Parkinson’s disease (PD) is the second-most-frequent neurodegenerative disorder worldwide. One major hallmark of PD is the degeneration of dopaminergic (DA) neurons in the substantia nigra. Glial cell line-derived neurotrophic factor (GDNF) potently increases DA neuron survival in models of PD; however, the underlying mechanisms are incompletely understood. MicroRNAs (miRNAs) are small, non-coding RNAs that are important for post-transcriptional regulation of gene expression. Using small RNA sequencing, we show that GDNF specifically increases the expression of miR-182-5p and miR-183-5p in primary midbrain neurons (PMNs). Transfection of synthetic miR-182-5p and miR-183-5p mimics leads to increased neurite outgrowth and mediates neuroprotection of DA neurons in vitro and in vivo, mimicking GDNF effects. This is accompanied by decreased expression of FOXO3 and FOXO1 transcription factors and increased PI3K-Akt signaling. Inhibition of endogenous miR-182-5p or miR-183-5p in GDNF-treated PMNs attenuated the pro-DA effects of GDNF. These findings unveil an unknown miR-mediated mechanism of GDNF action and suggest that targeting miRNAs is a new therapeutic avenue to PD phenotypes.

帕金森氏病（PD）是全球第二常见的神经退行性疾病。PD的一个主要标志是黑质中多巴胺能（DA）神经元的变性。胶质细胞源性神经营养因子（GDNF）在PD模型中有效地增加了DA神经元的存活。但是，潜在的机制尚不完全清楚。MicroRNA（miRNA）是小的非编码RNA，对于基因表达的转录后调控非常重要。使用小RNA测序，我们显示GDNF特异性地增加了miR-182-5p和miR-183-5p在原发性中脑神经元（PMNs）中的表达。合成的miR-182-5p和miR-183-5p模拟引线的转染到DA神经元的增加神经突向外生长和神经保护介导在体外和体内，模仿GDNF效果。这伴随着FOXO3和FOXO1转录因子的表达减少以及PI3K-Akt信号传导增加。GDNF处理的PMN中内源性miR-182-5p或miR-183-5p的抑制作用减弱了GDNF的pro-DA效应。这些发现揭示了未知的miR介导的GDNF作用机制，并表明靶向miRNA是PD表型的新治疗途径。