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...

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Detalles Bibliográficos
Autores: Tristán-Noguero, Alba, Fernández-Carasa, Irene, Calatayud, Carles, Bermejo-Casadesús, Cristina, Pons-Espinal, Meritxell, Colini Baldeschi, Arianna, Campa, Leticia, Artigas, Francesc, Bortolozzi, Analía, Domingo-Jiménez, Rosario, Ibáñez, Salvador, Pineda, Mercè, Artuch, Rafael, Raya, Ángel, García-Cazorla, Àngels, Consiglio, Antonella
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/337777
Acceso en línea:http://hdl.handle.net/10261/337777
Access Level:acceso abierto
Palabra clave:Dopamine
iPSC
L-Dopa
Parkinsonism
Tyrosine hydroxylase deficiency
Descripción
Sumario: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.

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