MiR-421 Aggravates Neurotoxicity and Promotes Cell Death in Parkinson's Disease Models by Directly Targeting MEF2D

Parkinson's disease (PD) is a severe neurodegenerative disease characterized by selective loss of dopaminergic neurons, which reduces quality of life of patients and poses a heavy burden to the society. The pathological mechanism of PD remains unclear, and increasing efforts are aimed to solve this problem. MiRNAs are a kind of small noncoding RNA regulating target gene expression. Previous studies have shown that dysregulation of miRNAs is involved in the development of PD. In the present study, we determined that miR-421 and MEF2D are increased and decreased, respectively, in a cellular model of PD. The data on the mechanism of action indicate that miR-421 directly binds to MEF2D mRNA and negatively regulates MEF2D expression. An increase in miR-421 disrupted the Bcl2/Bax system. Functional assays indicated that enhanced miR-421 promotes cell death by negative modulation of MEF2D expression. Inhibition of miR-421 or restoration of MEF2D protected neurons from neurotoxicity in cellular and animal models of PD. Our study is the first to demonstrate that miR-421 is decreased in PD models and to determine a novel putative mechanism of PD pathogenesis.