Shaw, M.P., Higginbottom, A. orcid.org/0000-0002-3246-6695, McGown, A. et al. (5 more authors) (2018) Stable transgenic C9orf72 zebrafish model key aspects of the ALS/FTD phenotype and reveal novel pathological features. Acta Neuropathologica Communications, 6 (1). 125. ISSN 2051-5960
Abstract
A hexanucleotide repeat expansion (HRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is the most prevalent cause of amyotrophic lateral sclerosis/fronto-temporal dementia (ALS/FTD). Current evidence suggests HREs induce neurodegeneration through accumulation of RNA foci and/or dipeptide repeat proteins (DPR). C9orf72 patients are known to have transactive response DNA binding protein 43 kDa (TDP-43) proteinopathy, but whether there is further cross over between C9orf72 pathology and the pathology of other ALS sub-types has yet to be revealed.To address this, we generated and characterised two zebrafish lines expressing C9orf72 HREs. We also characterised pathology in human C9orf72-ALS cases. In addition, we utilised a reporter construct that expresses DsRed under the control of a heat shock promoter, to screen for potential therapeutic compounds.Both zebrafish lines showed accumulation of RNA foci and DPR. Our C9-ALS/FTD zebrafish model is the first to recapitulate the motor deficits, cognitive impairment, muscle atrophy, motor neuron loss and mortality in early adulthood observed in human C9orf72-ALS/FTD. Furthermore, we identified that in zebrafish, human cell lines and human post-mortem tissue, C9orf72 expansions activate the heat shock response (HSR). Additionally, HSR activation correlated with disease progression in our C9-ALS/FTD zebrafish model. Lastly, we identified that the compound ivermectin, as well as riluzole, reduced HSR activation in both C9-ALS/FTD and SOD1 zebrafish models.Thus, our C9-ALS/FTD zebrafish model is a stable transgenic model which recapitulates key features of human C9orf72-ALS/FTD, and represents a powerful drug-discovery tool.
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Copyright, Publisher and Additional Information: | © The Author(s). 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. | ||||
Keywords: | Amyotrophic lateral sclerosis; C9orf72; Drug-screening; SOD1; TDP-43; Zebrafish | ||||
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Institution: | The University of Sheffield | ||||
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals | ||||
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Depositing User: | Symplectic Sheffield | ||||
Date Deposited: | 01 Feb 2019 12:20 | ||||
Last Modified: | 01 Feb 2019 12:20 | ||||
Published Version: | https://doi.org/10.1186/s40478-018-0629-7 | ||||
Status: | Published | ||||
Publisher: | BMC | ||||
Refereed: | Yes | ||||
Identification Number: | https://doi.org/10.1186/s40478-018-0629-7 | ||||
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