miR-let-7a suppresses α-Synuclein-induced microglia inflammation through targeting STAT3 in Parkinson's disease

https://doi.org/10.1016/j.bbrc.2019.08.140Get rights and content

Highlights

  • miR-let-7a and STAT3 are reversely changed.

  • STAT3 is identified as a target of miR-let-7a.

  • miR-let-7a limits microglia inflammation and ameliorates disease progression.

Abstract

Microglia-mediated neuroinflammation is critical for the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). microRNA-let-7a (miR-let-7a) targets the signal transducer and activator of transcription-3 (STAT3) and regulates microglia function. However, less is known about whether it plays a functional role in PD. In this report, by utilizing a mouse PD model induced by the overexpression of α-Synuclein (α-Syn), a pathological hallmark of PD, we found that miR-let-7a expression was downregulated, while STAT3 was synchronously activated in the substantia nigra pars compacta (SNpc). Similar results were obtained in α-Syn-treated BV-2 microglia cells cultured in vitro. Additionally, STAT3 was proven to be a direct target of miR-let-7a in BV-2 microglia cells, suggesting that miR-let-7a downregulation may contribute to STAT3 activation in α-Syn-induced mouse PD. Moreover, miR-let-7a overexpression suppressed α-Syn-induced BV-2 microglia cell activation and pro-inflammatory cytokine production, and these effects were abrogated by restoring STAT3 protein, hence establishing that miR-let-7a suppresses microglia-mediated inflammation through targeting STAT3. Lastly, miR-let-7a overexpression via injection of miR-7 mimics into mouse striatum suppressed microglia activation and reduced pro-inflammatory cytokine production, which were accompanied by relieved movement disorder and improved spatial memory deficits in α-Syn-induced PD mice. Altogether, these results may identify miR-let-7a as a negative regulator of microglia-elicited neuroinflammation, at least partially explaining its alleviating effects on PD symptoms.

Introduction

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), aggregation of α-Synuclein (α-Syn), and excessive neuroinflammation [[1], [2], [3]]. Increasing evidence has revealed that microglia-mediated neuroinflammation is pivotal for PD progression [4]. In addition, as reported, the aggregated α-Syn is able to activate microglia and induce subsequent neuroinflammation in PD [5]. However, the molecular mechanisms that underlie α-Syn-induced microglia activation are not well understood. Addressing this issue may provide useful hint to discover potential therapeutic targets for PD treatment.

Recently, several microRNAs (miRNAs), a group of small RNA molecules functioning in the post-transcriptional regulation of gene expression, have emerged as important regulators involved in the pathogenesis of PD [6]. Studies have also shown that miRNAs exhibit regulatory roles in microglia neuroinflammation induced by α-syn. For example, miR-7 suppresses microglia neuroinflammation by targeting the Nod-like receptor protein 3 (NLRP3) inflammasome [7]. Moreover, miR-155 deficiency reduces proinflammatory responses to α-Syn in microglia and also blocks α-Syn-induced neurodegeneration in PD animal model [8]. However, our understanding of the association between miRNAs and microglia neuroinflammation in PD is still very limited.

Previous studies have reported that in cancer cells [9] and in patients with psoriasis [10], miR-let-7a regulates the expression of the signal transducer and activator of transcription-3 (STAT3), a transcriptional factor that regulates inflammation in microglia [11]. Further, miR-let-7a was found to regulate microglia inflammation under in vitro conditions [12]. Based on these hints, we hypothesized that miR-let-7a may play a role in PD pathogenesis. We investigated this issue by taking advantage of a mouse PD model developed with α-Syn overexpression. We report that miR-let-7a inhibits α-Syn-induced microglia inflammation by targeting STAT3, which constitutes a critical mechanism that explains its beneficial roles in PD mice.

Section snippets

PD animal model

Male C57BL/6 mice aged 12–16 weeks were used for building PD model. AAV2 viral vector expressing α-Syn was constructed and purified as previously described [13]. AAV2-vector and AAV2-α-Syn viruses were delivered into the mouse SNpc via stereotaxic injection [8]. For overexpressing miR-let-7a in vivo, miR-let-7a mimics were injected into mouse striatum. NC mimics were injected into control mice. Twelve mice were included in each group. The movement disorder and spatial memory deficits were

miR-let-7a is decreased and STAT3 is activated in α-Syn-induced mouse PD and -treated BV2 microglia cells

To seek the possible role and regulation of miR-let-7a and STAT3 involved in PD pathology, we initially examined their expression patterns in a PD mouse model developed via injection of AAV2-α-Syn viruses to the substantia nigra pars compacta (SNpc) [16]. Strikingly, as shown by the quantitative real-time PCR (qRT-PCR) analysis, the expression level of miR-let-7a tended to be much lower in the SNpc from mice following 2-week of AAV2-α-Syn transduction than vector control group (Fig. 1A).

Disscussion

Microglial activation and ensuing generated inflammatory responses have been considered to be vital factors involved in PD pathogenesis. However, the molecular mechanisms that regulate microglial inflammation are not thoroughly understood, which impedes the development of potential therapeutic interventions for targeting microglia in PD treatment. In this study, we found that miR-let-7a was decreased in α-Syn-induced mouse PD model and -treated BV2 microglia cells, and that this expression

Funding

This study was supported by The Key Research and Development Program of Jiangxi Province (2018BBG78047) and the Natural Science Fund of Jiangxi Province (2014ZBAB205019).

Disclosure of conflict of interest

None.

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