Abstract
Parkinson’s disease (PD) is mainly driven by dopaminergic neuronal degeneration in the substantia nigra pars compacta accompanied by chronic neuroinflammation. Despite being mainly sporadic, approximately 10% of all cases are defined as heritable forms of PD, with mutations in the leucine-rich repeat kinase (LRRK2) gene being the most frequent known cause of familial PD. MicroRNAs (miRNAs or miRs), including miR-335, are frequently deregulated in neurodegenerative diseases, such as PD. Here, we aimed to dissect the protective role of miR-335 during inflammation and/or neurodegenerative events in experimental models of PD. Our results showed that miR-335 is significantly downregulated in different PD-mimicking conditions, including BV2 microglia cells stimulated with lipopolysaccharide (LPS) and/or overexpressing wild-type LRRK2. Importantly, these results were confirmed in serum of mice injected with 1-methyl-1-4-phenyl-1,2,3,6-tetrahydripyridine hydrochloride (MPTP), and further validated in patients with idiopathic PD (iPD) and those harboring mutations in LRRK2 (LRRK2-PD), thus corroborating potential clinical relevance. Mechanistically, miR-335 directly targeted LRRK2 mRNA. In the BV2 and N9 microglia cell lines, miR-335 strongly counteracted LPS-induced proinflammatory gene expression, and downregulated receptor interacting protein 1 (RIP1) and RIP3, two important players of necroptotic and inflammatory signaling pathways. Further, miR-335 inhibited LPS-mediated ERK1/2 activation. LRRK2-Wt-induced proinflammatory gene expression was also significantly reduced by miR-335 overexpression. Finally, in SH-SY5Y neuroblastoma cells, miR-335 decreased the expression of pro-inflammatory genes triggered by α-synuclein. In conclusion, we revealed novel roles for miR-335 in both microglia and neuronal cells that strongly halt the effects of classical inflammatory stimuli or LRRK2-Wt overexpression, thus attenuating chronic neuroinflammation.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, mainly instigated by dopaminergic neurodegeneration in the substantia nigra pars compacta (Poewe et al, 2017)
Recent studies have shown that miR335 may be linked to PD pathogenesis, since we and others have found reduced expression levels in whole blood, peripheral blood mononuclear cells (PBMCs) and serum of PD patients compared with control subjects (Martins et al, 2011; Yılmaz et al, 2016; Oliveira et al, 2020)
Others have suggested that the role of miR-335 in PD pathogenesis is mediated by leucine-rich repeat kinase 2 (LRRK2) (Yılmaz et al, 2016; Patil et al, 2019)
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, mainly instigated by dopaminergic neurodegeneration in the substantia nigra pars compacta (Poewe et al, 2017). An exacerbation of LRRK2 levels in different immune cells, such as microglia or macrophages, has been reported in response to inflammatory stimuli, such as lipopolysaccharide (LPS) or interferon-γ (IFN-γ), thereby perpetuating inflammation (Gardet et al, 2010; Gillardon et al, 2012). The discoveries that both pharmacological and genetic inhibition of LRRK2 can be neuroprotective in preclinical models of PD (Chan and Tan, 2017; West, 2017; Zhao et al, 2017; Chen et al, 2018) have placed LRRK2 at the center of disease modifying PD strategies. Recent findings suggest that LRRK2 plays a role in the pathogenesis of PD, indicating that LRRK2-targeted therapies might, be beneficial in both subtypes of PD (Tolosa et al, 2020)
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