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

Tristan Noguero, A.; Fernandez-Carasa, I.; Calatayud, C.; Bermejo-Casadesus, C.; Campa, L.; Artigas, F.; Domingo-Jimenez, R.; Ibanez, S.; Pineda, M.; Artuch, R.; Raya, A.; Garcia Cazorla, A.; Consiglio, A.

doi:10.1101/2022.02.24.481741

bioRxiv · 10.1101/2022.02.24.481741

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

Tristan Noguero, A.·Fernandez-Carasa, I.·Calatayud, C.·Bermejo-Casadesus, C.·Campa, L.·Artigas, F.·Domingo-Jimenez, R.·Ibanez, S.·Pineda, M.·Artuch, R.·Raya, A.·Garcia Cazorla, A.·Consiglio, A.

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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 either an abnormal TH proximodistal gradient (THDA), or neurite arborization defects (THDB). 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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Tristan Noguero, A., Fernandez-Carasa, I., Calatayud, C., Bermejo-Casadesus, C., Campa, L., Artigas, F., Domingo-Jimenez, R., Ibanez, S., Pineda, M., Artuch, R., Raya, A., Garcia Cazorla, A., Consiglio, A.. 2022-02-26. iPSC-based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation. https://doi.org/10.1101/2022.02.24.481741

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