MicroRNA-30e regulates neuroinflammation in MPTP model of Parkinson’s disease by targeting Nlrp3

Abstract

Accumulating evidences suggest that neuroinflammation is a pathological hallmark of Parkinson’s disease (PD), a neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). MicroRNAs have been recently recognized as crucial regulators of inflammatory responses. Here, we found significant downregulation of microRNA-30e (miR-30e) in SNpc of MPTP-induced PD mice. Next, we employed miR-30e agomir to upregulate miR-30e expression in MPTP-treated mice. Our results showed that delivery of miR-30e agomir remarkably improved motor behavioral deficits and neuronal activity, and inhibited the loss of dopamine neurons. Moreover, the increased α-synuclein protein expression in SNpc of MPTP-PD mice was alleviated by the upregulation of miR-30e. Further, miR-30e agomir administration also attenuated the marked increase of inflammatory cytokines, such as TNF-α, COX-2, iNOS, and restored the decreased secretion of BDNF in SNpc. In addition, we demonstrated for the first time that miR-30e directly targeted to Nlrp3, thus suppressing Nlrp3 mRNA and protein expression. Finally, miR-30e upregulation significantly inhibited the activation of Nlrp3 inflammasome as evident from the decreased Nlrp3, Caspase-1 and ASC expressions and IL-18 and IL-1β secretions. Taken together, our study demonstrates that miR-30e ameliorates neuroinflammation in the MPTP model of PD by decreasing Nlrp3 inflammasome activity. These findings suggesting that miR30e may be a key inflammation-mediated molecule that could be a potential target for PD therapeutics.Electronic supplementary materialThe online version of this article (doi:10.1007/s13577-017-0187-5) contains supplementary material, which is available to authorized users.

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

“…Further studies confirmed that miR‐30e directly targets NLRP3, suppresses its expression, and prevents subsequent activation of the NLRP3 inflammasome. It is associated with decreased expression of caspase‐1 and ASC and a reduction in IL‐1β and IL‐18 release …”

“…It is associated with decreased expression of caspase-1 and ASC and a reduction in IL-1β and IL-18 release. 136…”

Update of inflammasome activation in microglia/macrophage in aging and aging‐related disease

“…46,47 Besides, several kinds of microRNA (eg, miR-7 and miR-30e), which are increased in PD brains, could directly activate inflammasome in microglia. 46,48 Similar to the situation in AD, inflammasome products released by microglia within substantia nigra trigger the inflammatory cascades in PD brains. Processive inflammasome activation in microglia may be a sustained stimuli of neuroinflammation that drives progressive dopaminergic neuropathology and promotes fibrillar α-synuclein accumulation.…”

“…Fibrillar α‐synuclein in microglia leads to impairment of mitochondrial endocytosis and lysosomal dysfunction, which cause ROS dysregulation and activate inflammasome . Besides, several kinds of microRNA (eg, miR‐7 and miR‐30e), which are increased in PD brains, could directly activate inflammasome in microglia . Similar to the situation in AD, inflammasome products released by microglia within substantia nigra trigger the inflammatory cascades in PD brains.…”

Noncoding RNAs in disease

“…However, miR‐155 knockout mice models transduced with AAV2‐SYN, exhibit a remarkably decreased proinflammatory response, without a loss of dopaminergic neurons . It was recently shown that miR‐30e improves neuronal damage, neuroinflammation and dyskinesia via targeting Nlrp3 expression and inhibiting NLRP3 inflammasome activation in a MPTP‐induced PD mice model . MiR‐30e levels were downregulated after MPTP injection, suggesting miR‐30 might also have a role in the pathogenesis of PD.…”