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Front Cell Neurosci. 2019 Sep 13;13:399. doi: 10.3389/fncel.2019.00399. eCollection 2019.

Upregulated Expression of MicroRNA-204-5p Leads to the Death of Dopaminergic Cells by Targeting DYRK1A-Mediated Apoptotic Signaling Cascade.

Chiu CC1,2,3,4,5, Yeh TH6,7, Chen RS1,2,4,8, Chen HC9, Huang YZ1,2,4,8,10, Weng YH1,2,4,8, Cheng YC11, Liu YC12, Cheng AJ5, Lu YC5, Chen YJ1, Lin YW1, Hsu CC1,4, Chen YL3, Lu CS1,2,4,8, Wang HL1,2,4,13.

Author information

1
Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
2
Healthy Aging Research Center, Chang Gung University College of Medicine, Taoyuan, Taiwan.
3
Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
4
Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
5
Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
6
Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan.
7
School of Medicine, Taipei Medical University, Taipei, Taiwan.
8
College of Medicine, Chang Gung University, Taoyuan, Taiwan.
9
Genomic Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
10
Institute of Cognitive Neuroscience, National Central University, Taoyuan, Taiwan.
11
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
12
Division of Sports Medicine, Taiwan Landseed Hospital, Taoyuan, Taiwan.
13
Department of Physiology and Pharmacology, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Abstract

MicroRNAs (miRs) downregulate or upregulate the mRNA level by binding to the 3'-untranslated region (3'UTR) of target gene. Dysregulated miR levels can be used as biomarkers of Parkinson's disease (PD) and could participate in the etiology of PD. In the present study, 45 brain-enriched miRs were evaluated in serum samples from 50 normal subjects and 50 sporadic PD patients. The level of miR-204-5p was upregulated in serum samples from PD patients. An upregulated level of miR-204-5p was also observed in the serum and substantia nigra (SN) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Expression of miR-204-5p increased the level of α-synuclein (α-Syn), phosphorylated (phospho)-α-Syn, tau, or phospho-tau protein and resulted in the activation of endoplasmic reticulum (ER) stress in SH-SY5Y dopaminergic cells. Expression of miR-204-5p caused autophagy impairment and activation of c-Jun N-terminal kinase (JNK)-mediated apoptotic cascade in SH-SY5Y dopaminergic cells. Our study using the bioinformatic method and dual-luciferase reporter analysis suggests that miR-204-5p positively regulates mRNA expression of dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) by directly interacting with 3'UTR of DYRK1A. The mRNA and protein levels of DYRK1A were increased in SH-SY5Y dopaminergic cells expressing miR-204-5p and SN of MPTP-induced PD mouse model. Knockdown of DYRK1A expression or treatment of the DYRK1A inhibitor harmine attenuated miR-204-5p-induced increase in protein expression of phospho-α-Syn or phospho-tau, ER stress, autophagy impairment, and activation of JNK-mediated apoptotic pathway in SH-SY5Y dopaminergic cells or primary cultured dopaminergic neurons. Our results suggest that upregulated expression of miR-204-5p leads to the death of dopaminergic cells by targeting DYRK1A-mediated ER stress and apoptotic signaling cascade.

KEYWORDS:

DYRK1A; ER stress; Parkinson’s disease; apoptotic signaling; autophagy; microRNA-204-5p

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