MiR-29a efficiently suppresses the generation of reactive oxygen species and α-synuclein in a cellular model of Parkinson's disease by potentially targeting GSK-3β

Ya-Ling Yang; Tsu-Kung Lin; Ying-Hsien Huang

doi:10.1016/j.ejphar.2024.176615

MiR-29a efficiently suppresses the generation of reactive oxygen species and α-synuclein in a cellular model of Parkinson's disease by potentially targeting GSK-3β

Eur J Pharmacol. 2024 Apr 27:974:176615. doi: 10.1016/j.ejphar.2024.176615. Online ahead of print.

Authors

Ya-Ling Yang¹, Tsu-Kung Lin², Ying-Hsien Huang³

Affiliations

¹ Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan.
² Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan.
³ Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital, and Chang, Gung University College of Medicine, Kaohsiung, 83301, Taiwan; Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, and Chang, Gung University College of Medicine, Kaohsiung, 83301, Taiwan. Electronic address: yhhuang123@yahoo.com.tw.

PMID: 38685306
DOI: 10.1016/j.ejphar.2024.176615

Abstract

MicroRNA-29a (miR-29a) has been suggested to serve a potential protective function against Parkinson's disease (PD); however, the exact molecular mechanisms remain elusive. This study explored the protective role of miR-29a in a cellular model of PD using SH-SY5Y cell lines through iTRAQ-based quantitative proteomic and biochemistry analysis. The findings showed that using a miR-29a mimic in SH-SY5Y cells treated with 1-methyl-4-phenylpyridinium (MPP+) significantly decreased cell death and increased mitochondrial membrane potential. It also reduced mitochondrial reactive oxygen species (ROS) and the production of α-synuclein. Subsequent heatmap analysis using iTRAQ-based quantitative proteomics revealed remarkably contrasting protein expression profiles for 882 genes when comparing the groups treated with miR-29a mimic plus MPP + against the control group treated solely with MPP+. The KEGG pathway analysis of these 882 genes indicated the substantial role of miR-29a in the PD pathway (P = 1.58x10^-5) and highlighted its function in mitochondrial genes. Furthermore, treatment with a miR-29a mimic in SH-SY5Y cells reduced the levels of GSK-3β, phosphorylated GSK-3β, and cleaved caspase-7 following exposure to MPP+. The miR-29a mimic also upregulated the expressions of α-synuclein clearance proteins FYCO1 and Rab7 in this cellular PD model, thereby inhibiting the production of α-synuclein. Luciferase activity analysis confirmed the specific binding of miR-29a to the 3' untranslated region (3'UTR) of GSK-3β, leading to its repression. Our findings demonstrated miR-29a's neuroprotective role in mitochondrial function and highlighted its potential to inhibit ROS and α-synuclein production, offering possible therapeutic avenues for PD treatment.

Keywords: Cellular death; GSK-3β; MicroRNA-29a; Parkinson's disease; α-synuclein.