Tetrahydrobiopterin deficiency in the pathogenesis of Fabry disease

Shen, Jinsong; Arning, Erland; West, Michael; Day, Taniqua S.; Chen, Shuyuan; Meng, Xing-Li; Forni, Sabrina; McNeill, Nathan; Göker-Alpan, Özlem; Wang, Xuan; Ashcraft, Paula; Moore, David F.; Cheng, Seng H.; Schiffmann, Raphael

doi:10.1093/hmg/ddx032

Cited by 19 publications

(24 citation statements)

References 38 publications

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“…The presented data confirms and significantly expands on published work demonstrating that GCS inhibitors can reduce accumulated Gb3 in cultured cells derived from Fabry patients (33,45). In particular, Itier and colleagues have shown that GCS inhibitors can reduce accumulated Gb3, suggesting a role for clearance mechanisms other than α-GalA (45).…”

Section: Discussionsupporting

confidence: 90%

“…Lucerastat also dose-dependently reduced the acidic compartment staining, a cellular phenotype associated with LSDs (44). The effectiveness of lucerastat observed here in Fabry patients’ fibroblasts, in Fabry patients (39), combined with studies of GCS inhibitors in mice null for α-GalA activity (20,32,33,37), suggests that the lucerastat SRT mode of action may be appropriate for all Fabry patients.…”

Section: Discussionmentioning

confidence: 67%

“…ERT generally had a smaller effect on Gb3 than lucerastat, this may be due to ERT only reducing lysosomal Gb3, while SRT reduces all Gb3. In a study of Fabry patient-derived microvascular endothelial cells ERT was found to reduce punctuate (presumably lysosomal) immunofluorescence staining of Gb3, while not effecting overall Gb3 levels (33). In the same study, a GCS inhibitor reduced all Gb3 staining and the total level.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, in Fabry mice, GCS inhibitors reduce tissue Gb3 by inhibiting production of the metabolic precursor glucosylceramide (GlcCer) (Fig. 1) (20,32,33). In Fabry mice, GCS inhibitors and ERT have complementary pharmacodynamic profiles, with GCS inhibitors more effectively clearing Gb3 from the kidneys (20,32) .…”

Section: Introductionmentioning

confidence: 99%

“…In Fabry mice, GCS inhibitors and ERT have complementary pharmacodynamic profiles, with GCS inhibitors more effectively clearing Gb3 from the kidneys (20,32) . Additionally, GCS inhibitors and not ERT delayed loss of the thermal nociceptive response (20) and increased tetrahydrobiopterin, thereby reducing renal hypertrophy (33). …”

Section: Introductionmentioning

confidence: 99%

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Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types

Welford

Mühlemann

Garzotti

et al. 2018

Human Molecular Genetics

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Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene coding for α-galactosidase A (α-GalA). The deleterious mutations lead to accumulation of α-GalA substrates, including globotriaosylceramide (Gb3) and globotriaosylsphingosine. Progressive glycolipid storage results in cellular dysfunction, leading to organ damage and clinical disease, i.e. neuropathic pain, impaired renal function and cardiomyopathy. Many Fabry patients are treated by bi-weekly intravenous infusions of replacement enzyme. While the only available oral therapy is an α-GalA chaperone, which is indicated for a limited number of patients with specific ‘amenable’ mutations. Lucerastat is an orally bioavailable inhibitor of glucosylceramide synthase (GCS) that is in late stage clinical development for Fabry disease. Here we investigated the ability of lucerastat to lower Gb3, globotriaosylsphingosine and lysosomal staining in cultured fibroblasts from 15 different Fabry patients. Patients’ cells included 13 different pathogenic variants, with 13 cell lines harboring GLA mutations associated with the classic disease phenotype. Lucerastat dose dependently reduced Gb3 in all cell lines. For 13 cell lines the Gb3 data could be fit to an IC50 curve, giving a median IC50 [interquartile range (IQR)] = 11 μM (8.2–18); the median percent reduction (IQR) in Gb3 was 77% (70–83). Lucerastat treatment also dose dependently reduced LysoTracker Red staining of acidic compartments. Lucerastat’s effects in the cell lines were compared to those with current treatments—agalsidase alfa and migalastat. Consequently, the GCS inhibitor lucerastat provides a viable mechanism to reduce Gb3 accumulation and lysosome volume, suitable for all Fabry patients regardless of genotype.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types

Welford

Mühlemann

Garzotti

et al. 2018

Human Molecular Genetics

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Priapism caused by partial deficiency of tetrahydrobiopterin through hypofunction of the sympathetic neurons in sepiapterin reductase gene‐disrupted mice

Sumi‐Ichinose

Suganuma

Kano

et al. 2022

J of Inher Metab Disea

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6R‐L‐erythro‐5,6,7,8‐tetrahydrobiopterin (BH4) is an essential cofactor for aromatic L‐amino acid hydroxylases, including tyrosine hydroxylase (TH), alkylglycerol monooxygenase, and three types of nitric oxide (NO) synthases (NOS). Sepiapterin reductase (SPR) catalyzes the third step of BH4 biosynthesis. SPR gene‐disrupted (Spr−/−) mice exhibit a dystonic posture, low body weight, hyperphenylalaninemia, and unstable hypertension with endothelial dysfunction. In this study, we found that Spr−/− mice suffered from a high incidence of severe priapism. Their erections persisted for months. The biopterin, BH4, and norepinephrine contents, and TH protein levels in the penile tissue of Spr−/− mice without and with priapism were significantly reduced compared to those of Spr+/+ mice. In contrast, their neural NOS (nNOS) protein levels were increased, and the cyclic guanosine monophosphate (cGMP) levels were remarkably elevated in the penises of Spr−/− mice with priapism. The symptoms were relieved by repeated administration of BH4. The biopterin, BH4, and norepinephrine contents were increased in penile homogenates from BH4‐supplemented Spr−/− mice, and the TH protein levels tended to increase, and their nitrite plus nitrate levels were significantly lower than those of vehicle‐treated Spr−/− mice and were approximately the same as vehicle‐ and BH4‐supplemented Spr+/+ mice. Thus, we deduced that the priapism of Spr−/− mice is primarily caused by hypofunction of the sympathetic neurons due to cofactor depletion and the loss of TH protein and, further, dysregulation of the NO/cGMP signaling pathway, which would be caused by disinhibition of nNOS‐containing neurons and/or abnormal catabolism of cyclic nucleotides is suggested.

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A plant-based mutant huntingtin model-driven discovery of impaired expression of GTPCH and DHFR

Hung

Zhu

Kittur

et al. 2022

Cell. Mol. Life Sci.

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Pathophysiology associated with Huntington’s disease (HD) has been studied extensively in various cell and animal models since the 1993 discovery of the mutant huntingtin (mHtt) with abnormally expanded polyglutamine (polyQ) tracts as the causative factor. However, the sequence of early pathophysiological events leading to HD still remains elusive. To gain new insights into the early polyQ-induced pathogenic events, we expressed Htt exon1 (Httex1) with a normal (21), or an extended (42 or 63) number of polyQ in tobacco plants. Here, we show that transgenic plants accumulated Httex1 proteins with corresponding polyQ tracts, and mHttex1 induced protein aggregation and affected plant growth, especially root and root hair development, in a polyQ length-dependent manner. Quantitative proteomic analysis of young roots from severely affected Httex1Q63 and unaffected Httex1Q21 plants showed that the most reduced protein by polyQ63 is a GTP cyclohydrolase I (GTPCH) along with many of its related one-carbon (C1) metabolic pathway enzymes. GTPCH is a key enzyme involved in folate biosynthesis in plants and tetrahydrobiopterin (BH4) biosynthesis in mammals. Validating studies in 4-week-old R6/2 HD mice expressing a mHttex1 showed reduced levels of GTPCH and dihydrofolate reductase (DHFR, a key folate utilization/alternate BH4 biosynthesis enzyme), and impaired C1 and BH4 metabolism. Our findings from mHttex1 plants and mice reveal impaired expressions of GTPCH and DHFR and may contribute to a better understanding of mHtt-altered C1 and BH4 metabolism, and their roles in the pathogenesis of HD.

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Tetrahydrobiopterin deficiency in the pathogenesis of Fabry disease

Cited by 19 publications

References 38 publications

Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types

Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types

Priapism caused by partial deficiency of tetrahydrobiopterin through hypofunction of the sympathetic neurons in sepiapterin reductase gene‐disrupted mice

A plant-based mutant huntingtin model-driven discovery of impaired expression of GTPCH and DHFR

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