LncRNA MALAT1 facilitates inflammasome activation via epigenetic suppression of Nrf2 in Parkinson’s disease

Abstract

The goal of the present study was to elucidate the mechanism by which long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) promotes inflammation in Parkinson’s disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to induce PD development in C57BL/6 mice, and tyrosine hydroxylase (TH) expression was analysed by immunohistochemical analysis. Western blot and qPCR analyses were conducted to assess the expression of protein and mRNA levels, respectively. Lipopolysaccharide/adenosine triphosphate (LPS/ATP) was used to activate microglia in vitro. Chromatin immunoprecipitation (ChIP), RNA pull-down and RNA immunoprecipitation chip (RIP) assays were performed to investigate the interaction among specific molecules. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate cell viability and proliferation. Flow cytometry was performed to analyse cell apoptosis after staining. The dichlorofluorescein diacetate (DCFH-DA) assay was used to measure the generation of reactive oxygen species (ROS) in cells. The results showed that MALAT1 was highly expressed in the brains of MPTP-induced PD model mice and in LPS/ATP-induced microglia cells. Knockdown of MALAT1 inhibited elevated nuclear factor (erythroid-derived 2)-like-2 factor (NRF2) expression, thereby inhibiting inflammasome activation and ROS production. MALAT1 was shown to promote neuroinflammation by recruiting enhancer of zeste homologue 2 (EZH2) to the promoter of NRF2, suppressing Nrf2 expression. In summary, MALAT1 epigenetically inhibits NRF2, thereby inducing inflammasome activation and reactive oxygen species (ROS) production in PD mouse and microglial cell models.

Long non‐coding RNA MALAT1 regulates cell proliferation and apoptosis via miR-135b-5p/GPNMB axis in Parkinson’s disease cell model

“…Besides, Liu et al indicated that MALAT1 promoted the apoptosis by sponging miR-124 in mouse models of PD and in vitro model of PD [ 33 ]. Cai et al showed that MALAT1 could induce inflammasome activation and reactive oxygen species (ROS) production in PD mouse and microglial cell models by epigenetically inhibiting NRF2 [ 34 ]. Consistent with previous research, in our study, MALAT1 depletion rescued the decreased cell proliferation and increased apoptosis in MPP + -treated SK-N-BE and SK-N-BE cells, indicating the pivotal role of MALAT1 in the apoptosis of neurons in PD.…”

Commentary: LncRNA-T199678 Mitigates α-Synuclein-Induced Dopaminergic Neuron Injury via miR-101-3p

“…Mounting evidence has shown that lncRNAs are involved in regulating neuroinflammation, oxidative stress (Cai et al, 2020), apoptosis (Zhang et al, 2020), and autophagy (Yan et al, 2018) that are related to the pathogenesis of PD. Differentially expressed lncRNAs were identified in the circulating leukocytes of patients with PD as well as healthy subjects (Fan et al, 2019).…”

Epigenetic Modulation of Microglia Function and Phenotypes in Neurodegenerative Diseases

“…Additionally, long ncRNAs (lncRNAs) have major roles in NDDs. Cai et al [ 162 ] have demonstrated that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1(lncRNA MALAT1) epigenetically suppresses the expression of Nrf2 and triggers inflammatory response in PD mice and BV-2 cells. A novel lncRNA termed Nostrill is highly expressed in LPS-stimulated microglia cells with concomitant increased expression of iNOS.…”