Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration
Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration
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DOI：
10.1172/jci70317
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发表时间：
2013-12-01
影响因子：
15.9
通讯作者：
FitzGerald, Garret A.
中科院分区：
文献类型：
--
作者：
Musiek, Erik S.;Lim, Miranda M.;FitzGerald, Garret A.
脑老化与生物钟输出减少和核心时钟蛋白表达减少有关，核心时钟蛋白调节细胞生物化学和代谢的许多方面。编码时钟蛋白的基因在整个大脑中表达，尽管这些蛋白质是否调节大脑内稳态尚不清楚。我们观察到，删除昼夜节律钟转录激活因子芳香烃受体核转位样（Bmal 1）单独，或昼夜节律运动输出周期kaput（时钟）与神经元PAS结构域蛋白2（Npas 2）相结合，诱导严重的年龄依赖性星形胶质细胞增生的皮质和海马。缺乏时钟基因抑制子周期昼夜节律钟1（Per 1）和周期昼夜节律钟2（Per 2）的小鼠没有观察到星形胶质细胞增生。Bmal 1缺失导致突触末梢变性和皮质功能连接受损，以及神经元氧化损伤和几种氧化还原防御基因的表达受损。在神经元和神经胶质细胞中靶向删除Bmal 1引起了类似的神经病理学，尽管保留了完整的昼夜行为和睡眠-觉醒节律。Bmal 1表达的减少促进了原代培养物和用氧化损伤和纹状体神经变性的化学诱导剂处理的小鼠中的神经元死亡。我们的研究结果表明，BMAL 1与CLOCK或NPAS 2的复合物调节大脑氧化还原稳态，并将受损的时钟基因功能与神经退行性变联系起来。
Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.