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EMBO Mol Med - 2023 - Trist n‐Noguero - iPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal.pdf (17.74 MB)

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2023-02-06

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cc by (c) Tristá Noguero, Alba et al., 2023
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/198344

IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation

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Recurs relacionat

https://doi.org/10.15252/emmm.202215847

Resum

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.

Matèries

Malalties rares, Cèl·lules mare, Fenotip, Dopamina

Matèries (anglès)

Rare diseases, Stem cells, Phenotype, Dopamine

Citació

Col·leccions

Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut de Biomedicina (IBUB))

Citació

TRISTÁ NOGUERO, Alba, FERNÁNDEZ CARASA, Irene, CALATAYUD, Carles, BERMEJO CASADESÚS, Cristina, PONS ESPINAL, Meritxell, COLINI BALDESCHI, Arianna, CAMPA, Leticia, ARTIGAS PÉREZ, Francesc, BORTOLOZZI, Analia, DOMINGO JIMÉNEZ, Rosario, IBÁÑEZ, Salvador, PINEDA, Mercè, ARTUCH IRIBERRI, Rafael, RAYA CHAMORRO, Ángel, GARCÍA CAZORLA, Àngels, CONSIGLIO, Antonella. IPSC‐based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation. _EMBO Molecular Medicine_. 2023. Vol. 15, núm. 3, pàgs. e15847. [consulta: 23 de gener de 2026]. ISSN: 1757-4684. [Disponible a: https://hdl.handle.net/2445/198344]

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