1. miR-103a-3p regulates mitophagy in Parkinson's disease through Parkin/Ambra1 signaling.
- Author
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Zhou J, Zhao Y, Li Z, Zhu M, Wang Z, Li Y, Xu T, Feng D, Zhang S, Tang F, and Yao J
- Subjects
- 3' Untranslated Regions genetics, Animals, Cell Line, Computational Biology, Dopamine metabolism, Humans, MPTP Poisoning drug therapy, MPTP Poisoning genetics, Male, Mice, Mice, Inbred C57BL, MicroRNAs antagonists & inhibitors, Mitochondria drug effects, Mitochondria metabolism, Neuroprotective Agents pharmacology, Neuroprotective Agents therapeutic use, Point Mutation, RNA, Small Interfering pharmacology, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, MicroRNAs genetics, Mitophagy genetics, Parkinson Disease genetics, Parkinson Disease metabolism, Signal Transduction drug effects, Signal Transduction genetics, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism
- Abstract
Parkin is a crucial protein that promotes the clearance of damaged mitochondria via mitophagy in neuron, and parkin mutations result in autosomal-recessive Parkinson's disease (AR-PD). However, the exact mechanisms underlying the regulation of Parkin-mediated mitophagy in PD remain unclear. In this study, PD models were generated through incubation of SH-SY5Y cells with 1-methyl-4-phenylpyridinium ion (MPP
+ , 1.5 mM for 24 h) and intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg for five consecutive days) in mice. A Bioinformatics database was used to identify Parkin-targeting microRNAs (miRNAs). Then, miR-103a-3p agomir, miR-103a-3p antagomir and Parkin siRNA were used to assess the effects of miR-103a-3p/Parkin/Ambra1 signaling-mediated mitophagy in PD in vitro and in vivo. The protein and mRNA levels of Parkin and Ambra1 were significantly decreased, while miR-103a-3p, which is a highly expressed miRNA in the human brain, was obviously increased in PD mouse and SH-SY5Y cell models. Moreover, miR-103a-3p suppressed Parkin expression by targeting a conserved binding site in the 3'-untranslated region (UTR) of Parkin mRNA. Importantly, miR-103a-3p inhibition resulted in neuroprotective effects and improved mitophagy in vitro and in vivo, whereas Parkin siRNA strongly abolished these effects. These findings suggested that miR-103a-3p inhibition has neuroprotective effects in PD, which may be involved in regulating mitophagy through the Parkin/Ambra1 pathway. Modulating miR-103a-3p levels may be an applicable therapeutic strategy for PD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2020
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