Suppression of microRNA-342-3p increases glutamate transporters and prevents dopaminergic neuron loss through activating the Wnt signaling pathway via p21-activated kinase 1 in mice with Parkinson's disease

Abstract

Development of effective therapeutic drugs for Parkinson's disease (PD) is of great importance. Aberrant microRNA (miRNA) expression has been identified in postmortem human PD brain samples, in vitro and in vivo PD models. However, the role of miR-342-3p in PD has been understudied. The study explores the effects of miR-342-3p on expression of glutamate (Glu) transporter, and dopaminergic neuron apoptosis and proliferation by targeting p21-activated kinase 1 (PAK1) through the Wnt signaling pathway in PD mice. After establishment of PD mouse models, gain- or loss-of-function assay was performed to explore the functional role of miR-342-3p in PD. Number of apoptotic neurons and Glu concentration was then determined. Subsequently, PC12 cells were treated with miR-342-3p mimic, miR-342-3p inhibitor, dickkopf-1 (DKK1), and miR-342-3p inhibitor + DKK1. The expression of miR-342-3p, PAK1, the Wnt signaling pathway-related and apoptosis-related genes, Glutamate transporter subtype 1 (GLT-1), l-glutamate/ l-aspartate transporter (GLAST), tyrosine hydroxylase (TH) was measured. Also, cell viability and apoptosis were evaluated. PD mice exhibited increased miR-342-3p, while decreased expression of PAK1, GLT-1, GLAST, TH, and the Wnt signaling pathway-related and antiapoptosis genes. miR-342-3p downregulation could promote expression of PAK1, the Wnt signaling pathway-related and antiapoptosis genes. GLT-1, GLAST, and TH as well as cell viability, but reduce cell apoptosis rate. The results indicated that suppression of miR-342-3p improves expression of Glu transporter and promotes dopaminergic neuron proliferation while suppressing apoptosis through the Wnt signaling pathway by targeting PAK1 in mice with PD.