Abstract
BackgroundMicroglia-mediated neuroinflammation plays an important role in Parkinson’s disease (PD), and it exerts proinflammatory or anti-inflammatory effects depending on the M1/M2 polarization phenotype. Hence, promoting microglia toward the anti-inflammatory M2 phenotype is a potential therapeutic approach for PD. Long noncoding RNAs (lncRNAs) are crucial in the progression of neurodegenerative diseases, but little is known about their role in microglial polarization in PD.MethodsIn our study, we profiled the expression of lncRNAs in the peripheral blood mononuclear cells (PBMCs) of PD patients using a microarray. RT-qPCR was used to evaluate the lncRNA levels and mRNA levels of cytokines and microglial cell markers both in vitro and in vivo. RIP and ChIP assays were analyzed for the underlying mechanism of lncRNA regulating microglial polarization.ResultsWe found that HOXA-AS2 was upregulated in the PBMCs of PD patients and negatively associated with peroxisome proliferator-activated receptor gamma coactivator-1a (PGC-1α) expression. Moreover, HOXA-AS2 knockdown significantly repressed microglial M1 polarization and promoted M2 polarization by regulating PGC-1α expression. Mechanistic investigations demonstrated that HOXA-AS2 could directly interact with polycomb repressive complex 2 (PRC2) and modulate the histone methylation of the promoter of PGC-1α.ConclusionsOur findings identify the upregulated lncRNA HOXA-AS2 promotes neuroinflammation by regulating microglial polarization through interacts with the PRC2 complex and epigenetically silencing PGC-1α. HOXA-AS2 may be a potential therapeutic target for microglia-mediated neuroinflammation in patients with PD.
Highlights
Microglia-mediated neuroinflammation plays an important role in Parkinson’s disease (PD), and it exerts proinflammatory or anti-inflammatory effects depending on the M1/M2 polarization phenotype
HOXA-AS2 is involved in microglial polarization in PD To identify potential Long noncoding RNAs (lncRNAs) participating in the regulation of microglial polarization in PD patients, we performed RNA-sequencing (RNA-seq) analysis to detect differentially expressed lncRNAs in peripheral blood mononuclear cells (PBMCs) from 5 PD patients and 4 healthy controls
HOXA cluster antisense RNA 2 (HOXA-AS2) was one of the most abundantly expressed lncRNAs, which was significantly increased in PD patients (5.35 ± 0.27 vs. 11.39 ± 0.07, Fig. 1B) and has been found to be associated with multiple inflammationlinked cancers [25]
Summary
Microglia-mediated neuroinflammation plays an important role in Parkinson’s disease (PD), and it exerts proinflammatory or anti-inflammatory effects depending on the M1/M2 polarization phenotype. Promoting microglia toward the anti-inflammatory M2 phenotype is a potential therapeutic approach for PD. Long noncoding RNAs (lncRNAs) are crucial in the progression of neurodegenerative diseases, but little is known about their role in microglial polarization in PD. Parkinson’s disease (PD) is a neurodegenerative disorder caused by genetic and environmental factors that result in the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) of the midbrain [1]. Microglia-mediated neuroinflammation plays an important role in the pathogenesis of PD and is inversely related to the survival of DA neurons [2]. Promoting microglia toward the M2 phenotype is a potential therapeutic approach to suppress neuroinflammation
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