IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation

Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder leading to dopaminergic depletion and early-onset Parkinsonism. Affected children present with either a severe form that does not respond to L-Dopa treatment (THD-B) or a milder L-Dopa responsive form (THD-A). We generated induced plur...

ver descrição completa

Detalhes bibliográficos
Autores: Tristá Noguero, Alba, Fernández Carasa, Irene, Calatayud, Carles, Bermejo Casadesús, Cristina, Pons Espinal, Meritxell, Colini Baldeschi, Arianna, Campa, Leticia, Artigas Pérez, Francesc, Bortolozzi, Analia, Domingo Jiménez, Rosario, Ibáñez, Salvador, Pineda, Mercè, Artuch Iriberri, Rafael, Raya Chamorro, Ángel, García Cazorla, Àngels, Consiglio, Antonella
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/198344
Acesso em linha:https://hdl.handle.net/2445/198344
Access Level:acceso abierto
Palavra-chave:Malalties rares
Cèl·lules mare
Fenotip
Dopamina
Rare diseases
Stem cells
Phenotype
Dopamine
id ES_2b4eba878e452cf01337d523e5a2e65a
oai_identifier_str oai:diposit.ub.edu:2445/198344
network_acronym_str ES
network_name_str España
repository_id_str
spelling IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformationTristá Noguero, AlbaFernández Carasa, IreneCalatayud, CarlesBermejo Casadesús, CristinaPons Espinal, MeritxellColini Baldeschi, AriannaCampa, LeticiaArtigas Pérez, FrancescBortolozzi, AnaliaDomingo Jiménez, RosarioIbáñez, SalvadorPineda, MercèArtuch Iriberri, RafaelRaya Chamorro, ÁngelGarcía Cazorla, ÀngelsConsiglio, AntonellaMalalties raresCèl·lules mareFenotipDopaminaRare diseasesStem cellsPhenotypeDopamineTyrosine hydroxylase deficiency (THD) is a rare genetic disorder leading to dopaminergic depletion and early-onset Parkinsonism. Affected children present with either a severe form that does not respond to L-Dopa treatment (THD-B) or a milder L-Dopa responsive form (THD-A). We generated induced pluripotent stem cells (iPSCs) from THD patients that were differentiated into dopaminergic neurons (DAn) and compared with control-DAn from healthy individuals and gene-corrected isogenic controls. Consistent with patients, THD iPSC-DAn displayed lower levels of DA metabolites and reduced TH expression, when compared to controls. Moreover, THD iPSC-DAn showed abnormal morphology, including reduced total neurite length and neurite arborization defects, which were not evident in DAn differentiated from control-iPSC. Treatment of THD-iPSC-DAn with L-Dopa rescued the neuronal defects and disease phenotype only in THDA-DAn. Interestingly, L-Dopa treatment at the stage of neuronal precursors could prevent the alterations in THDB-iPSC-DAn, thus suggesting the existence of a critical developmental window in THD. Our iPSC-based model recapitulates THD disease phenotypes and response to treatment, representing a promising tool for investigating pathogenic mechanisms, drug screening, and personalized management.EMBO2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/198344Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.15252/emmm.202215847EMBO Molecular Medicine, 2023, vol. 15, num. 3, p. e15847https://doi.org/10.15252/emmm.202215847cc by (c) Tristá Noguero, Alba et al., 2023http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1983442026-05-27T06:46:51Z
dc.title.none.fl_str_mv IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation
title IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation
spellingShingle IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation
Tristá Noguero, Alba
Malalties rares
Cèl·lules mare
Fenotip
Dopamina
Rare diseases
Stem cells
Phenotype
Dopamine
title_short IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation
title_full IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation
title_fullStr IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation
title_full_unstemmed IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation
title_sort IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation
dc.creator.none.fl_str_mv Tristá Noguero, Alba
Fernández Carasa, Irene
Calatayud, Carles
Bermejo Casadesús, Cristina
Pons Espinal, Meritxell
Colini Baldeschi, Arianna
Campa, Leticia
Artigas Pérez, Francesc
Bortolozzi, Analia
Domingo Jiménez, Rosario
Ibáñez, Salvador
Pineda, Mercè
Artuch Iriberri, Rafael
Raya Chamorro, Ángel
García Cazorla, Àngels
Consiglio, Antonella
author Tristá Noguero, Alba
author_facet Tristá Noguero, Alba
Fernández Carasa, Irene
Calatayud, Carles
Bermejo Casadesús, Cristina
Pons Espinal, Meritxell
Colini Baldeschi, Arianna
Campa, Leticia
Artigas Pérez, Francesc
Bortolozzi, Analia
Domingo Jiménez, Rosario
Ibáñez, Salvador
Pineda, Mercè
Artuch Iriberri, Rafael
Raya Chamorro, Ángel
García Cazorla, Àngels
Consiglio, Antonella
author_role author
author2 Fernández Carasa, Irene
Calatayud, Carles
Bermejo Casadesús, Cristina
Pons Espinal, Meritxell
Colini Baldeschi, Arianna
Campa, Leticia
Artigas Pérez, Francesc
Bortolozzi, Analia
Domingo Jiménez, Rosario
Ibáñez, Salvador
Pineda, Mercè
Artuch Iriberri, Rafael
Raya Chamorro, Ángel
García Cazorla, Àngels
Consiglio, Antonella
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malalties rares
Cèl·lules mare
Fenotip
Dopamina
Rare diseases
Stem cells
Phenotype
Dopamine
topic Malalties rares
Cèl·lules mare
Fenotip
Dopamina
Rare diseases
Stem cells
Phenotype
Dopamine
description Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder leading to dopaminergic depletion and early-onset Parkinsonism. Affected children present with either a severe form that does not respond to L-Dopa treatment (THD-B) or a milder L-Dopa responsive form (THD-A). We generated induced pluripotent stem cells (iPSCs) from THD patients that were differentiated into dopaminergic neurons (DAn) and compared with control-DAn from healthy individuals and gene-corrected isogenic controls. Consistent with patients, THD iPSC-DAn displayed lower levels of DA metabolites and reduced TH expression, when compared to controls. Moreover, THD iPSC-DAn showed abnormal morphology, including reduced total neurite length and neurite arborization defects, which were not evident in DAn differentiated from control-iPSC. Treatment of THD-iPSC-DAn with L-Dopa rescued the neuronal defects and disease phenotype only in THDA-DAn. Interestingly, L-Dopa treatment at the stage of neuronal precursors could prevent the alterations in THDB-iPSC-DAn, thus suggesting the existence of a critical developmental window in THD. Our iPSC-based model recapitulates THD disease phenotypes and response to treatment, representing a promising tool for investigating pathogenic mechanisms, drug screening, and personalized management.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/198344
url https://hdl.handle.net/2445/198344
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.15252/emmm.202215847
EMBO Molecular Medicine, 2023, vol. 15, num. 3, p. e15847
https://doi.org/10.15252/emmm.202215847
dc.rights.none.fl_str_mv cc by (c) Tristá Noguero, Alba et al., 2023
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Tristá Noguero, Alba et al., 2023
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv EMBO
publisher.none.fl_str_mv EMBO
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869405135993569280
score 15.301603

Registos relacionados