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Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease
Published on: January 7, 2014
MicroRNA-218-5p-Ddx41 axis restrains microglia-mediated neuroinflammation through downregulating type I interferon
Danlei Wang1, Hongling Gao2, Qixiong Qin1
1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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.
Insights
MicroRNA-218-5p (miR-218-5p) protects against Parkinson's disease (PD) by reducing neuroinflammation and preserving dopaminergic neurons. This microRNA targets Ddx41, offering a potential therapeutic strategy for PD.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Parkinson's disease (PD) involves dopaminergic (DA) neuron loss in the substantia nigra (SN), with microglia-driven neuroinflammation as a key factor.
- The role of microRNA-218-5p (miR-218-5p) in PD pathogenesis and neuroinflammation is not well understood.
Purpose of the Study:
- To investigate the role of miR-218-5p in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease.
- To elucidate the molecular mechanisms underlying miR-218-5p's effects on neuroinflammation and neuronal survival.
Main Methods:
- Overexpression of miR-218-5p in the substantia nigra (SN) of MPTP-treated mice via stereotaxic infusion.
- Assessment of dopaminergic (DA) neuron loss, microglial inflammation, and motor function.
- RNA sequencing (RNA-seq) to identify regulated pathways and dual luciferase reporter assays to confirm target genes, including Ddx41.
- In vitro studies using BV2 microglial cells stimulated with 1-methyl-4-phenylpyridinium (MPP+)-conditioned media (CM).
Main Results:
- Reduced miR-218-5p expression was observed in MPTP-induced mice and MPP+-treated BV2 cells.
- miR-218-5p overexpression ameliorated microglial inflammation, DA neuron loss, and motor deficits in mice.
- RNA-seq identified the type I interferon (IFN-I) pathway as significantly upregulated in MPTP mice, an effect reversed by miR-218-5p.
- Ddx41 was confirmed as a direct miR-218-5p target; miR-218-5p/Ddx41 modulation inhibited IFN-I signaling and inflammatory cytokine production in BV2 cells.
Conclusions:
- miR-218-5p exerts neuroprotective effects by suppressing microglia-mediated neuroinflammation and preserving DA neurons through the Ddx41/IFN-I pathway.
- The miR-218-5p-Ddx41 axis represents a potential therapeutic target for Parkinson's disease.
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