神经炎症,突触修剪和蛋白质聚合的核心昼夜时钟组件.
- 在大脑中REV-ERB-α和REV-ERB-β的细胞类型特异性作用和补偿作用仍然在很大程度上不明.
研究的目的:
- 为了研究REV-ERB核受体的中枢神经系统功能.
- 阐明REV-ERB-α和REV-ERB-β在大脑中的细胞类型特定的作用和补偿作用.
- 探索REV-ERB在神经退行性疾病中的治疗潜力.
主要方法:
- 开发具有全球性或天体细胞特异性REV-ERB-α和REV-ERB-β条件淘汰的小鼠模型.
- 在REV-ERBs的诱导性产后全球删除后,对大脑的转录变化的分析.
- 研究天体细胞的反应性和STAT3信号通路.
- 在体外和体内对α-synuclein吸收,降解和病理传播的评估.
主要成果:
- 可诱导的REV-ERB-α和REV-ERB-β的全局删除诱导了疾病相关途径和自发星球细胞反应的广泛的转录变化.
- 对REV-ERBs的天体细胞特异性删除回顾了天体细胞的反应性,表明细胞自主调节.
- 发现REV-ERB-α/-β抑制了STAT3转录,并且它们的删除诱导了星球细胞中的STAT3表达.
- 在帕金森病模型中,双REV-ERB删除增强了星球细胞α-synuclein的吸收和降解,并减轻了α-synuclein的扩散.
结论:
- REV-ERBs是天体细胞功能和激活的关键调节者.
- 天体细胞REV-ERBs作用于核心昼夜时钟的下游,通过STAT3信号控制天体细胞的反应.
- 向天体细胞REV-ERBs为同核蛋白病变和其他神经退行性病理提供了潜在的治疗策略.
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