SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits

Guillaume M. Hautbergue (), Lydia M. Castelli, Laura Ferraiuolo, Alvaro Sanchez-Martinez, Johnathan Cooper-Knock, Adrian Higginbottom, Ya-Hui Lin, Claudia S. Bauer, Jennifer E. Dodd, Monika A. Myszczynska, Sarah M. Alam, Pierre Garneret, Jayanth S. Chandran, Evangelia Karyka, Matthew J. Stopford, Emma F. Smith, Janine Kirby, Kathrin Meyer, Brian K. Kaspar, Adrian M. Isaacs, Sherif F. El-Khamisy, Kurt J. De Vos, Ke Ning, Mimoun Azzouz, Alexander J. Whitworth () and Pamela J. Shaw
Additional contact information
Guillaume M. Hautbergue: Sheffield Institute for Translational Neuroscience, University of Sheffield
Lydia M. Castelli: Sheffield Institute for Translational Neuroscience, University of Sheffield
Laura Ferraiuolo: Sheffield Institute for Translational Neuroscience, University of Sheffield
Alvaro Sanchez-Martinez: MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus
Johnathan Cooper-Knock: Sheffield Institute for Translational Neuroscience, University of Sheffield
Adrian Higginbottom: Sheffield Institute for Translational Neuroscience, University of Sheffield
Ya-Hui Lin: Sheffield Institute for Translational Neuroscience, University of Sheffield
Claudia S. Bauer: Sheffield Institute for Translational Neuroscience, University of Sheffield
Jennifer E. Dodd: Sheffield Institute for Translational Neuroscience, University of Sheffield
Monika A. Myszczynska: Sheffield Institute for Translational Neuroscience, University of Sheffield
Sarah M. Alam: MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus
Pierre Garneret: Sheffield Institute for Translational Neuroscience, University of Sheffield
Jayanth S. Chandran: Sheffield Institute for Translational Neuroscience, University of Sheffield
Evangelia Karyka: Sheffield Institute for Translational Neuroscience, University of Sheffield
Matthew J. Stopford: Sheffield Institute for Translational Neuroscience, University of Sheffield
Emma F. Smith: Sheffield Institute for Translational Neuroscience, University of Sheffield
Janine Kirby: Sheffield Institute for Translational Neuroscience, University of Sheffield
Kathrin Meyer: Nationwide Children’s Research Institute, The Ohio State University
Brian K. Kaspar: Nationwide Children’s Research Institute, The Ohio State University
Adrian M. Isaacs: UCL Institute of Neurology
Sherif F. El-Khamisy: Krebs Institute, University of Sheffield
Kurt J. De Vos: Sheffield Institute for Translational Neuroscience, University of Sheffield
Ke Ning: Sheffield Institute for Translational Neuroscience, University of Sheffield
Mimoun Azzouz: Sheffield Institute for Translational Neuroscience, University of Sheffield
Alexander J. Whitworth: MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus
Pamela J. Shaw: Sheffield Institute for Translational Neuroscience, University of Sheffield

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: Abstract Hexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression of repeat transcripts and dipeptide repeat proteins trigger multiple mechanisms of neurotoxicity. How repeat transcripts get exported from the nucleus is unknown. Here, we show that depletion of the nuclear export adaptor SRSF1 prevents neurodegeneration and locomotor deficits in a Drosophila model of C9ORF72-related disease. This intervention suppresses cell death of patient-derived motor neuron and astrocytic-mediated neurotoxicity in co-culture assays. We further demonstrate that either depleting SRSF1 or preventing its interaction with NXF1 specifically inhibits the nuclear export of pathological C9ORF72 transcripts, the production of dipeptide-repeat proteins and alleviates neurotoxicity in Drosophila, patient-derived neurons and neuronal cell models. Taken together, we show that repeat RNA-sequestration of SRSF1 triggers the NXF1-dependent nuclear export of C9ORF72 transcripts retaining expanded hexanucleotide repeats and reveal a novel promising therapeutic target for neuroprotection.

Date: 2017
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/ncomms16063 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms16063

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms16063

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().