title: Downregulation of miR-384-5p attenuates rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through inhibiting endoplasmic reticulum stress.
abstract: Endoplasmic reticulum (ER) stress has been linked to the pathogenesis of Parkinson's disease (PD). However, the role of microRNAs (miRNAs) in this process involved in PD remains poorly understood. Recent studies indicate that miR-384-5p plays an important role for cell survival in response to different insults, but the role of miR-384-5p in PD-associated neurotoxicity remains unknown. In this study, we investigated the role of miR-384-5p in an in vitro model of PD using dopaminergic SH-SY5Y cells treated with rotenone. We found that miR-384-5p was persistently induced by rotenone in neurons. Also, the inhibition of miR-384-5p significantly suppressed rotenone-induced neurotoxicity, while overexpression of miR-384-5p aggravated rotenone-induced neurotoxicity. Through bioinformatics and dual-luciferase reporter assay, miR-384-5p was found to directly target the 3'-untranslated region of glucose-regulated protein 78 (GRP78), the master regulator of ER stress sensors. Quantitative polymerase chain reaction and Western blotting analysis showed that miR-384-5p negatively regulated the expression of GRP78. Inhibition of miR-384-5p remarkably suppressed rotenone-evoked ER stress, which was evident by a reduction in the phosphorylation of activating transcription factor 4 (ATF4) and inositol-requiring enzyme 1 (IRE1α). The downstream target genes of ER stress including CCAAT/enhancer-binding protein-homologous protein (CHOP) and X box-binding protein-1 (XBP-1) were also decreased by the miR-384-5p inhibitor. In contrast, overexpression of miR-384-5p enhanced ER stress signaling. In addition, knockdown of GRP78 significantly abrogated the inhibitory effect of miR-384-5p inhibitors on cell apoptosis and ER stress signaling. Moreover, we observed a significant increase of miR-384-5p expression in primary neurons induced by rotenone. Taken together, our results suggest that miR-384-5p mediated ER stress by negatively regulating GRP78 and that miR-384-5p inhibition might be a novel and promising approach for the treatment of PD.
authors: Department of Neurology, Chinese PLA General Hospital, Beijing, China; Department of Neurology, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China;
authors: Mingfang
authors: M
authors: Jiang
authors: Department of Neurosurgery, Inner Mongolia People's Hospital, Hohhot, China;
authors: Qiang
authors: Q
authors: Yun
authors: Department of Radiology, Inner Mongolia Chinese Medicine Hospital, Hohhot, China; and.
authors: Feng
authors: F
authors: Shi
authors: Department of Radiology, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China.
authors: Guangming
authors: G
authors: Niu
authors: Department of Radiology, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China.
authors: Yang
authors: Y
authors: Gao
authors: Department of Radiology, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China.
authors: Shenghui
authors: S
authors: Xie
authors: Department of Neurology, Chinese PLA General Hospital, Beijing, China; shengyuanyubj@sina.com.
authors: Shengyuan
authors: S
authors: Yu
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D012402:Rotenone / Q000633:toxicity*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000619341:MIRN384 microRNA, human; D035683:MicroRNAs; D009498:Neurotoxins; D012402:Rotenone
keywords: GRP78; Parkinson's disease; endoplasmic reticulum stress; miR-384-5p