miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons

Anna-Elisa Roser; Lucas Caldi Gomes; Rashi Halder; Gaurav Jain; Fabian Maass; Lars Tönges; Lars Tatenhorst; Mathias Bähr; André Fischer; Paul Lingor

doi:10.1016/j.omtn.2018.01.005

miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons

Mol Ther Nucleic Acids. 2018 Jun 1:11:9-22. doi: 10.1016/j.omtn.2018.01.005. Epub 2018 Feb 2.

Authors

Affiliations

¹ 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.
² Department of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Lower-Saxony, Germany.
³ Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075 Göttingen, Lower-Saxony, Germany.
⁴ Department of Neurology, Ruhr-Universität Bochum, Universitätsstr. 150, 44801 Bochum, NRW, Germany.
⁵ 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 for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075 Göttingen, Lower-Saxony, Germany; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Von-Siebold-Str. 3a, 37075 Göttingen, Lower-Saxony, Germany.
⁶ 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. Electronic address: plingor@gwdg.de.

Abstract

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.

Keywords: GDNF; MPTP; dopaminergic neuron; miRNA.