2026-04-17T07:44:41Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/2191142025-12-05T10:05:30Zcom_2072_1057col_2072_478916col_2072_478917col_2072_478929

00925njm 22002777a 4500 dc Kunwar, Jung-KC author Tristán Noguero, Alba author Altankhuyag, Altanchimeg author Piñol Belenguer, David author Prestegård, Karina S. author Fernández Carasa, Irene author Colini Baldeschi, Arianna author Sigatullina Bondarenko, Maria author García-Cazorla, Angeles author Consiglio, Antonella author Martinez, Aurora author 2025-02-21T17:56:21Z 2025-02-21T17:56:21Z 2024-01-09 2025-02-21T17:56:21Z 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 (BH4) 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 BH4 a knock-in THD mouse model with Th variant corresponding to R233H in patients. Importantly, treatment with BH4 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 BH4 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 BH4 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. Coenzims Dopamina Malalties dels animals Animals Coenzymes Dopamine Animal diseases Animals Tetrahydrobiopterin (BH4) treatment stabilizes tyrosine hydroxylase: Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock-in mouse model