Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Cell Rep. 2018 Oct 2;25(1):1-9.e5. doi: 10.1016/j.celrep.2018.09.015.
Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults and plays a critical role in brain health and disease. We report that the core circadian clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism and a lesser non-cell-autonomous signal from neurons. Astrocyte-specific Bmal1 deletion induces astrocyte activation and inflammatory gene expression in vitro and in vivo, mediated in part by suppression of glutathione-S-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. Our results demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo, elucidating a mechanism by which the circadian clock could influence many aspects of brain function and neurological disease.
生物钟功能障碍是衰老和神经退行性疾病的常见症状，但其对大脑健康的影响尚不清楚。星形胶质细胞的激活是对各种损伤的反应，在大脑健康和疾病中起着关键作用。我们报告称，核心生物钟蛋白 BMAL1 通过自主机制和来自神经元的较小非自主信号以协同方式调节星形胶质细胞增生。星形胶质细胞特异性 Bmal1 缺失会在体外和体内诱导星形胶质细胞激活和炎性基因表达，部分是通过抑制谷胱甘肽 S-转移酶信号转导来介导的。功能上，星形胶质细胞中 Bmal1 的缺失会促进体外神经元死亡。我们的研究结果表明，核心生物钟蛋白 BMAL1 在体内调节星形胶质细胞的激活和功能，阐明了生物钟影响大脑功能和神经疾病诸多方面的机制。
