Goncalves, Ines do Carmo G., Brecht, Johanna, Thelen, Maximilian P., Rehorst, Wiebke A., Peters, Miriam, Lee, Hyun Ju, Motameny, Susanne, Torres-Benito, Laura, Ebrahimi-Fakhari, Darius ORCID: 0000-0002-0026-4714, Kononenko, Natalia L., Altmueller, Janine, Vilchez, David ORCID: 0000-0002-0801-0743, Sahin, Mustafa, Wirth, Brunhilde ORCID: 0000-0003-4051-5191 and Kye, Min Jeong ORCID: 0000-0002-1323-7256 (2018). Neuronal activity regulates DROSHA via autophagy in spinal muscular atrophy. Sci Rep, 8. LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Goncalves, Ines do Carmo G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brecht, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thelen, Maximilian P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rehorst, Wiebke A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peters, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, Hyun JuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torres-Benito, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ebrahimi-Fakhari, DariusUNSPECIFIEDorcid.org/0000-0002-0026-4714UNSPECIFIED
Kononenko, Natalia L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vilchez, DavidUNSPECIFIEDorcid.org/0000-0002-0801-0743UNSPECIFIED
Sahin, MustafaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDorcid.org/0000-0003-4051-5191UNSPECIFIED
Kye, Min JeongUNSPECIFIEDorcid.org/0000-0002-1323-7256UNSPECIFIED
URN: urn:nbn:de:hbz:38-186076
DOI: 10.1038/s41598-018-26347-y
Journal or Publication Title: Sci Rep
Volume: 8
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2045-2322
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
AMYOTROPHIC-LATERAL-SCLEROSIS; MICRORNA BIOGENESIS; MIRNA BIOGENESIS; MESSENGER-RNA; MOUSE MODEL; MOTOR-NEURONS; EXPRESSION; MUTATIONS; LOCALIZATION; DGCR8Multiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18607

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