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.

帕金森病(Parkinson's disease, PD)是一种严重的神经退行性疾病，其特征是多巴胺能神经元选择性丢失，降低了患者的生活质量，给社会带来了沉重的负担。PD的病理机制尚不明确，解决这一问题的努力也在不断加大。miRNA是一种调控靶基因表达的非编码小RNA。先前的研究表明，miRNA 的失调参与了 PD 的发展。在本研究中，我们确定 miR-421 和 MEF2D 在 PD 细胞模型中分别增加和减少。有关作用机制的数据表明，miR-421 直接与 MEF2D mRNA 结合并负调节 MEF2D 表达。miR-421 的增加破坏了 Bcl2/Bax 系统。功能分析表明，增强的 miR-421 通过对 MEF2D 表达的负调节来促进细胞死亡。抑制 miR-421 或恢复 MEF2D 可保护神经元免受 PD 细胞和动物模型中的神经毒性。我们的研究首次证明 miR-421 在 PD 模型中降低，并确定了一种新的 PD 发病机制。