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| Item Type: | Article |
|---|---|
| Title: | Neuronal activity regulates DROSHA via autophagy in spinal muscular atrophy |
| Creators Name: | Gonçalves, I.C.G. and Brecht, J. and Thelen, M.P. and Rehorst, W.A. and Peters, M. and Lee, H.J. and Motameny, S. and Torres-Benito, L. and Ebrahimi-Fakhari, D. and Kononenko, N.L. and Altmüller, J. and Vilchez, D. and Sahin, M. and Wirth, B. and Kye, M.J. |
| Abstract: | Dysregulated miRNA expression and mutation of genes involved in miRNA biogenesis have been reported in motor neuron diseases including spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Therefore, identifying molecular mechanisms governing miRNA expression is important to understand these diseases. Here, we report that expression of DROSHA, which is a critical enzyme in the microprocessor complex and essential for miRNA biogenesis, is reduced in motor neurons from an SMA mouse model. We show that DROSHA is degraded by neuronal activity induced autophagy machinery, which is also dysregulated in SMA. Blocking neuronal activity or the autophagy-lysosome pathway restores DROSHA levels in SMA motor neurons. Moreover, reducing DROSHA levels enhances axonal growth. As impaired axonal growth is a well described phenotype of SMA motor neurons, these data suggest that DROSHA reduction by autophagy may mitigate the phenotype of SMA. In summary, these findings suggest that autophagy regulates RNA metabolism and neuronal growth via the DROSHA/miRNA pathway and this pathway is dysregulated in SMA. |
| Keywords: | Autophagy, Animal Disease Models, Knockout Mice, MicroRNAs, Motor Neurons, Spinal Muscular Atrophy, Phenotype, Ribonuclease III, Subcellular Fractions, Survival of Motor Neuron 1 Protein, Animals, Mice |
| Source: | Scientific Reports |
| ISSN: | 2045-2322 |
| Publisher: | Nature Publishing Group |
| Volume: | 8 |
| Number: | 1 |
| Page Range: | 7907 |
| Date: | 21 May 2018 |
| Additional Information: | Erratum in: Sci Rep 8(1):10294 and Sci Rep 10(1):8206 |
| Official Publication: | https://doi.org/10.1038/s41598-018-26347-y |
| PubMed: | View item in PubMed |
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