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SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits
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 fr...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504286/ https://www.ncbi.nlm.nih.gov/pubmed/28677678 http://dx.doi.org/10.1038/ncomms16063 |
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author | Hautbergue, Guillaume M. Castelli, Lydia M. Ferraiuolo, Laura Sanchez-Martinez, Alvaro Cooper-Knock, Johnathan Higginbottom, Adrian Lin, Ya-Hui Bauer, Claudia S. Dodd, Jennifer E. Myszczynska, Monika A. Alam, Sarah M. Garneret, Pierre Chandran, Jayanth S. Karyka, Evangelia Stopford, Matthew J. Smith, Emma F. Kirby, Janine Meyer, Kathrin Kaspar, Brian K. Isaacs, Adrian M. El-Khamisy, Sherif F. De Vos, Kurt J. Ning, Ke Azzouz, Mimoun Whitworth, Alexander J. Shaw, Pamela J. |
author_facet | Hautbergue, Guillaume M. Castelli, Lydia M. Ferraiuolo, Laura Sanchez-Martinez, Alvaro Cooper-Knock, Johnathan Higginbottom, Adrian Lin, Ya-Hui Bauer, Claudia S. Dodd, Jennifer E. Myszczynska, Monika A. Alam, Sarah M. Garneret, Pierre Chandran, Jayanth S. Karyka, Evangelia Stopford, Matthew J. Smith, Emma F. Kirby, Janine Meyer, Kathrin Kaspar, Brian K. Isaacs, Adrian M. El-Khamisy, Sherif F. De Vos, Kurt J. Ning, Ke Azzouz, Mimoun Whitworth, Alexander J. Shaw, Pamela J. |
author_sort | Hautbergue, Guillaume M. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5504286 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-55042862017-07-14 SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits Hautbergue, Guillaume M. Castelli, Lydia M. Ferraiuolo, Laura Sanchez-Martinez, Alvaro Cooper-Knock, Johnathan Higginbottom, Adrian Lin, Ya-Hui Bauer, Claudia S. Dodd, Jennifer E. Myszczynska, Monika A. Alam, Sarah M. Garneret, Pierre Chandran, Jayanth S. Karyka, Evangelia Stopford, Matthew J. Smith, Emma F. Kirby, Janine Meyer, Kathrin Kaspar, Brian K. Isaacs, Adrian M. El-Khamisy, Sherif F. De Vos, Kurt J. Ning, Ke Azzouz, Mimoun Whitworth, Alexander J. Shaw, Pamela J. Nat Commun Article 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. Nature Publishing Group 2017-07-05 /pmc/articles/PMC5504286/ /pubmed/28677678 http://dx.doi.org/10.1038/ncomms16063 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ Open Access 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/ |
spellingShingle | Article Hautbergue, Guillaume M. Castelli, Lydia M. Ferraiuolo, Laura Sanchez-Martinez, Alvaro Cooper-Knock, Johnathan Higginbottom, Adrian Lin, Ya-Hui Bauer, Claudia S. Dodd, Jennifer E. Myszczynska, Monika A. Alam, Sarah M. Garneret, Pierre Chandran, Jayanth S. Karyka, Evangelia Stopford, Matthew J. Smith, Emma F. Kirby, Janine Meyer, Kathrin Kaspar, Brian K. Isaacs, Adrian M. El-Khamisy, Sherif F. De Vos, Kurt J. Ning, Ke Azzouz, Mimoun Whitworth, Alexander J. Shaw, Pamela J. SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits |
title | SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits |
title_full | SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits |
title_fullStr | SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits |
title_full_unstemmed | SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits |
title_short | SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits |
title_sort | srsf1-dependent nuclear export inhibition of c9orf72 repeat transcripts prevents neurodegeneration and associated motor deficits |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504286/ https://www.ncbi.nlm.nih.gov/pubmed/28677678 http://dx.doi.org/10.1038/ncomms16063 |
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