MicroRNA-124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease
MicroRNA-124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease
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MicroRNA-124在帕金森病炎症发病机制中调节p62/p38表达并促进自噬
DOI：
10.1096/fj.201900363r
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发表时间：
2019-07-01
期刊：
影响因子：
4.8
通讯作者：
Lu, Guohui
中科院分区：
文献类型：
--
作者：
Yao, Longping;Zhu, Zhiyuan;Lu, Guohui
帕金森病（PD）是一种以运动和非运动症状为特征的神经退行性疾病，由于中脑多巴胺能神经元的选择性丧失。在PD中，由脑内小胶质细胞介导的慢性炎症反应的证据尤其强烈。在我们之前的研究中，我们发现脑特异性microRNA-124 （miR-124）在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD小鼠模型中显著下调，并且它还可以抑制PD发展过程中的神经炎症。然而，需要进一步的研究来了解miR-124的异常表达是否调节小胶质细胞的激活。在本研究中，我们发现在mptp诱导的小鼠PD模型中，lps处理的永活小鼠小胶质细胞系BV2细胞中，sequestosome 1 （p62）和phospho-p38丝裂原活化蛋白激酶（p-p38）的表达显著增加。敲低p62可抑制小胶质细胞促炎因子和p-p38的分泌。此外，p38的抑制抑制了BV2细胞的促炎细胞因子的分泌，促进了自噬。此外，我们的研究首次确定了miR-124在PD中通过靶向p62和p38介导小胶质细胞炎症反应中的独特作用。在小胶质细胞培养上清转移模型中，BV2细胞中p62的敲低可阻止人神经母细胞瘤细胞系SH-SY5Y （SH-SY5Y）细胞在小胶质细胞激活后的凋亡和死亡。此外，外源性递送miR-124可以抑制p62和p-p38的表达，也可以减弱mptp处理小鼠黑质致密小胶质细胞的活化。综上所述，我们的数据表明，miR-124可以通过靶向p62、p38和自噬来抑制PD发展过程中的神经炎症，这表明miR-124可能是调节PD炎症反应的潜在治疗靶点。-姚磊，朱志军，吴建军，张勇，张海华，孙晓军，钱春春，王斌，谢磊，张树军，卢刚，MicroRNA-124调控p62/p38的表达并促进自噬在帕金森病炎症发病机制中的作用。
Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor symptoms due to the selective loss of midbrain dopaminergic neurons. The evidence for a chronic inflammatory reaction mediated by microglial cells in the brain is particularly strong in PD. In our previous study, we have shown that brain-specific microRNA-124 (miR-124) is significantly down-regulated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD and that it can also inhibit neuroinflammation during the development of PD. However, further investigation is required to understand whether the abnormal expression of miR-124 regulates microglial activation. In this study, we found that the expression of sequestosome 1 (p62) and phospho-p38 mitogen-activated protein kinases (p-p38) showed a significant increase in LPS-treated immortalized murine microglial cell line BV2 cells in an MPTP-induced mouse model of PD. Knockdown of p62 could suppress the secretion of proinflammatory cytokines and p-p38 of microglia. Besides, inhibition of p38 suppressed the secretion of proinflammatory cytokines and promoted autophagy in BV2 cells. Moreover, our study is the first to identify a unique role of miR-124 in mediating the microglial inflammatory response by targeting p62 and p38 in PD. In the microglial culture supernatant transfer model, the knockdown of p62 in BV2 cells prevented apoptosis and death of human neuroblastoma cell lines SH-SY5Y (SH-SY5Y) cells following microglia activation. In addition, the exogenous delivery of miR-124 could suppress p62 and p-p38 expression and could also attenuate the activation of microglia in the substantia nigra par compacta of MPTP-treated mice. Taken together, our data suggest that miR-124 could inhibit neuroinflammation during the development of PD by targeting p62, p38, and autophagy, indicating that miR-124 could be a potential therapeutic target for regulating the inflammatory response in PD.-Yao, L., Zhu, Z., Wu, J., Zhang, Y., Zhang, H., Sun, X., Qian, C., Wang, B., Xie, L., Zhang, S., Lu, G. MicroRNA-124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease.