Webster, C.P. orcid.org/0000-0003-4197-2036, Hall, B. orcid.org/0009-0008-4274-9796, Crossley, O.M. et al. (14 more authors) (2025) RuvBL1/2 reduce toxic dipeptide repeat protein burden in multiple models of C9orf72-ALS/FTD. Life Science Alliance, 8 (2). e202402757. ISSN 2575-1077
Abstract
A G4C2 hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Bidirectional transcription and subsequent repeat-associated non-AUG (RAN) translation of sense and antisense transcripts leads to the formation of five dipeptide repeat (DPR) proteins. These DPRs are toxic in a wide range of cell and animal models. Therefore, decreasing RAN-DPRs may be of therapeutic benefit in the context of C9ALS/FTD. In this study, we found that C9ALS/FTD patients have reduced expression of the AAA+ family members RuvBL1 and RuvBL2, which have both been implicated in aggregate clearance. We report that overexpression of RuvBL1, but to a greater extent RuvBL2, reduced C9orf72-associated DPRs in a range of in vitro systems including cell lines, primary neurons from the C9-500 transgenic mouse model, and patient-derived iPSC motor neurons. In vivo, we further demonstrated that RuvBL2 overexpression and consequent DPR reduction in our Drosophila model was sufficient to rescue a number of DPR-related motor phenotypes. Thus, modulating RuvBL levels to reduce DPRs may be of therapeutic potential in C9ALS/FTD.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 Webster et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/ licenses/by/4.0/). |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Funding Information: | Funder Grant number EUROPEAN COMMISSION - HORIZON 2020 945473 ALZHEIMER'S RESEARCH UK ARUK-PG2018B-005 MEDICAL RESEARCH COUNCIL MR/V000470/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 11 Dec 2024 12:22 |
Last Modified: | 11 Dec 2024 12:22 |
Status: | Published |
Publisher: | Life Science Alliance, LLC |
Refereed: | Yes |
Identification Number: | 10.26508/lsa.202402757 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:220549 |