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Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration

Topoisomerase 1 (TOP1) relieves torsional stress in DNA during transcription and facilitates the expression of long (>100 kb) genes, many of which are important for neuronal functions. To evaluate how loss of Top1 affected neurons in vivo, we conditionally deleted (cKO) Top1 in postmitotic excita...

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Autores principales: Fragola, Giulia, Mabb, Angela M., Taylor-Blake, Bonnie, Niehaus, Jesse K., Chronister, William D., Mao, Hanqian, Simon, Jeremy M., Yuan, Hong, Li, Zibo, McConnell, Michael J., Zylka, Mark J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181881/
https://www.ncbi.nlm.nih.gov/pubmed/32327659
http://dx.doi.org/10.1038/s41467-020-15794-9
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author Fragola, Giulia
Mabb, Angela M.
Taylor-Blake, Bonnie
Niehaus, Jesse K.
Chronister, William D.
Mao, Hanqian
Simon, Jeremy M.
Yuan, Hong
Li, Zibo
McConnell, Michael J.
Zylka, Mark J.
author_facet Fragola, Giulia
Mabb, Angela M.
Taylor-Blake, Bonnie
Niehaus, Jesse K.
Chronister, William D.
Mao, Hanqian
Simon, Jeremy M.
Yuan, Hong
Li, Zibo
McConnell, Michael J.
Zylka, Mark J.
author_sort Fragola, Giulia
collection PubMed
description Topoisomerase 1 (TOP1) relieves torsional stress in DNA during transcription and facilitates the expression of long (>100 kb) genes, many of which are important for neuronal functions. To evaluate how loss of Top1 affected neurons in vivo, we conditionally deleted (cKO) Top1 in postmitotic excitatory neurons in the mouse cerebral cortex and hippocampus. Top1 cKO neurons develop properly, but then show biased transcriptional downregulation of long genes, signs of DNA damage, neuroinflammation, increased poly(ADP-ribose) polymerase-1 (PARP1) activity, single-cell somatic mutations, and ultimately degeneration. Supplementation of nicotinamide adenine dinucleotide (NAD(+)) with nicotinamide riboside partially blocked neurodegeneration, and increased the lifespan of Top1 cKO mice by 30%. A reduction of p53 also partially rescued cortical neuron loss. While neurodegeneration was partially rescued, behavioral decline was not prevented. These data indicate that reducing neuronal loss is not sufficient to limit behavioral decline when TOP1 function is disrupted.
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spelling pubmed-71818812020-04-29 Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration Fragola, Giulia Mabb, Angela M. Taylor-Blake, Bonnie Niehaus, Jesse K. Chronister, William D. Mao, Hanqian Simon, Jeremy M. Yuan, Hong Li, Zibo McConnell, Michael J. Zylka, Mark J. Nat Commun Article Topoisomerase 1 (TOP1) relieves torsional stress in DNA during transcription and facilitates the expression of long (>100 kb) genes, many of which are important for neuronal functions. To evaluate how loss of Top1 affected neurons in vivo, we conditionally deleted (cKO) Top1 in postmitotic excitatory neurons in the mouse cerebral cortex and hippocampus. Top1 cKO neurons develop properly, but then show biased transcriptional downregulation of long genes, signs of DNA damage, neuroinflammation, increased poly(ADP-ribose) polymerase-1 (PARP1) activity, single-cell somatic mutations, and ultimately degeneration. Supplementation of nicotinamide adenine dinucleotide (NAD(+)) with nicotinamide riboside partially blocked neurodegeneration, and increased the lifespan of Top1 cKO mice by 30%. A reduction of p53 also partially rescued cortical neuron loss. While neurodegeneration was partially rescued, behavioral decline was not prevented. These data indicate that reducing neuronal loss is not sufficient to limit behavioral decline when TOP1 function is disrupted. Nature Publishing Group UK 2020-04-23 /pmc/articles/PMC7181881/ /pubmed/32327659 http://dx.doi.org/10.1038/s41467-020-15794-9 Text en © The Author(s) 2020 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Fragola, Giulia
Mabb, Angela M.
Taylor-Blake, Bonnie
Niehaus, Jesse K.
Chronister, William D.
Mao, Hanqian
Simon, Jeremy M.
Yuan, Hong
Li, Zibo
McConnell, Michael J.
Zylka, Mark J.
Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration
title Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration
title_full Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration
title_fullStr Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration
title_full_unstemmed Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration
title_short Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration
title_sort deletion of topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181881/
https://www.ncbi.nlm.nih.gov/pubmed/32327659
http://dx.doi.org/10.1038/s41467-020-15794-9
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