miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons
| Autor: | Lucas Caldi Gomes, Gaurav Jain, Lars Tatenhorst, Anna-Elisa Roser, Fabian Maass, Rashi Halder, Andre Fischer, Lars Tönges, Paul Lingor, Mathias Bähr |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Neurite Substantia nigra Biochemistry biophysics & molecular biology [F05] [Life sciences] Neuroprotection Article 03 medical and health sciences chemistry.chemical_compound Neurotrophic factors dopaminergic neuron Drug Discovery Glial cell line-derived neurotrophic factor ddc:610 Biochimie biophysique & biologie moléculaire [F05] [Sciences du vivant] MPTP miRNA Regulation of gene expression biology Dopaminergic lcsh:RM1-950 GDNF Cell biology 030104 developmental biology lcsh:Therapeutics. Pharmacology chemistry nervous system biology.protein Molecular Medicine |
| Zdroj: | Molecular Therapy. Nucleic Acids Molecular Therapy: Nucleic Acids, Vol 11, Iss C, Pp 9-22 (2018) Molecular Therapy: Nucleic Acids. Elsevier (2018). Molecular Therapy / Nucleic Acids 11, 9-22 (2018). doi:10.1016/j.omtn.2018.01.005 |
| ISSN: | 2162-2531 |
| DOI: | 10.1016/j.omtn.2018.01.005 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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