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Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/198344
IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation
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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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TRISTÁ NOGUERO, Alba, et al. IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation. EMBO Molecular Medicine. 2023. Vol. 15, num. 3, pags. e15847. ISSN 1757-4684. [consulted: 6 of June of 2026]. Available at: https://hdl.handle.net/2445/198344