iPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation
Abstract 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 ind...
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| Language: | English |
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Springer Nature
2023-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202215847 |
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| author | Alba Tristán‐Noguero Irene Fernández‐Carasa Carles Calatayud Cristina Bermejo‐Casadesús Meritxell Pons‐Espinal Arianna Colini Baldeschi Leticia Campa Francesc Artigas Analia Bortolozzi Rosario Domingo‐Jiménez Salvador Ibáñez Mercè Pineda Rafael Artuch Ángel Raya Àngels García‐Cazorla Antonella Consiglio |
| author_facet | Alba Tristán‐Noguero Irene Fernández‐Carasa Carles Calatayud Cristina Bermejo‐Casadesús Meritxell Pons‐Espinal Arianna Colini Baldeschi Leticia Campa Francesc Artigas Analia Bortolozzi Rosario Domingo‐Jiménez Salvador Ibáñez Mercè Pineda Rafael Artuch Ángel Raya Àngels García‐Cazorla Antonella Consiglio |
| author_sort | Alba Tristán‐Noguero |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-e22ef144c32047569cfc1dd967018c9c |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-e22ef144c32047569cfc1dd967018c9c2024-11-10T12:37:28ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-02-0115311510.15252/emmm.202215847iPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformationAlba Tristán‐Noguero0Irene Fernández‐Carasa1Carles Calatayud2Cristina Bermejo‐Casadesús3Meritxell Pons‐Espinal4Arianna Colini Baldeschi5Leticia Campa6Francesc Artigas7Analia Bortolozzi8Rosario Domingo‐Jiménez9Salvador Ibáñez10Mercè Pineda11Rafael Artuch12Ángel Raya13Àngels García‐Cazorla14Antonella Consiglio15Neurometabolic Unit and Synaptic Metabolism Lab, Neurology Department, Institut Pediàtric de Recerca, Hospital Sant Joan de DéuDepartment of Pathology and Experimental Therapeutics, Bellvitge University Hospital‐IDIBELL, Hospitalet de LlobregatDepartment of Pathology and Experimental Therapeutics, Bellvitge University Hospital‐IDIBELL, Hospitalet de LlobregatNeurometabolic Unit and Synaptic Metabolism Lab, Neurology Department, Institut Pediàtric de Recerca, Hospital Sant Joan de DéuDepartment of Pathology and Experimental Therapeutics, Bellvitge University Hospital‐IDIBELL, Hospitalet de LlobregatDepartment of Pathology and Experimental Therapeutics, Bellvitge University Hospital‐IDIBELL, Hospitalet de LlobregatInstitut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC)Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC)Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC)Department of Pediatric Neurology, Hospital Virgen de la ArrixacaDepartment of Pediatric Neurology, Hospital Virgen de la ArrixacaFundació Sant Joan de Déu (FSJD), Hospital Sant Joan de Déu (HSJD)Centro de Investigación Biomédica En Red Enfermedades Raras (CIBERER)Regenerative Medicine Program, Bellvitge Biomedical Research Institute (IDIBELL)Neurometabolic Unit and Synaptic Metabolism Lab, Neurology Department, Institut Pediàtric de Recerca, Hospital Sant Joan de DéuDepartment of Pathology and Experimental Therapeutics, Bellvitge University Hospital‐IDIBELL, Hospitalet de LlobregatAbstract 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.https://doi.org/10.15252/emmm.202215847dopamineiPSCL‐DopaParkinsonismtyrosine hydroxylase deficiency |
| spellingShingle | Alba Tristán‐Noguero Irene Fernández‐Carasa Carles Calatayud Cristina Bermejo‐Casadesús Meritxell Pons‐Espinal Arianna Colini Baldeschi Leticia Campa Francesc Artigas Analia Bortolozzi Rosario Domingo‐Jiménez Salvador Ibáñez Mercè Pineda Rafael Artuch Ángel Raya Àngels García‐Cazorla Antonella Consiglio iPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation EMBO Molecular Medicine dopamine iPSC L‐Dopa Parkinsonism tyrosine hydroxylase deficiency |
| title | 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_short | 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 |
| topic | dopamine iPSC L‐Dopa Parkinsonism tyrosine hydroxylase deficiency |
| url | https://doi.org/10.15252/emmm.202215847 |
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