Tetrahydrobiopterin (BH4) treatment stabilizes tyrosine hydroxylase : Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock-in mouse model
Jung-KC, Kunwar (University of Bergen)
Tristán-Noguero, A. (Institut de Recerca Sant Pau)
Altankhuyag, Altanchimeg (University of Bergen)
Piñol Belenguer, David (Universitat de Barcelona)
Prestegård, Karina S. (University of Bergen)
Fernandez Carasa, Irene (Universitat de Barcelona)
Colini Baldeschi, Arianna (Universitat de Barcelona)
Sigatulina Bondarenko, Maria (Hospital Sant Joan de Déu (Esplugues de Llobregat, Catalunya))
García-Cazorla, Angels (Centro de Investigación Biomédica En Red Enfermedades Raras (CIBERER))
Consiglio, Antonella (University of Brescia)
Martinez, Aurora (Haukeland University Hospital (Bergen, Noruega))
Universitat Autònoma de Barcelona

Data:	2024
Resum:	Proteostatic regulation of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis, is crucial for maintaining proper brain neurotransmitter homeostasis. Variants of the TH gene are associated with tyrosine hydroxylase deficiency (THD), a rare disorder with a wide phenotypic spectrum and variable response to treatment, which affects protein stability and may lead to accelerated degradation, loss of TH function and catecholamine deficiency. In this study, we investigated the effects of the TH cofactor tetrahydrobiopterin (BH) on the stability of TH in isolated protein and in DAn- differentiated from iPSCs from a human healthy subject, as well as from THD patients with the R233H variant in homozygosity (THDA) and R328W and T399M variants in heterozygosity (THDB). We report an increase in TH and dopamine levels, and an increase in the number of TH+ cells in control and THDA cells. To translate this in vitro effect, we treated with BH a knock-in THD mouse model with Th variant corresponding to R233H in patients. Importantly, treatment with BH significantly improved motor function in these mice, as demonstrated by increased latency on the rotarod test and improved horizontal activity (catalepsy). In conclusion, our study demonstrates the stabilizing effects of BH on TH protein levels and function in THD neurons and mice, rescuing disease phenotypes and improving motor outcomes. These findings highlight the therapeutic potential of BH as a treatment option for THDA patients with specific variants and provide insights into the modulation of TH stability and its implications for THD management.
Ajuts:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-899 European Commission 2012-StG-311736-PD-HUMMODEL Ministerio de Economía y Competitividad RTI2018-095377-B-100 Ministerio de Economía y Competitividad PID2019-108792-GB-I00 Ministerio de Economía y Competitividad RD16/0011/0024 Instituto de Salud Carlos III FI21/00073 Agencia Estatal de Investigación CEX2018-000792-M Fundació la Marató de TV3 202012-31 Fundació la Marató de TV3 202012-32 Fundació la Marató de TV3 202012-33
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Dopamine ; Ipsc-derived neurons ; Mice model ; Pharmacological chaperones ; Tetrahydrobiopterin (BH4) ; Tyrosine hydroxylase deficiency (THD)
Publicat a:	Journal of Inherited Metabolic Disease, Vol. 47 Núm. 3 (may 2024) , p. 494-508, ISSN 1573-2665

DOI: 10.1002/jimd.12702
PMID: 38196161

15 p, 3.6 MB

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