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DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity
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 i...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316199/ https://www.ncbi.nlm.nih.gov/pubmed/34173837 http://dx.doi.org/10.1007/s00018-021-03872-0 |
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author | Kok, Jannigje Rachel Palminha, Nelma M. Dos Santos Souza, Cleide El-Khamisy, Sherif F. Ferraiuolo, Laura |
author_facet | Kok, Jannigje Rachel Palminha, Nelma M. Dos Santos Souza, Cleide El-Khamisy, Sherif F. Ferraiuolo, Laura |
author_sort | Kok, Jannigje Rachel |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8316199 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-83161992021-08-13 DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity Kok, Jannigje Rachel Palminha, Nelma M. Dos Santos Souza, Cleide El-Khamisy, Sherif F. Ferraiuolo, Laura Cell Mol Life Sci Review 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. Springer International Publishing 2021-06-26 2021 /pmc/articles/PMC8316199/ /pubmed/34173837 http://dx.doi.org/10.1007/s00018-021-03872-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Review Kok, Jannigje Rachel Palminha, Nelma M. Dos Santos Souza, Cleide El-Khamisy, Sherif F. Ferraiuolo, Laura DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity |
title | DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity |
title_full | DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity |
title_fullStr | DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity |
title_full_unstemmed | DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity |
title_short | DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity |
title_sort | dna damage as a mechanism of neurodegeneration in als and a contributor to astrocyte toxicity |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316199/ https://www.ncbi.nlm.nih.gov/pubmed/34173837 http://dx.doi.org/10.1007/s00018-021-03872-0 |
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