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Sci Rep. 2018 May 21;8(1):7907. doi: 10.1038/s41598-018-26347-y.

Neuronal activity regulates DROSHA via autophagy in spinal muscular atrophy.

Author information

1
Institute of Human Genetics, University of Cologne, Cologne, 50931, Germany.
2
Center for Molecular Medicine Cologne, University of Cologne, Cologne, 50931, Germany.
3
Institute for Genetics, University of Cologne, Cologne, 50931, Germany.
4
Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany.
5
Cologne Center for Genomics (CCG), University of Cologne, 50931, Cologne, Germany.
6
Department of Neurology, The F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
7
Center for Rare Diseases, University Hospital Cologne, Cologne, Germany.
8
Institute of Human Genetics, University of Cologne, Cologne, 50931, Germany. Min.kye@uk-koeln.de.

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.

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