Pro-survival and anti-inflammatory roles of NF-κB c-Rel in the Parkinson's disease models
Pro-survival and anti-inflammatory roles of NF-κB c-Rel in the Parkinson's disease models
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NF-κB c-Rel 在帕金森病模型中的促生存和抗炎作用
DOI：
10.1016/j.redox.2020.101427
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发表时间：
2020-02-01
期刊：
影响因子：
11.4
通讯作者：
Huang, Fang
中科院分区：
文献类型：
--
作者：
Wang, Zishan;Dong, Hongtian;Huang, Fang
帕金森病（PD）的病理特征是黑质致密部（SNpc）中多巴胺能（DA）神经元进行性丧失，以及存在过度活化的神经胶质细胞和神经炎症。活化B细胞的核因子κ -轻链增强子（NF - κB）c - Rel亚基与帕金森病的病理进程密切相关，然而c - Rel在帕金森病发展中的作用和机制仍不清楚。在此，在神经毒素诱导的帕金森病模型中，对NF - κB c - Rel的动态变化及其功能进行了评估。我们发现c - Rel在黑质 - 纹状体通路中迅速活化，主要发生在多巴胺能神经元和小胶质细胞中。在经1 - 甲基 - 4 - 苯基吡啶离子（MPP⁺）处理的人神经母细胞瘤细胞（SH - SY5Y）中，c - Rel可通过启动抗凋亡基因表达来维持神经元存活；在经脂多糖（LPS）刺激的小鼠小胶质细胞（BV2）中，它可通过抑制炎症基因表达来抑制小胶质细胞过度活化。c - Rel抑制剂IT901加重了1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶（MPTP）对多巴胺能神经元的损伤，并促进了小鼠黑质 - 纹状体通路中小胶质细胞的活化。此外，帕金森病患者血液样本中c - Rel的表达显著降低。我们的研究结果表明，NF - κB / c - Rel亚基在帕金森病进展过程中的神经保护和神经炎症抑制中起重要作用。
The pathological hallmarks of Parkinson's disease (PD) are the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of overactivated glial cells and neuroinflammation. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) c-Rel subunit is closely related in the pathological progress of PD, however the roles and mechanisms of c-Rel in PD development remain unclear. Here, in neurotoxins-induced PD models, the dynamic changes of NF-kappa B c-Rel and its functions were evaluated. We found that c-Rel was rapidly activated in the nigrostriatal pathway, which mainly occurred in dopaminergic neurons and microglia. c-Rel could maintain neuronal survival by initiating the anti-apoptotic gene expression in MPP+-treated SH-SY5Y cells and it could inhibit microglial overactivation by suppressing the inflammatory gene expression in LPS-challenged BV2 cells. c-Rel inhibitor IT901 aggravated the damage of MPTP on dopaminergic neurons and promoted the activation of microglia in the nigrostriatal pathway of mice. Moreover, the expression of c-Rel in blood samples of PD patients decreased dramatically. Our results indicate that the NF-kappa B/c-Rel subunit plays an important role in neuroprotection and neuroinflammation inhibition during PD progression.