DNA repair pathways are altered in neural cell models of frataxin deficiency

Friedreich’s ataxia (FRDA) is a hereditary and predominantly neurodegenerative disease caused by a deficiency of the protein frataxin (FXN). As part of the overall efforts to understand the molecular basis of neurodegeneration in FRDA, a new human neural cell line with doxycycline-induced FXN knockd...

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Authors: Pérez Luz, Sara, Moreno-Lorite, Jara, Katsu-Jiménez, Yurika, Oberdoerfer, Daniel, Díaz-Nido, Javier
Format: article
Publication Date:2020
Country:España
Institution:Universidad Complutense de Madrid (UCM)
Repository:Docta Complutense
Language:English
OAI Identifier:oai:docta.ucm.es:20.500.14352/102036
Online Access:https://hdl.handle.net/20.500.14352/102036
Access Level:Open access
Keyword:636.09
Friedreich’s ataxia
Frataxin
Cellular models
DNA damage
Neurodegeneration
Biología
2407 Biología Celular
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oai_identifier_str oai:docta.ucm.es:20.500.14352/102036
network_acronym_str ES
network_name_str España
repository_id_str
spelling DNA repair pathways are altered in neural cell models of frataxin deficiencyPérez Luz, SaraMoreno-Lorite, JaraKatsu-Jiménez, YurikaOberdoerfer, DanielDíaz-Nido, Javier636.09Friedreich’s ataxiaFrataxinCellular modelsDNA damageNeurodegenerationBiología2407 Biología CelularFriedreich’s ataxia (FRDA) is a hereditary and predominantly neurodegenerative disease caused by a deficiency of the protein frataxin (FXN). As part of the overall efforts to understand the molecular basis of neurodegeneration in FRDA, a new human neural cell line with doxycycline-induced FXN knockdown was established. This cell line, hereafter referred to as iFKD-SY, is derived from the human neuroblastoma SH-SY5Y and retains the ability to differentiate into mature neuron-like cells. In both proliferating and differentiated iFKD-SY cells, the induction of FXN deficiency is accompanied by increases in oxidative stress and DNA damage, reduced aconitase enzyme activity, higher levels of p53 and p21, activation of caspase-3, and subsequent apoptosis. More interestingly, FXN-deficient iFKD-SY cells exhibit an important transcriptional deregulation in many of the genes implicated in DNA repair pathways. The levels of some crucial proteins involved in DNA repair appear notably diminished. Furthermore, similar changes are found in two additional neural cell models of FXN deficit: primary cultures of FXN-deficient mouse neurons and human olfactory mucosa stem cells obtained from biopsies of FRDA patients. These results suggest that the deficiency of FXN leads to a down-regulation of DNA repair pathways that synergizes with oxidative stress to provoke DNA damage, which may be involved in the pathogenesis of FRDA. Thus, a failure in DNA repair may be considered a shared common molecular mechanism contributing to neurodegeneration in a number of hereditary ataxias including FRDA.ElsevierUniversidad Complutense de Madrid20202020-12-2620202020-12-26journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/102036reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1020362026-06-02T12:44:21Z
dc.title.none.fl_str_mv DNA repair pathways are altered in neural cell models of frataxin deficiency
title DNA repair pathways are altered in neural cell models of frataxin deficiency
spellingShingle DNA repair pathways are altered in neural cell models of frataxin deficiency
Pérez Luz, Sara
636.09
Friedreich’s ataxia
Frataxin
Cellular models
DNA damage
Neurodegeneration
Biología
2407 Biología Celular
title_short DNA repair pathways are altered in neural cell models of frataxin deficiency
title_full DNA repair pathways are altered in neural cell models of frataxin deficiency
title_fullStr DNA repair pathways are altered in neural cell models of frataxin deficiency
title_full_unstemmed DNA repair pathways are altered in neural cell models of frataxin deficiency
title_sort DNA repair pathways are altered in neural cell models of frataxin deficiency
dc.creator.none.fl_str_mv Pérez Luz, Sara
Moreno-Lorite, Jara
Katsu-Jiménez, Yurika
Oberdoerfer, Daniel
Díaz-Nido, Javier
author Pérez Luz, Sara
author_facet Pérez Luz, Sara
Moreno-Lorite, Jara
Katsu-Jiménez, Yurika
Oberdoerfer, Daniel
Díaz-Nido, Javier
author_role author
author2 Moreno-Lorite, Jara
Katsu-Jiménez, Yurika
Oberdoerfer, Daniel
Díaz-Nido, Javier
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 636.09
Friedreich’s ataxia
Frataxin
Cellular models
DNA damage
Neurodegeneration
Biología
2407 Biología Celular
topic 636.09
Friedreich’s ataxia
Frataxin
Cellular models
DNA damage
Neurodegeneration
Biología
2407 Biología Celular
description Friedreich’s ataxia (FRDA) is a hereditary and predominantly neurodegenerative disease caused by a deficiency of the protein frataxin (FXN). As part of the overall efforts to understand the molecular basis of neurodegeneration in FRDA, a new human neural cell line with doxycycline-induced FXN knockdown was established. This cell line, hereafter referred to as iFKD-SY, is derived from the human neuroblastoma SH-SY5Y and retains the ability to differentiate into mature neuron-like cells. In both proliferating and differentiated iFKD-SY cells, the induction of FXN deficiency is accompanied by increases in oxidative stress and DNA damage, reduced aconitase enzyme activity, higher levels of p53 and p21, activation of caspase-3, and subsequent apoptosis. More interestingly, FXN-deficient iFKD-SY cells exhibit an important transcriptional deregulation in many of the genes implicated in DNA repair pathways. The levels of some crucial proteins involved in DNA repair appear notably diminished. Furthermore, similar changes are found in two additional neural cell models of FXN deficit: primary cultures of FXN-deficient mouse neurons and human olfactory mucosa stem cells obtained from biopsies of FRDA patients. These results suggest that the deficiency of FXN leads to a down-regulation of DNA repair pathways that synergizes with oxidative stress to provoke DNA damage, which may be involved in the pathogenesis of FRDA. Thus, a failure in DNA repair may be considered a shared common molecular mechanism contributing to neurodegeneration in a number of hereditary ataxias including FRDA.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-12-26
2020
2020-12-26
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/102036
url https://hdl.handle.net/20.500.14352/102036
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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