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...

Descripción completa

Detalles Bibliográficos
Autores: Tristán-Noguero A, Fernández-Carasa I, Calatayud C, Bermejo-Casadesús C, Pons-Espinal M, Colini Baldeschi A, Campa L, Artigas F, Bortolozzi A, Domingo-Jiménez R, Ibáñez S, Pineda M, Artuch R, Raya Á, García-Cazorla À, Consiglio A
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p22872
Acceso en línea:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=22872
Access Level:acceso abierto
Palabra clave:dopamine
iPSC
L-Dopa
Parkinsonism
tyrosine hydroxylase deficiency
id ES_3e211dae4c047f7d4718377d3fb82d2f
oai_identifier_str oai:fsjd.fundanetsuite.com:p22872
network_acronym_str ES
network_name_str España
repository_id_str
spelling iPSC-based modeling of THD recapitulates disease phenotypes and reveals neuronal malformationTristán-Noguero AFernández-Carasa ICalatayud CBermejo-Casadesús CPons-Espinal MColini Baldeschi ACampa LArtigas FBortolozzi ADomingo-Jiménez RIbáñez SPineda MArtuch RRaya ÁGarcía-Cazorla ÀConsiglio AdopamineiPSCL-DopaParkinsonismtyrosine hydroxylase deficiencyTyrosine 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.SPRINGERNATURE2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=22872EMBO Molecular MedicineISSN: 17574676ISSNe: 17574684reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p228722026-05-27T12:37:41Z
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
Tristán-Noguero A
dopamine
iPSC
L-Dopa
Parkinsonism
tyrosine hydroxylase deficiency
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 Tristán-Noguero A
Fernández-Carasa I
Calatayud C
Bermejo-Casadesús C
Pons-Espinal M
Colini Baldeschi A
Campa L
Artigas F
Bortolozzi A
Domingo-Jiménez R
Ibáñez S
Pineda M
Artuch R
Raya Á
García-Cazorla À
Consiglio A
author Tristán-Noguero A
author_facet Tristán-Noguero A
Fernández-Carasa I
Calatayud C
Bermejo-Casadesús C
Pons-Espinal M
Colini Baldeschi A
Campa L
Artigas F
Bortolozzi A
Domingo-Jiménez R
Ibáñez S
Pineda M
Artuch R
Raya Á
García-Cazorla À
Consiglio A
author_role author
author2 Fernández-Carasa I
Calatayud C
Bermejo-Casadesús C
Pons-Espinal M
Colini Baldeschi A
Campa L
Artigas F
Bortolozzi A
Domingo-Jiménez R
Ibáñez S
Pineda M
Artuch R
Raya Á
García-Cazorla À
Consiglio A
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv dopamine
iPSC
L-Dopa
Parkinsonism
tyrosine hydroxylase deficiency
topic dopamine
iPSC
L-Dopa
Parkinsonism
tyrosine hydroxylase deficiency
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://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=22872
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=22872
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv SPRINGERNATURE
publisher.none.fl_str_mv SPRINGERNATURE
dc.source.none.fl_str_mv EMBO Molecular Medicine
ISSN: 17574676
ISSNe: 17574684
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869406505792438272
score 15.811543

Similares en LA Referencia