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

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

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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.

Original languageEnglish
Article number399
JournalFrontiers in Cellular Neuroscience
Volume13
DOIs
Publication statusPublished - Sep 13 2019

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Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Chiu, C. C., Yeh, T. H., Chen, R. S., Chen, H. C., Huang, Y. Z., Weng, Y. H., Cheng, Y. C., Liu, Y. C., Cheng, A. J., Lu, Y. C., Chen, Y. J., Lin, Y. W., Hsu, C. C., Chen, Y. L., Lu, C. S., & Wang, H. L. (2019). Upregulated Expression of MicroRNA-204-5p Leads to the Death of Dopaminergic Cells by Targeting DYRK1A-Mediated Apoptotic Signaling Cascade. Frontiers in Cellular Neuroscience, 13, [399]. https://doi.org/10.3389/fncel.2019.00399