Biochemical and Biophysical Research Communications
miR-let-7a suppresses α-Synuclein-induced microglia inflammation through targeting STAT3 in Parkinson's disease
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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2022, Ageing Research ReviewsCitation Excerpt :Semaglutide, a synthetic analogue of GLP1, stimulates the GLP1R and has been approved by the FDA to treat people with type 2 diabetes, and is currently undergoing phase II clinical trials to test neuroprotective and anti-inflammatory effects in idiopathic PD (NCT036559682). Several products protect dopaminergic neurons against inflammatory damage by inhibiting microglia activation, such as naloxone (a nonselective opioid receptor antagonist) (Liu et al., 2000) and miR-let-7a (Zhang et al., 2019), in models of PD. A phase II randomised study showed that AZD3241 treatment, an inhibitor of myeloperoxidase, decreased microglia activity in PD patients (Jucaite et al., 2015).
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2022, Analytica Chimica ActaCitation Excerpt :Although the biological functions of miRNAs have not been fully revealed, current studies have shown that the tissue expression levels of miRNAs are significantly correlated with the development of many cancers and other diseases, which are an essential field of research in liquid biopsy [7–9]. Let-7a is one of the first miRNAs identified, and the let-7 families play a critical role in the development of cancer [10,11]. The family includes 13 members on 9 chromosomes [12].
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2021, Experimental GerontologyCitation Excerpt :It is also associated with human disease, including roles as a tumor suppressor (Esquela-Kerscher and Slack, 2006; Johnson et al., 2005). Consistent with its ubiquity in the animal world, let-7 has been shown to have PD-associated roles across most model systems: low levels result in dopaminergic neuronal cell loss in C. elegans, suppression of microglia inflammation caused by α-synuclein expression in mice by targeting STAT3 and down-regulation in a 6-OHDA-induced cell model of PD while targeting caspase-3 (Shamsuzzama et al., 2015, 2017; J. Zhang et al., 2019; Li et al., 2017). Intriguingly, let-7 was observed to be one of the most highly down-regulated miRNAs during aging in C. elegans (de Lencastre et al., 2010; Kato et al., 2011).