MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor symptoms due to the selective loss of midbrain dopaminergic neurons. The evidence for a chronic inflammatory reaction mediated by microglial cells in the brain is particularly strong in PD. In our previous study, we have shown that brain‐specific microRNA‐124 (miR‐124) is significantly down‐regulated in the 1‐methy1‐4‐pheny1‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced mouse model of PD and that it can also inhibit neuroinflammation during the development of PD. However, further investigation is required to understand whether the abnormal expression of miR‐124 regulates microglial activation. In this study, we found that the expression of sequestosome 1 (p62) and phospho‐p38 mitogen‐activated protein kinases (p‐p38) showed a significant increase in LPS‐treated immortalized murine microglial cell line BV2 cells in an MPTP‐induced mouse model of PD. Knockdown of p62 could suppress the secretion of proinflammatory cytokines and p‐p38 of microglia. Besides, inhibition of p38 suppressed the secretion of proinflammatory cytokines and promoted autophagy in BV2 cells. Moreover, our study is the first to identify a unique role of miR‐124 in mediating the microglial inflammatory response by targeting p62 and p38 in PD. In the microglial culture supernatant transfer model, the knockdown of p62 in BV2 cells prevented apoptosis and death of human neuroblastoma cell lines SH‐SY5Y (SH‐SY5Y) cells following microglia activation. In addition, the exogenous delivery of miR‐124 could suppress p62 and p‐p38 expression and could also attenuate the activation of microglia in the substantia nigra par compacta of MPTP‐treated mice. Taken together, our data suggest that miR‐124 could inhibit neuroinflammation during the development of PD by targeting p62, p38, and autophagy, indicating that miR‐124 could be a potential therapeutic target for regulating the inflammatory response in PD.—Yao, L., Zhu, Z., Wu, J., Zhang, Y., Zhang, H., Sun, X., Qian, C., Wang, B., Xie, L., Zhang, S., Lu, G. MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease. FASEB J. 33,8648–8665 (2019). http://www.fasebj.org

MiR-124 and the Underlying Therapeutic Promise of Neurodegenerative Disorders

“…It has been suggested that miR-124 is significantly downregulated in the MPTP-induced PD mouse model and that it inhibits neuroinflammation during the development of PD (Ridolfi and Abdel-Haq, 2017;Yao et al, 2018). Yao et al (2019) reported that miR-124 inhibits inflammation during the development of PD by targeting p38, p62, and autophagy, suggesting that miR-124 may be a promising treatment target for regulating the inflammatory response in patients with PD. Dong et al (2018) evaluated the mechanism and effects of miR-124 on SH-SY5Y cells and 6hydroxydopamine (6-OHDA)-induced neurotoxicity in PC12 and reported that the miR-124-3p level was downregulated.…”

“…A similar approach has been used to treat PD. Yao et al (2019) reported that exogenous delivery of miR-124 suppresses the expression of p38 and p62 and attenuates microglia activation in the substantia nigra pars compacta of MPTP-treated mice. However, the disadvantages of viral vectors (such as the immunogenicity/inflammatory response and low loading capacity) limit their application in gene delivery and make it difficult to achieve large-scale manufacturing and quality control (Itaka and Kataoka, 2009;Ma et al, 2018;Pfister et al, 2018).…”

Circulating Brain‐Enriched MicroRNAs for Detection and Discrimination of Idiopathic and Genetic Parkinson's Disease

“…and ) or target PD‐associated proteins including leucine‐rich repeat kinase 2 (LRRK2; miR‐205), SNCA (miR‐7, miR‐153), GBA (miR‐22), Parkinson disease protein 7 (PARK7/DJ‐1; miR‐544), and nuclear receptor subfamily 4 group A2 (NR4A2/nuclear receptor related 1 protein (Nurr1); miR‐132) . In addition, several miRNAs, whose expression is enriched in the brain, target PD‐relevant processes, including mammalian target of rapamycin (mTOR) signaling, autophagy, and inflammation or protect neurons from PD stressors such 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and 6‐hydroxydopamine …”

“…25 and 26) or target PD-associated proteins including leucine-rich repeat kinase 2 (LRRK2; miR-205), 27 SNCA (miR-7, miR-153), 28,29 GBA (miR-22), 30 Parkinson disease protein 7 (PARK7/DJ-1; miR-544), 31 and nuclear receptor subfamily 4 group A2 (NR4A2/nuclear receptor related 1 protein (Nurr1); miR-132). 32 In addition, several miRNAs, whose expression is enriched in the brain, target PD-relevant processes, including mammalian target of rapamycin (mTOR) signaling, 33,34 autophagy, [34][35][36] and inflammation [37][38][39][40][41] or protect neurons from PD stressors such 1-methyl-4-phenyl-1,-2,3,6-tetrahydropyridine (MPTP) 33,42-44 and 6hydroxydopamine. 45,46 Recent studies, yet of not a critical mass, have identified deregulated miRNAs in the cerebral spinal fluid or blood (peripheral blood mononuclear cells (PBMC), serum, plasma) of PD patients.…”

The Potential Role of MicroRNA-124 in Cerebral Ischemia Injury

“…Yao et al identified a unique protective role of the exogenous delivery of miR-124, which could effectively attenuate the activation of microglial in the substantia nigra pars compacta of MPTP-induced PD model via targeting and suppressing mitogen-activated protein kinase kinase kinase 3 (MEKK3)/NF-kB signaling pathway [52]. Moreover, miR-124 could also target and downregulate the expression of sequestosome 1 (p62) and phosphor-p38 mitogen-activated protein kinase (p-p38), suppressing the activation of microglia and downregulating inflammatory response in PD [53].…”