Castelli, L.M., Lin, Y.H., Ferraiuolo, L. et al. (6 more authors) (2018) SRSF1-dependent nuclear export of C9ORF72 repeat-transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection. Therapeutic Targets for Neurological Diseases, 4. e1619. ISSN 2376-0478
Abstract
Microsatellite repeat expansions cause several incurable and lethal neurodegenerative disorders including ataxias, myotonic dystrophy, Huntington's disease and C9ORF72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Abnormal repeat transcripts generated from the expanded loci are substrates of repeat-associated non-AUG (RAN) translation, an unconventional form of translation leading to the production of polymeric repeat proteins with cytotoxic and aggregating properties. The mechanisms involved in the pathogenesis of microsatellite repeat expansion disorders remain a hotly debated topic. They are shared between toxic loss/gain of functions due to intranuclear RNA foci that sequesters RNA-binding proteins and RAN translation of repeat proteins in the cytoplasm. We recently elucidated the molecular mechanism driving the nuclear export of C9ORF72 repeat transcripts and showed for the first time that this pathway can be manipulated to confer neuroprotection. Strikingly, we discovered that intron-retaining C9ORF72 repeat transcripts hijack the physiological NXF1-dependent export pathway by selective RNA-repeat sequestration of SRSF1. Antagonizing SRSF1 and the nuclear export of C9ORF72 repeat transcripts promoted in turn the survival of patient-derived motor neurons and suppressed neurodegeneration-associated motor deficits in Drosophila (Hautbergue et al. Nature Communications 2017; 8:16063). In this invited Research Highlight review, we aim to place this work in the context of our previous studies on the nuclear export of mRNAs, provide a summary of the published research and highlight the significance of these findings as a novel therapeutic strategy for neuroprotection in C9ORF72-ALS/FTD. In addition, we emphasize that protein sequestration, often thought as of inducing loss-of-function mechanisms, can also trigger unwanted protein interactions and toxic gain-of-functions.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 The Authors. Licensed under a Creative Commons Attribution 4.0 International License which allows users including authors of articles to copy and redistribute the material in any medium or format, in addition to remix, transform, and build upon the material for any purpose, even commercially, as long as the author and original source are properly cited or credited. |
Keywords: | Amyotrophic lateral sclerosis; Frontotemporal dementia; Neurodegeneration; Microsatellite repeat expansions; C9ORF72; RNA nuclear export; SRSF1; NXF1; RAN translation; Therapeutic strategy |
Dates: |
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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 EUROPEAN RESEARCH COUNCIL GTNCTV - 294745 EUROPEAN RESEARCH COUNCIL DYNAMITO - 309742 MEDICAL RESEARCH COUNCIL MR/M010864/1 MOTOR NEURONE DISEASE ASSOCIATION MND005891 THIERRY LATRAN FOUNDATION FTL AAP 2016 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 19 Jan 2018 15:32 |
Last Modified: | 19 Jan 2018 15:39 |
Published Version: | https://doi.org/10.14800/ttnd.1619 |
Status: | Published |
Publisher: | Smart Science and Technology |
Refereed: | Yes |
Identification Number: | 10.14800/ttnd.1619 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:126422 |