Tetrahydrobiopterin (BH4) treatment stabilizes tyrosine hydroxylase: Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock-in mouse model

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Kunwar Jung-KC, Alba Tristán-Noguero, Altanchimeg Altankhuyag, David Piñol Belenguer, Karina S. Prestegård, Irene Fernandez-Carasa, Arianna Colini Baldeschi, Maria Sigatulina Bondarenko, Angeles García-Cazorla, Antonella Consiglio, Aurora Martinez
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Abstract

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.

Abstract Image

四氢生物蝶呤(BH4)能稳定酪氨酸羟化酶:拯救人类神经元和基因敲入小鼠模型中的酪氨酸羟化酶缺乏表型。
酪氨酸羟化酶(TH)是多巴胺生物合成过程中的限速酶,其蛋白静态调节对维持大脑神经递质的正常平衡至关重要。TH基因的变异与酪氨酸羟化酶缺乏症(THD)有关,THD是一种罕见的疾病,具有广泛的表型谱和对治疗的不同反应,它影响蛋白质的稳定性,可能导致加速降解、TH功能丧失和儿茶酚胺缺乏。在这项研究中,我们研究了 TH 辅因子四氢生物蝶呤(BH4)对分离蛋白中的 TH 和从人类健康受试者的 iPSCs 分化出的 DAn- 中的 TH 的稳定性的影响,以及从同源性 R233H 变体(THDA)和异源性 R328W 和 T399M 变体(THDB)的 THD 患者中的 TH 的稳定性的影响。我们报告说,在对照组和 THDA 细胞中,TH 和多巴胺水平增加,TH+ 细胞数量增加。为了将这一体外效应转化为体内效应,我们用 BH4 处理了一个基因敲入型 THD 小鼠模型,该模型中的 Th 变异与患者体内的 R233H 相对应。重要的是,用 BH4 治疗可显著改善这些小鼠的运动功能,这表现在转体测试潜伏期的延长和水平活动(催眠)的改善。总之,我们的研究证明了 BH4 对 THD 神经元和小鼠体内 TH 蛋白水平和功能的稳定作用,从而挽救了疾病表型并改善了运动结果。这些发现凸显了 BH4 作为特定变异型 THDA 患者治疗选择的潜力,并提供了有关 TH 稳定性调节及其对 THD 治疗影响的见解。
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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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