Tristá 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, Antonella2023-05-232023-05-232023-02-061757-4684https://hdl.handle.net/2445/198344Tyrosine 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.15 p.application/pdfengcc by (c) Tristá Noguero, Alba et al., 2023http://creativecommons.org/licenses/by/3.0/es/Malalties raresCèl·lules mareFenotipDopaminaRare diseasesStem cellsPhenotypeDopamineinfo:eu-repo/semantics/article2023-04-14info:eu-repo/semantics/openAccess36740977