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

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.

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Item Type:	Article
Authors/Creators:	Hautbergue, G.M. https://orcid.org/0000-0002-1621-261X Castelli, L.M. Ferraiuolo, L. Sanchez-Martinez, A. Cooper-Knock, J. Higginbottom, A. Lin, Y.H. Bauer, C.S. Dodd, J.E. Myszczynska, M.A. Alam, S.M. Garneret, P. Chandran, J.S. Karyka, E. Stopford, M.J. Smith, E.F. Kirby, J. Meyer, K. Kaspar, B.K. Isaacs, A.M. El-Khamisy, S.F. De Vos, K.J. Ning, K. Azzouz, M. Whitworth, A.J. Shaw, P.J.
Copyright, Publisher and Additional Information:	© The Author(s) 2017. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit (http://creativecommons.org/licenses/by/4.0/)
Dates:	Accepted: 24 May 2017 Published: 5 July 2017
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals
Funding Information:	Funder Grant number ROYAL SOCIETY RG140690 EUROPEAN RESEARCH COUNCIL GTNCTV - 294745 SHEFFIELD HOSPITALS CHARITABLE TRUST 121340/2 MOTOR NEURONE DISEASE ASSOCIATION Hautberge/Mar16/900-790 MEDICAL RESEARCH COUNCIL MR/M010864/1 MEDICAL RESEARCH COUNCIL MR/M013251/1 MEDICAL RESEARCH COUNCIL MR/K003771/1 EUROPEAN COMMISSION - FP6/FP7 EUROMOTOR - 259867 MEDICAL RESEARCH COUNCIL MR/K005146/1 MOTOR NEURONE DISEASE ASSOCIATION MND005891 THIERRY LATRAN FOUNDATION FTL AAP 2016
Depositing User:	Symplectic Sheffield
Date Deposited:	02 Jun 2017 12:53
Last Modified:	30 Oct 2018 11:47
Published Version:	https://doi.org/10.1038/ncomms16063
Status:	Published
Publisher:	Nature Publishing Group
Refereed:	Yes
Identification Number:	10.1038/ncomms16063
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:116976

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

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