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Neuronal activity regulates DROSHA via autophagy in spinal muscular atrophy

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Item Type:Article
Title:Neuronal activity regulates DROSHA via autophagy in spinal muscular atrophy
Creators Name:Gonçalves, I.C.G., Brecht, J., Thelen, M.P., Rehorst, W.A., Peters, M., Lee, H.J., Motameny, S., Torres-Benito, L., Ebrahimi-Fakhari, D., Kononenko, N.L., Altmüller, J., Vilchez, D., Sahin, M., 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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