White, M.A., Kim, E., Duffy, A. et al. (20 more authors) (2018) TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD. Nature Neuroscience, 21. pp. 552-563. ISSN 1097-6256
Abstract
Amyotrophic lateral sclerosis–frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterized by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here we have created a TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43Q331K mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically, TDP-43 autoregulation is perturbed, leading to a gain of TDP-43 function and altered splicing of Mapt, another pivotal dementia-associated gene. Furthermore, a new approach to stratify transcriptomic data by phenotype in differentially affected mutant mice revealed 471 changes linked with improved behavior. These changes included downregulation of two known modifiers of neurodegeneration, Atxn2 and Arid4a, and upregulation of myelination and translation genes. With one base change in murine Tardbp, this study identifies TDP-43 misregulation as a pathogenic mechanism that may underpin ALS-FTD and exploits phenotypic heterogeneity to yield candidate suppressors of neurodegenerative disease.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 Nature America Inc., part of Springer Nature. This is an author produced version of a paper subsequently published in Nature Neuroscience. Uploaded in accordance with the publisher's self-archiving policy. |
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 MOTOR NEURONE DISEASE ASSOCIATION SITraN/Apr13/983-797 MOTOR NEURONE DISEASE ASSOCIATION SITraN/Jul16/987-797 MOTOR NEURONE DISEASE ASSOCIATION Mead/Jun16/900-790 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 16 Feb 2018 15:39 |
Last Modified: | 19 Sep 2018 00:39 |
Published Version: | https://doi.org/10.1038/s41593-018-0113-5 |
Status: | Published |
Publisher: | Nature Publishing Group |
Refereed: | Yes |
Identification Number: | 10.1038/s41593-018-0113-5 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:127211 |