Objective: To explore the effect of miR-218-5p on microglia activation and dopaminergic neurons damage in mice model of Parkinson’s disease(PD) and its potential mechanisms.

Background: Microglia-mediated neuroinflammation has been found to be associated with the pathogenesis of PD. miR-218-5p plays roles in diverse central nervous system disorders including PD. However, the relationship between miR-218-5p and microglia-mediated neuroinflammation in PD is currently unknown.

Method: 8-week-old male C57BL6/J mice were randomly divided into four groups (NC_Control,NC_MPTP,miR-218_Control,miR-218_MPTP). miR-218-5p agomir was delivered to the substantia nigra (SNc) via bilateral stereotaxic injections. Microglia activation, dopaminergic neurons damage and the motor function were determined. SNc RNA-Seq was performed, and target genes of mmu-miR-218-5p were predicted using TargetScan and confirmed by dual luciferase reporter assay. miR-218-5p overexpression or target gene knockdown was achieved by transfection with miR-218-5p mimic or target gene siRNA, and the effects of miR-218-5p or target gene on microglia activation and related pathways were verified in murine microglial BV2 cells and primary mouse microglia.

Results: The expression of miR-218-5p was significantly decreased in MPTP mice. miR-218-5p overexpression significantly alleviated microglia activation, dopaminergic neurons damage and motor dysfunction of PD mice. Gene set enrichment analysis (GSEA) showed that type I interferon (IFN-I) pathways enriched in MPTP mice but were inhibited in miR-218_MPTP mice. RNA-seq and RT-PCR results showed that IFN-I related genes (Irf7, Ddx60, Nlrc5) were significantly upregulated in the SNc of PD mice, while miR-218-5p overexpression inhibited the expression of these genes. In addition, TargetScan prediction and luciferase reporter assay confirmed that the IFN-I related gene Ddx41 was the target gene of miR-218-5p. In vitro, the expression of miR-218-5p decreased in LPS-stimulated BV2 cells and primary microglia. Furthermore, miR-218-5p overexpression orDdx41 knockdown inhibited LPS-stimulated IFN-I response and induction of inflammatory cytokines in microglia.

Conclusion: miR-218-5p alleviates microglia-mediated neuroinflammation in PD by targeting DDX41 through IFN-I pathway, thereby exhibiting a protective effect on dopaminergic neurons.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mir-218-5p-regulates-microglia-mediated-neuroinflammation-through-type-i-interferon-response-in-parkinsons-disease/