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Perturbed autophagy and DNA repair converge to promote neurodegeneration in amyotrophic lateral sclerosis and dementia

Maintaining genomic stability constitutes a major challenge facing cells. DNA breaks can arise from direct oxidative damage to the DNA backbone, the inappropriate activities of endogenous enzymes such as DNA topoisomerases, or due to transcriptionally-derived RNA/DNA hybrids (R-loops). The progressi...

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Detalles Bibliográficos
Autores principales: Walker, Callum, El-Khamisy, Sherif F
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917746/
https://www.ncbi.nlm.nih.gov/pubmed/29584802
http://dx.doi.org/10.1093/brain/awy076
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author Walker, Callum
El-Khamisy, Sherif F
author_facet Walker, Callum
El-Khamisy, Sherif F
author_sort Walker, Callum
collection PubMed
description Maintaining genomic stability constitutes a major challenge facing cells. DNA breaks can arise from direct oxidative damage to the DNA backbone, the inappropriate activities of endogenous enzymes such as DNA topoisomerases, or due to transcriptionally-derived RNA/DNA hybrids (R-loops). The progressive accumulation of DNA breaks has been linked to several neurological disorders. Recently, however, several independent studies have implicated nuclear and mitochondrial genomic instability, perturbed co-transcriptional processing, and impaired cellular clearance pathways as causal and intertwined mechanisms underpinning neurodegeneration. Here, we discuss this emerging paradigm in the context of amyotrophic lateral sclerosis and frontotemporal dementia, and outline how this knowledge paves the way to novel therapeutic interventions.
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spelling pubmed-59177462018-05-04 Perturbed autophagy and DNA repair converge to promote neurodegeneration in amyotrophic lateral sclerosis and dementia Walker, Callum El-Khamisy, Sherif F Brain Review Articles Maintaining genomic stability constitutes a major challenge facing cells. DNA breaks can arise from direct oxidative damage to the DNA backbone, the inappropriate activities of endogenous enzymes such as DNA topoisomerases, or due to transcriptionally-derived RNA/DNA hybrids (R-loops). The progressive accumulation of DNA breaks has been linked to several neurological disorders. Recently, however, several independent studies have implicated nuclear and mitochondrial genomic instability, perturbed co-transcriptional processing, and impaired cellular clearance pathways as causal and intertwined mechanisms underpinning neurodegeneration. Here, we discuss this emerging paradigm in the context of amyotrophic lateral sclerosis and frontotemporal dementia, and outline how this knowledge paves the way to novel therapeutic interventions. Oxford University Press 2018-05 2018-03-23 /pmc/articles/PMC5917746/ /pubmed/29584802 http://dx.doi.org/10.1093/brain/awy076 Text en © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Review Articles
Walker, Callum
El-Khamisy, Sherif F
Perturbed autophagy and DNA repair converge to promote neurodegeneration in amyotrophic lateral sclerosis and dementia
title Perturbed autophagy and DNA repair converge to promote neurodegeneration in amyotrophic lateral sclerosis and dementia
title_full Perturbed autophagy and DNA repair converge to promote neurodegeneration in amyotrophic lateral sclerosis and dementia
title_fullStr Perturbed autophagy and DNA repair converge to promote neurodegeneration in amyotrophic lateral sclerosis and dementia
title_full_unstemmed Perturbed autophagy and DNA repair converge to promote neurodegeneration in amyotrophic lateral sclerosis and dementia
title_short Perturbed autophagy and DNA repair converge to promote neurodegeneration in amyotrophic lateral sclerosis and dementia
title_sort perturbed autophagy and dna repair converge to promote neurodegeneration in amyotrophic lateral sclerosis and dementia
topic Review Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917746/
https://www.ncbi.nlm.nih.gov/pubmed/29584802
http://dx.doi.org/10.1093/brain/awy076
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