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dc.contributor.authorFang, Minggang
dc.contributor.authorDeibler, Sara K
dc.contributor.authorNana, Alissa L
dc.contributor.authorVatsavayai, Sarat C
dc.contributor.authorBanday, Shahid
dc.contributor.authorZhou, You
dc.contributor.authorAlmeida, Sandra
dc.contributor.authorWeiss, Alexandra
dc.contributor.authorBrown, Robert H
dc.contributor.authorSeeley, William W
dc.contributor.authorGao, Fen-Biao
dc.contributor.authorGreen, Michael R
dc.date.accessioned2023-11-30T20:10:33Z
dc.date.available2023-11-30T20:10:33Z
dc.date.issued2023-10-02
dc.identifier.citationFang M, Deibler SK, Nana AL, Vatsavayai SC, Banday S, Zhou Y, Almeida S, Weiss A, Brown RH, Seeley WW, Gao FB, Green MR. Loss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosis. Front Neurosci. 2023 Oct 2;17:1251228. doi: 10.3389/fnins.2023.1251228. PMID: 37849894; PMCID: PMC10577185.en_US
dc.identifier.issn1662-4548
dc.identifier.doi10.3389/fnins.2023.1251228en_US
dc.identifier.pmid37849894
dc.identifier.urihttp://hdl.handle.net/20.500.14038/52810
dc.description.abstractA common pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the cytoplasmic mislocalization and aggregation of the DNA/RNA-binding protein TDP-43, but how loss of nuclear TDP-43 function contributes to ALS and FTD pathogenesis remains largely unknown. Here, using large-scale RNAi screening, we identify TARDBP, which encodes TDP-43, as a gene whose loss-of-function results in elevated DNA mutation rate and genomic instability. Consistent with this finding, we observe increased DNA damage in induced pluripotent stem cells (iPSCs) and iPSC-derived post-mitotic neurons generated from ALS patients harboring TARDBP mutations. We find that the increase in DNA damage in ALS iPSC-derived neurons is due to defects in two major pathways for DNA double-strand break repair: non-homologous end joining and homologous recombination. Cells with defects in DNA repair are sensitive to DNA damaging agents and, accordingly, we find that ALS iPSC-derived neurons show a marked reduction in survival following treatment with a DNA damaging agent. Importantly, we find that increased DNA damage is also observed in neurons with nuclear TDP-43 depletion from ALS/FTD patient brain tissues. Collectively, our results demonstrate that ALS neurons with loss of nuclear TDP-43 function have elevated levels of DNA damage and contribute to the idea that genomic instability is a defining pathological feature of ALS/FTD patients with TDP-43 pathology.en_US
dc.language.isoenen_US
dc.relation.ispartofFrontiers in Neuroscienceen_US
dc.relation.urlhttps://doi.org/10.3389/fnins.2023.1251228en_US
dc.rights© 2023 Fang, Deibler, Nana, Vatsavayai, Banday, Zhou, Almeida, Weiss, Brown, Seeley, Gao and Green. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectDNA repairen_US
dc.subjectTDP-43en_US
dc.subjectamyotrophic lateral sclerosisen_US
dc.subjectfrontotemporal dementiaen_US
dc.subjectgenomic instabilityen_US
dc.subjecthomologous recombinationen_US
dc.titleLoss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosisen_US
dc.typeJournal Articleen_US
dc.source.journaltitleFrontiers in neuroscience
dc.source.volume17
dc.source.beginpage1251228
dc.source.endpage
dc.source.countrySwitzerland
dc.identifier.journalFrontiers in neuroscience
refterms.dateFOA2023-11-30T20:10:34Z
dc.contributor.departmentMolecular, Cell and Cancer Biologyen_US
dc.contributor.departmentNeurologyen_US
dc.contributor.departmentRNA Therapeutics Instituteen_US


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© 2023 Fang, Deibler, Nana, Vatsavayai,
Banday, Zhou, Almeida, Weiss, Brown, Seeley,
Gao and Green. This is an open-access article
distributed under the terms of the Creative
Commons Attribution License (CC BY). The
use, distribution or reproduction in other
forums is permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original publication in this
journal is cited, in accordance with accepted
academic practice. No use, distribution or
reproduction is permitted which does not
comply with these terms.
Except where otherwise noted, this item's license is described as © 2023 Fang, Deibler, Nana, Vatsavayai, Banday, Zhou, Almeida, Weiss, Brown, Seeley, Gao and Green. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.