小胶质细胞
MPTP公司
神经炎症
黑质
多巴胺能
帕金森病
炎症
小RNA
生物
细胞生物学
化学
神经科学
免疫学
医学
多巴胺
病理
生物化学
基因
疾病
作者
Danlei Wang,Hongling Gao,Qixiong Qin,Jingyi Li,J. W. Zhao,Yi Qu,Jiangting Li,Yi Xiong,Zhe Min,Zhijuan Mao,Zhenyi Xue
标识
DOI:10.1186/s12967-024-04881-w
摘要
Abstract Background Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Microglia-mediated neuroinflammation has been largely considered one of main factors to the PD pathology. MicroRNA-218-5p (miR-218-5p) is a microRNA that plays a role in neurodevelopment and function, while its potential function in PD and neuroinflammation remains unclear. Methods We explore the involvement of miR-218-5p in the PD in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model. The miR-218-5p agomir used for overexpression was delivered into the substantia nigra (SN) by bilateral stereotaxic infusions. The loss of dopaminergic (DA) neurons and microglial inflammation in the SN was determined using Western blotting and immunofluorescence. Motor function was assessed using the rotarod test. RNA sequencing (RNA-seq) was performed to explore the pathways regulated by miR-218-5p. The target genes of miR-218-5p were predicted using TargetScan and confirmed using dual luciferase reporter assays. The effects of miR-218-5p on microglial inflammation and related pathways were verified in murine microglia-like BV2 cells. To stimulate BV2 cells, SH-SY5Y cells were treated with 1-methyl-4-phenylpyridinium (MPP + ) and the conditioned media (CM) were collected. Results MiR-218-5p expression was reduced in both the SN of MPTP-induced mice and MPP + -treated BV2 cells. MiR-218-5p overexpression significantly alleviated MPTP-induced microglial inflammation, loss of DA neurons, and motor dysfunction. RNA sequence and gene set enrichment analysis showed that type I interferon (IFN-I) pathways were upregulated in MPTP-induced mice, while this upregulation was reversed by miR-218-5p overexpression. A luciferase reporter assay verified that Ddx41 was a target gene of miR-218-5p. In vitro, miR-218-5p overexpression or Ddx41 knockdown inhibited the IFN-I response and expression of inflammatory cytokines in BV2 cells stimulated with MPP + -CM. Conclusions MiR-218-5p suppresses microglia-mediated neuroinflammation and preserves DA neurons via Ddx41 /IFN-I. Hence, miR-218-5p- Ddx41 is a promising therapeutic target for PD.
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