miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons
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; howe...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253118300064 |
| _version_ | 1819226328623218688 |
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| author | Anna-Elisa Roser Lucas Caldi Gomes Rashi Halder Gaurav Jain Fabian Maass Lars Tönges Lars Tatenhorst Mathias Bähr André Fischer Paul Lingor |
| author_facet | Anna-Elisa Roser Lucas Caldi Gomes Rashi Halder Gaurav Jain Fabian Maass Lars Tönges Lars Tatenhorst Mathias Bähr André Fischer Paul Lingor |
| author_sort | Anna-Elisa Roser |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T10:23:45Z |
| format | Article |
| id | doaj.art-2b894efe541043428ce7a50a12cb929a |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-23T10:23:45Z |
| publishDate | 2018-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-2b894efe541043428ce7a50a12cb929a2022-12-21T17:50:37ZengElsevierMolecular Therapy: Nucleic Acids2162-25312018-06-0111C92210.1016/j.omtn.2018.01.005miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain NeuronsAnna-Elisa Roser0Lucas Caldi Gomes1Rashi Halder2Gaurav Jain3Fabian Maass4Lars Tönges5Lars Tatenhorst6Mathias Bähr7André Fischer8Paul Lingor9Department of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Lower-Saxony, GermanyDepartment of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Lower-Saxony, GermanyDepartment for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075 Göttingen, Lower-Saxony, GermanyDepartment for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075 Göttingen, Lower-Saxony, GermanyDepartment of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Lower-Saxony, GermanyDepartment of Neurology, Ruhr-Universität Bochum, Universitätsstr. 150, 44801 Bochum, NRW, GermanyDepartment of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Lower-Saxony, GermanyDepartment of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Lower-Saxony, GermanyDFG Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Lower-Saxony, GermanyDepartment of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Lower-Saxony, GermanyParkinson’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.http://www.sciencedirect.com/science/article/pii/S2162253118300064miRNAGDNFdopaminergic neuronMPTP |
| spellingShingle | Anna-Elisa Roser Lucas Caldi Gomes Rashi Halder Gaurav Jain Fabian Maass Lars Tönges Lars Tatenhorst Mathias Bähr André Fischer Paul Lingor miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons Molecular Therapy: Nucleic Acids miRNA GDNF dopaminergic neuron MPTP |
| title | miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons |
| title_full | miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons |
| title_fullStr | miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons |
| title_full_unstemmed | miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons |
| title_short | miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons |
| title_sort | mir 182 5p and mir 183 5p act as gdnf mimics in dopaminergic midbrain neurons |
| topic | miRNA GDNF dopaminergic neuron MPTP |
| url | http://www.sciencedirect.com/science/article/pii/S2162253118300064 |
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