Reply: Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.
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ABSTRACT:
SUBMITTER: Mencacci NE
PROVIDER: S-EPMC4407186 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
Publications
Reply: Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.
Mencacci Niccolo E NE Pittman Alan M AM Isaias Ioannis U IU Hardy John J Klebe Stephan S Bhatia Kailash P KP Wood Nicholas W NW
Brain : a journal of neurology 20141114 Pt 5
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Project description:GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.
| S-EPMC4132650 | biostudies-literature
Project description:BackgroundGBA mutation carriers with PD (PD-GBA) are at higher risk of cognitive decline, but there is limited data regarding whether there are differences in gait dysfunction between GBA mutation and non-mutation carriers with PD.Objectives/methodsThe primary aim of this study was to use quantitative inertial sensor-based gait analysis to compare gait asymmetry in 17 PD-GBA subjects, 17 non-mutation carriers with PD, and 15 healthy control subjects using parameters that had gait laterality and were markers of bradykinesia, in particular arm swing velocity and arm swing range of motion and stride length.ResultsArm swing velocity was more symmetric in PD-GBA subjects vs. non-mutation carriers in the OFF state (12.5 +/- 8.3 vs. 22.9 +/- 11.8%, respectively, p = 0.018). In the ON-medication state, non-mutation carriers with PD, but not PD-GBA subjects, exhibited arm swing velocity (16.8 +/- 8.6 vs. 22.9 +/- 11.8%, p = 0.006) and arm range of motion (26.7 +/- 16.3 vs. 33.4 +/- 18.6%, p = 0.02) that was more asymmetric compared with the OFF-medication state.ConclusionsIn the OFF medication state, arm swing velocity asymmetry may be a useful parameter in helping to distinguish GBA mutation carriers with PD from non-mutation carriers.
| S-EPMC6980620 | biostudies-literature
Project description: Not available
| S-EPMC4389628 | biostudies-literature
Project description:BackgroundBiallelic mutations in the GBA1 gene encoding glucocerebrosidase cause Gaucher's disease, whereas heterozygous carriers are at risk for Parkinson's disease (PD). Glucosylsphingosine is a clinically meaningful biomarker of Gaucher's disease but could not be assayed previously in heterozygous GBA1 carriers.ObjectiveThe aim of this study was to assess plasma glucosylsphingosine levels in GBA1 N370S carriers with and without PD.MethodsGlucosylsphingosine, glucosylceramide, and four other lipids were quantified in plasma from N370S heterozygotes with (n = 20) or without (n = 20) PD, healthy controls (n = 20), idiopathic PD (n = 20), and four N370S homozygotes (positive controls; Gaucher's/PD) using quantitative ultra-performance liquid chromatography tandem mass spectrometry.ResultsPlasma glucosylsphingosine was significantly higher in N370S heterozygotes compared with noncarriers, independent of disease status. As expected, Gaucher's/PD cases showed increases in both glucocerebrosidase substrates, glucosylsphingosine and glucosylceramide.ConclusionsPlasma glucosylsphingosine accumulation in N370S heterozygotes shown in this study opens up its future assessment as a clinically meaningful biomarker of GBA1-PD. © 2021 International Parkinson and Movement Disorder Society.
| S-EPMC8840974 | biostudies-literature
Project description:GTP cyclohydrolase I (GTPCH-1) is the rate-limiting enzyme involved in de novo biosynthesis of tetrahydrobiopterin (BH(4)), an essential cofactor for NO synthases and aromatic amino acid hydroxylases. GTPCH-1 undergoes negative feedback regulation by its end-product BH(4) via interaction with the GTP cyclohydrolase feedback regulatory protein (GFRP). Such a negative feedback mechanism should maintain cellular BH(4) levels within a very narrow range; however, we recently identified a phosphorylation site (S81) on human GTPCH-1 that markedly increases BH(4) production in response to laminar shear.We sought to define how S81 phosphorylation alters GTPCH-1 enzyme activity and how this is modulated by GFRP.Using prokaryotically expressed proteins, we found that the GTPCH-1 phospho-mimetic mutant (S81D) has increased enzyme activity, reduced binding to GFRP and resistance to inhibition by GFRP compared to wild-type GTPCH-1. Using small interfering RNA or overexpressing plasmids, GFRP was shown to modulate phosphorylation of GTPCH-1, BH(4) levels, and NO production in human endothelial cells. Laminar, but not oscillatory shear stress, caused dissociation of GTPCH-1 and GFRP, promoting GTPCH-1 phosphorylation. We also found that both GTPCH-1 phosphorylation and GFRP downregulation prevents endothelial NO synthase uncoupling in response to oscillatory shear. Finally oscillatory shear was associated with impaired GTPCH-1 phosphorylation and reduced BH(4) levels in vivo.These studies provide a new mechanism for regulation of endothelial GTPCH-1 by its phosphorylation and interplay with GFRP. This mechanism allows for escape from GFRP negative feedback and permits large amounts of BH(4) to be produced in response to laminar shear stress.
| S-EPMC2818799 | biostudies-literature
Project description:GTP cyclohydrolase I (GCH-1) is the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin, an essential cofactor for nitric oxide synthase and aromatic amino acid hydroxylase. To explore the interactome of GCH-1, we established a HEK 293 cell line stably expressing tetracycline-inducible FLAG-GCH-1. FLAG-GCH-1 and associated proteins were immunoprecipitated and analyzed by liquid chromatography/tandem mass spectrometry. Twenty-nine proteins, derived from different subcellular components such as cytosol, membranes, nucleus and mitochondria were identified to interact with GCH-1. Cell fractionation studies also showed that GCH-1 was present in the cytosol, membranes and nucleus. Gene ontology analysis revealed that GCH-1 interactome was involved in a variety of biological processes such as signal transduction, apoptosis, metabolism, transport and cell organization. To our knowledge, this study is the first to provide a comprehensive analysis of the GCH-1 interactome. Findings expand the number and diversity of proteins that are known to associate with GCH-1.
| S-EPMC2737525 | biostudies-literature
Project description:BackgroundGlucocerebrosidase gene mutations are a common genetic risk factor for Parkinson's disease. They exhibit incomplete penetrance. The objective of the present study was to measure microglial activation and dopamine integrity in glucocerebrosidase gene mutation carriers without Parkinson's disease compared to controls.MethodsWe performed PET scans on 9 glucocerebrosidase gene mutation carriers without Parkinson's disease and 29 age-matched controls. We measured microglial activation as 11 C-(R)-PK11195 binding potentials, and dopamine terminal integrity with 18 F-dopa influx constants.ResultsThe 11 C-(R)-PK11195 binding potential was increased in the substantia nigra of glucocerebrosidase gene carriers compared with controls (Student t test; right, t = -4.45, P = 0.0001). Statistical parametric mapping also localized significantly increased 11 C-(R)-PK11195 binding potential in the occipital and temporal lobes, cerebellum, hippocampus, and mesencephalon. The degree of hyposmia correlated with nigral 11 C-(R)-PK11195 regional binding potentials (Spearman's rank, P = 0.0066). Mean striatal 18 F-dopa uptake was similar to healthy controls.ConclusionsIn vivo 11 C-(R)-PK11195 PET imaging detects neuroinflammation in brain regions susceptible to Lewy pathology in glucocerebrosidase gene mutation carriers without Parkinson's. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC8048428 | biostudies-literature
Project description:IntroductionMutations in the teneurin transmembrane protein 4 (TENM4) gene, known to be involved in neuropsychiatric disorders, have been identified in three pedigree of essential tremor (ET) from Spain. ET has overlapping clinical manifestations and epidemiological symptoms with Parkinson's disease (PD), suggesting these two disorders may reflect common genetic risk factors. In this study, we investigated clinical and genetic manifestations in four unrelated pedigrees with both ET and PD in which TENM4 variants were identified.MethodsWe subsequently explored whether TENM4 variants contributed to the risk of developing PD. The frequency of TENM4 variants was evaluated from four PD pedigrees and other 407 subjects.ResultsThe results revealed 12 different novel heterozygous variants, all at low frequency. A clear general enrichment of TENM4 variants was detected in early onset PD patients (p < 0.001, OR = 5.264, 95% CI = 1.957-14.158).ConclusionThe results indicate that rare TENM4 variants may be associated with an increased risk of PD.
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Project description:Guanosine triphosphate cyclohydrolase I (GCH1) was previously identified as a regulator of reactive oxygen species (ROS) in brain tumor initiating cells (BTICs). Elucidating the GCH1/Tetrahydrobiopterin (BH4) pathway in BTICs has unveiled the necessity for GCH1 to protect BTICs from lipid peroxidation. Within this study, we observed differences in lipid pathways and lipid metabolites during GCH1 modulation. Alteration to polyunsaturated fatty acids (PUFAs), a species of oxidatively vulnerable lipids, were altered during GCH1 knockdown. Pharmacological inhibition of BH4 with drugs known to cross the blood brain barrier (sulfasalazine and pyrimethamine) successfully reduced growth in GCH1 overexpressed BTICs, induced lipid peroxidation.
2024-12-01 | GSE251878 | GEO
Project description:Ferroptosis is an iron-dependent form of regulated cell death linking iron, lipid, and glutathione levels to degenerative processes and tumor suppression. By performing a genome-wide activation screen, we identified a cohort of genes antagonizing ferroptotic cell death, including GTP cyclohydrolase-1 (GCH1) and its metabolic derivatives tetrahydrobiopterin/dihydrobiopterin (BH4/BH2). Synthesis of BH4/BH2 by GCH1-expressing cells caused lipid remodeling, suppressing ferroptosis by selectively preventing depletion of phospholipids with two polyunsaturated fatty acyl tails. GCH1 expression level in cancer cell lines stratified susceptibility to ferroptosis, in accordance with its expression in human tumor samples. The GCH1-BH4-phospholipid axis acts as a master regulator of ferroptosis resistance, controlling endogenous production of the antioxidant BH4, abundance of CoQ10, and peroxidation of unusual phospholipids with two polyunsaturated fatty acyl tails. This demonstrates a unique mechanism of ferroptosis protection that is independent of the GPX4/glutathione system.
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