iPSC-based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation.

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

Journal: EMBO molecular medicine 2023;15(3):e15847

PMID: 36740977

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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.

Address: Neurometabolic Unit and Synaptic Metabolism Lab, Neurology Department, Institut Pediàtric de Recerca, Hospital Sant Joan de Déu, Barcelona, Spain.; Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain.; Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain.; Regenerative Medicine Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.; Program for Translation of Regenerative Medicine in Catalonia (P-[CMRC]), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona, Spain.; Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain.; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.; Department of Pediatric Neurology, Hospital Virgen de la Arrixaca, Murcia, Spain.; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB), Murcia, Spain.; Centro de Investigación Biomédica En Red Enfermedades Raras (CIBERER), Madrid, Spain.; Department of Pediatric Neurology, Hospital Virgen de la Arrixaca, Murcia, Spain.; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB), Murcia, Spain.; Fundació Sant Joan de Déu (FSJD), Hospital Sant Joan de Déu (HSJD), Barcelona, Spain.; Centro de Investigación Biomédica En Red Enfermedades Raras (CIBERER), Madrid, Spain.; Metabolic Unit, Departments of Neurology, Nutrition Biochemistry and Genetics, Institut Pediàtric de Recerca, Hospital San Joan de Déu, Barcelona, Spain.; Regenerative Medicine Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.; Program for Translation of Regenerative Medicine in Catalonia (P-[CMRC]), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona, Spain.; Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.; Neurometabolic Unit and Synaptic Metabolism Lab, Neurology Department, Institut Pediàtric de Recerca, Hospital Sant Joan de Déu, Barcelona, Spain.; Centro de Investigación Biomédica En Red Enfermedades Raras (CIBERER), Madrid, Spain.; Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain.; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

DOI: 10.15252/emmm.202215847