Kok, J.R., Palminha, N.M., Dos Santos Souza, C. orcid.org/0000-0001-5314-6263 et al. (2 more authors) (2021) DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity. Cellular and Molecular Life Sciences, 78 (15). pp. 5707-5729. ISSN 1420-682X
Abstract
Increasing evidence supports the involvement of DNA damage in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Elevated levels of DNA damage are consistently observed in both sporadic and familial forms of ALS and may also play a role in Western Pacific ALS, which is thought to have an environmental cause. The cause of DNA damage in ALS remains unclear but likely differs between genetic subgroups. Repeat expansion in the C9ORF72 gene is the most common genetic cause of familial ALS and responsible for about 10% of sporadic cases. These genetic mutations are known to cause R-loops, thus increasing genomic instability and DNA damage, and generate dipeptide repeat proteins, which have been shown to lead to DNA damage and impairment of the DNA damage response. Similarly, several genes associated with ALS including TARDBP, FUS, NEK1, SQSTM1 and SETX are known to play a role in DNA repair and the DNA damage response, and thus may contribute to neuronal death via these pathways. Another consistent feature present in both sporadic and familial ALS is the ability of astrocytes to induce motor neuron death, although the factors causing this toxicity remain largely unknown. In this review, we summarise the evidence for DNA damage playing a causative or secondary role in the pathogenesis of ALS as well as discuss the possible mechanisms involved in different genetic subtypes with particular focus on the role of astrocytes initiating or perpetuating DNA damage in neurons.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2021. 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: | Amyotrophic lateral sclerosis; Neurodegeneration; DNA damage; DNA damage response; Astrocytes |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Funding Information: | Funder Grant number WELLCOME TRUST (THE) 103844/Z/14/Z |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 23 Mar 2022 12:49 |
Last Modified: | 10 Feb 2023 14:12 |
Status: | Published |
Publisher: | Springer Science and Business Media LLC |
Refereed: | Yes |
Identification Number: | 10.1007/s00018-021-03872-0 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:184884 |
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