MiR‐29c protects against inflammation and apoptosis in Parkinson's disease model in vivo and in vitro by targeting SP1

Abstract

MicroRNAs (miRNAs) have been shown to have complicated implications in the pathogenesis of Parkinson's disease (PD). However, the role of miR‐29c and the underlying mechanism in the development of PD remain not well understood. In this work, the MPTP‐treated mice or MPP+‐intoxicated SH‐SY5Y cells were established as an in vivo or in vitro PD model. Then the specific agomir of miR‐29c was employed to examine its biological function on PD progress. We found that miR‐29c was down‐expressed but SP1 was high‐expressed in substantia nigra pars compacta (SNpc) of MPTP‐induced PD mice. Overexpression of miR‐29c attenuated dopaminergic neuron loss and α‐synuclein accumulation in SNpc of PD mice. Furthermore, the increments of pro‐inflammatory cytokines (TNF‐α, IL‐1β and IL‐6) and TUNEL‐positive apoptotic cells in MPTP‐treated mice were ameliorated by miR‐29c. Similarly, in SH‐SY5Y cell models of PD, we also found that miR‐29c inhibited inflammatory cytokine production, reduced apoptotic rate and suppressed pro‐apoptotic regulator activity. In addition, the increased expression of SP1 in PD models was found to be inhibited by miR‐29c. Luciferase reporter assay confirmed that SP1 was complementary with miR‐29c. Knockdown of SP1 with siRNA restored α‐synuclein accumulation, inflammation and apoptosis in MPP+‐induced SH‐SY5Y cells. Collectively, this current work presents that miR‐29c may directly target SP1 to protect against the neuroinflammatory and apoptotic responses in PD, providing a potential biomarker for PD diagnosis and treatment.

miR‐29c‐3p inhibits microglial NLRP3 inflammasome activation by targeting NFAT5 in Parkinson's disease

“…Our previous study suggested that the decreased expression of miR‐29c in PD models exhibited protective effects for neuronal injury (Wang, Yang, et al, 2019). Thus, this present work was set out to investigate the role of miR‐29c in microglial activation and inflammation.…”

“…The intracerebral or systemic injection of LPS can induce microglial activation, dopaminergic neuron death and pro‐inflammatory factor secretion (Huang et al, 2017; Qin et al, 2007), which is commonly used to establish a PD model. Our previous study showed that the decreased expression of miR‐29c suppressed the inflammation in MPP + ‐induced SH‐SY5Y neurons and MPTP‐treated animals (Wang, Yang, et al, 2019). The main features of PD are defined as microglial activation and dopaminergic neuron loss (Kong et al, 2019; Sun et al, 2019).…”

“…NFAT5 is a direct target of miR‐29c that can reverse the effect of miR‐29c on microglial inflammation. In addition to the protective effects on neuronal injury (Wang, Yang, et al, 2019), miR‐29c may attenuate inflammatory responses in activated microglia of PD through the suppression of NLRP3 inflammasome by targeting NFAT5, which provides a novel insight for understanding PD pathogenesis more completely.…”

“…miR‐29c‐3p (miR‐29c) has been shown to be underexpressed in PD and Alzheimer's diseases (Bai et al, 2017; Botta‐Orfila et al, 2014; Gui, Liu, Zhang, Lv, & Hu, 2015; Yang et al, 2015). Our previous study suggests that low expression of miR‐29c ameliorates inflammation and apoptosis in MPP + ‐induced neurons and MPTP‐treated PD animal models (Wang, Yang, Wang, He, & Li, 2019). But the role of miR‐29c in activated microglia is unclear.…”

MicroRNA: A Key Player for the Interplay of Circadian Rhythm Abnormalities, Sleep Disorders and Neurodegenerative Diseases

“…The miR-29 family members are particularly interesting in this regard, because the expressions of miR-29a and miR-29c are both down-regulated in PD [145]. Further, blood miR-29a is overexpressed in levodopa-treated patients with PD [146] and miR-29c overexpression attenuated dopaminergic neuron loss and α-synuclein accumulation in the SN of PD mice [147]. The targets of the miR-29 family also include PER proteins, although the rhythmicity of the miR-29 family has not been reported yet [21,148].…”