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

Ching-Chi Chiu,Ching-Chi Chiu,Ching-Chi Chiu,Chia-Chen Hsu,Yan-Wei Lin,Rou-Shayn Chen,Chin-Song Lu,Yu-Jie Chen,Ya-Ching Lu,Hung-Li Wang,Tu-Hsueh Yeh,Yu-Chuan Liu,Yi-Hsin Weng,Yi-Chuan Cheng,Ying-Ling Chen,Ann-Joy Cheng,Rou-Shayn Chen,Ying-Zu Huang,Ying-Zu Huang,Ying-Zu Huang,Hung-Li Wang,Hua-Chien Chen

doi:10.3389/fncel.2019.00399

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.

Highlights

Parkinson’s disease (PD), the most common neurodegenerative motor disorder, is characterized by selective neuronal death of the substantia nigra (SN) pars compacta (SNpc) dopaminergic cells (Dickson et al, 2009)
To explore whether upregulated expression of miR-204-5p is involved in the pathogenesis of PD, we evaluated the level of miR204-5p in the SN of MPTP mouse model of PD (Chiu et al, 2015)
Dysregulated expression of miRs was identified in body fluids and brain tissues from patients affected with various neurodegenerative disorders, such as Alzheimer’s disease (AD), PD, and Huntington’s disease (HD) (Basak et al, 2016; Leggio et al, 2017; Khodadadian et al, 2018)

Summary

Introduction

Parkinson’s disease (PD), the most common neurodegenerative motor disorder, is characterized by selective neuronal death of the substantia nigra (SN) pars compacta (SNpc) dopaminergic cells (Dickson et al, 2009). Several studies reported that miRs regulate the level of PD genes, including SNCA, LRRK2, and Parkin (Arshad et al, 2017; Leggio et al, 2017; Martinez and Peplow, 2017; Singh and Sen, 2017). MiRs participate in the regulation of neuronal development, ER stress, mitochondrial function, and autophagy (Arshad et al, 2017; Lu et al, 2017; Singh and Sen, 2017). Dysregulated levels of miRs can be used for biomarkers of PD and are believed to participate in the etiology of PD (Lu et al, 2017; Ramaswamy et al, 2018; Roser et al, 2018)

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Results

Conclusion