Roser Anna-Elisa, Caldi Gomes Lucas, Halder Rashi, Jain Gaurav, Maass Fabian, Tönges Lars, Tatenhorst Lars, Bähr Mathias, Fischer André, Lingor Paul
Department of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Lower-Saxony, Germany; DFG Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Lower-Saxony, Germany.
Department of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Lower-Saxony, Germany.
Mol Ther Nucleic Acids. 2018 Jun 1;11:9-22. doi: 10.1016/j.omtn.2018.01.005. Epub 2018 Feb 2.
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）神经元的退化。胶质细胞系源性神经营养因子（GDNF）在PD模型中能有效提高DA神经元的存活率；然而，其潜在机制尚未完全明确。微小RNA（miRNA）是一类小的非编码RNA，对基因表达的转录后调控很重要。通过小RNA测序，我们发现GDNF能特异性增加原代中脑神经元（PMN）中miR-182-5p和miR-183-5p的表达。转染合成的miR-182-5p和miR-183-5p模拟物可导致神经突生长增加，并在体外和体内介导DA神经元的神经保护作用，模拟GDNF的效应。这伴随着FOXO3和FOXO1转录因子表达的降低以及PI3K-Akt信号通路的增强。在GDNF处理的PMN中抑制内源性miR-182-5p或miR-183-5p可减弱GDNF对DA的促进作用。这些发现揭示了一种未知的miR介导的GDNF作用机制，并表明靶向miRNA是治疗PD表型的一条新途径。
