Tyrosine hydroxylase deficiency (THD) is an ultra-rare genetic disease that affects children. This disease causes a significant decrease in dopamine—one of the most important neurotransmitters in the central nervous system—in the brain, leading to childhood parkinsonism. Some patients improve greatly with treatment, but others are refractory and continue to have severe motility symptoms and intellectual disability.
A team of researchers from the University of Barcelona (UB), the Bellvitge Biomedical Research Institute (IDIBELL), the Sant Joan de Déu Research Institute (IRSJD) and the Santa Creu i Sant Pau Research Institute (IIB Sant Pau) in Catalonia have created a new model based on human stem cells to study this ultra-rare genetic disease.
The model created faithfully reproduces the pathological characteristics of the disease: it has been made from patients’ skin cells, which have been reprogrammed into pluripotent stem cells capable of becoming any cell type, and have subsequently differentiated into neurons.
“The model provides a very valuable tool to investigate the pathogenic mechanisms of this pathology, as well as to develop new therapies that improve patient management. It can even help to implement personalized therapies, since not all patients respond to treatment”, explains Professor Antonella Consiglio, head of the research group at the Faculty of Medicine and Health Sciences, the Institute of Biomedicine of the University de Barcelona (IBUB) and IDIBELL, ICREA Academia researcher and one of the project leaders.
As occurs at the physiological level, neurons differentiated from patient stem cells have very low levels of dopamine. “In addition, these neurons show morphological defects that had not been detected with other experimental approaches”, details Alba Tristán Noguero, first signatory of the work and postdoctoral researcher at the Department of Genetics, Microbiology and Statistics of the Faculty of Biology of the UB and the IIB Sant Pau.
The model also manages to reproduce the response to treatment that had been observed in patients: treatment with dopamine only makes it possible to reverse the symptoms of those patients with mild THD; on the other hand, severe patients do not respond to treatment and end up developing cognitive impairments.
As an outstanding conclusion, the study reveals that in the model that reproduces the most severe condition of THD, the early administration of dopamine —when the neurons are still differentiating— manages to prevent the effects of the disease. This result suggests that the treatment could work in the most severe patients if it is applied during brain development.
“This is the first THD model capable of differentially reproducing the characteristics of mild and severe patients, and which also reproduces their differential response to treatment,” says Àngels García Cazorla, co-leader of the study, professor at the Faculty of Medicine and Health Sciences, group leader at the IRSJD and at the Neurometabolic Diseases Unit of the Sant Joan de Déu Hospital in Barcelona, and member of the Center for Biomedical Research in the Network for Rare Diseases (CIBERER) in Spain.
The experts Irene Fernández Carasa, Carlos Calatayud, Arianna Colini Baldeschi, Meritxell Pons Espinal and Ángel Raya (UB-IDIBELL); Cristina Bermejo Casadesús, Mercè Pineda and Rafael Artuch (IRSJD); Leticia Campa, Francesc Artigas and Analia Bortolozzi (August Pi i Sunyer Biomedical Research Institute), and Rosario Domingo Jiménez and Salvador Ibáñez (Virgen de la Arrixaca Hospital and Virgen de la Arrixaca Biosanitary Research Institute in Murcia) in Spain.
From left to right, researchers Àngels García Cazorla, Irene Fernández Carasa, Alba Tristán Noguero, Meritxell Pons-Espinal and Antonella Consiglio.
The research team presents the technical details of the new model in the academic journal EMBO Molecular Medicine, under the title “iPSC-based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation”. (Source: UB)