BMAL1 regulation of microglia-mediated neuroinflammation in MPTP-induced Parkinson's disease mouse model
BMAL1 regulation of microglia-mediated neuroinflammation in MPTP-induced Parkinson's disease mouse model
复制标题
BMAL1 对 MPTP 诱导的帕金森病小鼠模型中小胶质细胞介导的神经炎症的调节
DOI：
10.1096/fj.201901565rr
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发表时间：
2020-04-04
期刊：
影响因子：
4.8
通讯作者：
Liu, Chun-Feng
中科院分区：
文献类型：
--
作者：
Liu, Wen-Wen;Wei, Shi-Zhuang;Liu, Chun-Feng
昼夜节律功能障碍是帕金森病 (PD) 最常见的非运动症状之一，但昼夜节律在 PD 中的分子作用尚不清楚。我们在这里发现，在1-甲基-4-苯基-1,2,4,5-四氢吡啶（MPTP）处理的小鼠中，大脑和肌肉ARNT样1（BMAL1）失活导致明显的运动功能缺陷，黑质致密部（SNpc）中的多巴胺能神经元（DAN）丢失，多巴胺（DA）递质减少，以及小胶质细胞和星形胶质细胞的激活增加。纹状体。 MPTP 治疗后，Bmal1(-/-) 小鼠的旋转时间或卡路里消耗以及食物和水摄入量均减少，表明 Bmal1 的缺失可能会加剧昼夜节律和 PD 运动功能。我们观察到，在 MPTP 处理的 Bmal1(-/-) 小鼠中，SNpc 中的 DAN（大约为 35%）、纹状体中的酪氨酸羟化酶蛋白水平（大约为 60%）、DA（大约为 22%）和 3,4-二羟基苯乙酸含量（大约为 29%）显着降低。 Bmal1的缺失加剧了体内和体外的炎症反应。这些发现表明，BMAL1 可能在 DAN 的存活中发挥重要作用，并通过调节大脑中小胶质细胞介导的神经炎症来维持 DA 信号通路的正常功能。
Dysfunction of the circadian rhythm is one of most common nonmotor symptoms in Parkinson's disease (PD), but the molecular role of the circadian rhythm in PD is unclear. We here showed that inactivation of brain and muscle ARNT-like 1 (BMAL1) in 1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine (MPTP)-treated mice resulted in obvious motor functional deficit, loss of dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNpc), decrease of dopamine (DA) transmitter, and increased activation of microglia and astrocytes in the striatum. Time on the rotarod or calorie consumption, and food and water intake were reduced in the Bmal1(-/-) mice after MPTP treatment, suggesting that absence of Bmal1 may exacerbate circadian and PD motor function. We observed a significant reduction of DANs (similar to 35%) in the SNpc, the tyrosine hydroxylase protein level in the striatum (similar to 60%), the DA (similar to 22%), and 3,4-dihydroxyphenylacetic acid content (similar to 29%), respectively, in MPTP-treated Bmal1(-/-) mice. Loss of Bmal1 aggravated the inflammatory reaction both in vivo and in vitro. These findings suggest that BMAL1 may play an essential role in the survival of DANs and maintain normal function of the DA signaling pathway via regulating microglia-mediated neuroinflammation in the brain.