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Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene.

ABSTRACT: Oxidative stress could be involved in the pathophysiology of schizophrenia, a major psychiatric disorder. Glutathione (GSH), a redox regulator, is decreased in patients' cerebrospinal fluid and prefrontal cortex. The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study. GCLM gene expression is decreased in patients' fibroblasts. Thus, GSH metabolism dysfunction is proposed as one of the vulnerability factors for schizophrenia.

SUBMITTER: Tosic M

PROVIDER: S-EPMC1559555 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene.

Tosic Mirjana M Ott Jurg J Barral Sandra S Bovet Pierre P Deppen Patricia P Gheorghita Fulvia F Matthey Marie-Louise ML Parnas Josef J Preisig Martin M Saraga Michael M Solida Alessandra A Timm Sally S Wang August G AG Werge Thomas T Cuénod Michel M Do Kim Quang KQ

American journal of human genetics 20060731 3

Oxidative stress could be involved in the pathophysiology of schizophrenia, a major psychiatric disorder. Glutathione (GSH), a redox regulator, is decreased in patients' cerebrospinal fluid and prefrontal cortex. The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study. GCLM gene expression is decreased in patients' fibroblasts. Thus, GSH metabolism dysfunction is ...[more]

PMID: 16909399

Similar Datasets

Exercise induced upregulation of glutamate-cysteine ligase catalytic subunit and glutamate-cysteine ligase modifier subunit gene expression in Thoroughbred horses.

Project description:ObjectiveThis study was performed to reveal the molecular structure and expression patterns of horse glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase modifier subunit (GCLM) genes whose products form glutamate cysteine ligase, which were identified as differentially expressed genes in the previous study.MethodsWe performed bioinformatics analyses, and gene expression assay with quantitative polymerase chain reaction (qPCR) for horse GCLC and GCLM genes in muscle and blood leukocytes of Thoroughbred horses.ResultsExpression of GCLC showed the same pattern in both blood and muscle tissues after exercise. Expression of GCLC increased in the muscle and blood of Thoroughbreds, suggesting a tissue-specific regulatory mechanism for the expression of GCLC. In addition, expression of the GCLM gene increased after exercise in both the blood and muscle of Thoroughbreds.ConclusionWe established the expression patterns of GCLC and GCLM in the skeletal muscle and blood of Thoroughbred horses in response to exercise. Further study is now warranted to uncover the functional importance of these genes in exercise and recovery in racehorses.

| S-EPMC5411833 | biostudies-literature

Rapid activation of glutamate cysteine ligase following oxidative stress.

Project description:Glutamate cysteine ligase (GCL) catalyzes the rate-limiting step in the formation of the cellular antioxidant glutathione (GSH). The GCL holoenzyme consists of two separately coded proteins, a catalytic subunit (GCLC) and a modifier subunit (GCLM). Both GCLC and GLCM are controlled transcriptionally by a variety of cellular stimuli, including oxidative stress. This study addresses post-translational control of GCL activity, which increased rapidly in human lymphocytes following oxidative stress. Activation of GCL occurred within minutes of treatment and without any change in GCL protein levels and coincided with an increase in the proportion of GCLC in the holoenzyme form. Likewise, GCLM shifted from the monomeric form to holoenzyme and higher molecular weight species. Normal rat tissues also showed a distribution of monomeric and higher molecular weight forms. Neither GCL activation, nor the formation of holoenzyme, required a covalent intermolecular disulfide bridge between GCLC and GCLM. However, in immunoprecipitation studies, a neutralizing epitope associated with enzymatic activity was protected following cellular oxidative stress. Thus, the N-terminal portion of GCLC may undergo a change that stabilizes the GCL holoenzyme. Our results suggest that a dynamic equilibrium exists between low and high activity forms of GCL and is altered by transient oxidative stress. This provides a mechanism for the rapid post-translational activation of GCL and maintenance of cellular GSH homeostasis.

| S-EPMC2871480 | biostudies-literature

Functional significance of glutamate-cysteine ligase modifier for erythrocyte survival in vitro and in vivo.

Project description:Erythrocytes endure constant exposure to oxidative stress. The major oxidative stress scavenger in erythrocytes is glutathione. The rate-limiting enzyme for glutathione synthesis is glutamate-cysteine ligase, which consists of a catalytic subunit (GCLC) and a modifier subunit (GCLM). Here, we examined erythrocyte survival in GCLM-deficient (gclm(-/-)) mice. Erythrocytes from gclm(-/-) mice showed greatly reduced intracellular glutathione. Prolonged incubation resulted in complete lysis of gclm(-/-) erythrocytes, which could be reversed by exogenous delivery of the antioxidant Trolox. To test the importance of GCLM in vivo, mice were treated with phenylhydrazine (PHZ; 0.07 mg/g b.w.) to induce oxidative stress. Gclm(-/-) mice showed dramatically increased hemolysis compared with gclm(+/+) controls. In addition, PHZ-treated gclm(-/-) mice displayed markedly larger accumulations of injured erythrocytes in the spleen than gclm(+/+) mice within 24 h of treatment. Iron staining indicated precipitations of the erythrocyte-derived pigment hemosiderin in kidney tubules of gclm(-/-) mice and none in gclm(+/+) controls. In fact, 24 h after treatment, kidney function began to diminish in gclm(-/-) mice as evident from increased serum creatinine and urea. Consequently, while all PHZ-treated gclm(+/+) mice survived, 90% of PHZ-treated gclm(-/-) mice died within 5 days of treatment. In vitro, upon incubation in the absence or presence of additional oxidative stress, gclm(-/-) erythrocytes exposed significantly more phosphatidylserine, a cell death marker, than gclm(+/+) erythrocytes, an effect at least partially due to increased cytosolic Ca(2+) concentration. Under resting conditions, gclm(-/-) mice exhibited reticulocytosis, indicating that the enhanced erythrocyte death was offset by accelerated erythrocyte generation. GCLM is thus indispensable for erythrocyte survival, in vitro and in vivo, during oxidative stress.

| S-EPMC3770325 | biostudies-other

Tuberous sclerosis complex neuropathology requires glutamate-cysteine ligase.

Project description:IntroductionTuberous sclerosis complex (TSC) is a genetic disease resulting from mutation in TSC1 or TSC2 and subsequent hyperactivation of mammalian Target of Rapamycin (mTOR). Common TSC features include brain lesions, such as cortical tubers and subependymal giant cell astrocytomas (SEGAs). However, the current treatment with mTOR inhibitors has critical limitations. We aimed to identify new targets for TSC pharmacotherapy.ResultsThe results of our shRNA screen point to glutamate-cysteine ligase catalytic subunit (GCLC), a key enzyme in glutathione synthesis, as a contributor to TSC-related phenotype. GCLC inhibition increased cellular stress and reduced mTOR hyperactivity in TSC2-depleted neurons and SEGA-derived cells. Moreover, patients' brain tubers showed elevated GCLC and stress markers expression. Finally, GCLC inhibition led to growth arrest and death of SEGA-derived cells.ConclusionsWe describe GCLC as a part of redox adaptation in TSC, needed for overgrowth and survival of mutant cells, and provide a potential novel target for SEGA treatment.

| S-EPMC4518593 | biostudies-literature

Variants in the glutamate-cysteine-ligase gene are associated with cystic fibrosis lung disease.

Project description:BackgroundChronic progressive lung disease is the most serious complication of cystic fibrosis (CF). Glutathione plays an important role in the protection of the CF lung against oxidant-induced lung injury.ObjectivesWe hypothesized that a polymorphism in a novel candidate gene that regulates glutathione synthesis might influence CF lung disease.MethodsIn a cross-sectional study, subjects were recruited from CF clinics in Seattle and multiple centers in Canada. We tested for an association between CF lung disease and a functional polymorphism in the glutamate-cysteine ligase catalytic subunit (GCLC) gene. Multiple linear regression was used to test for association between polymorphisms of GCLC and severity of CF lung disease while adjusting for age, Pseudomonas aeruginosa infection, and cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Analysis was repeated for patients with CF stratified by CFTR genotype.Measurements and main resultsA total of 440 subjects with CF participated in the study (51% male; mean [+/- SD] age, 26 +/- 11 yr; mean FEV(1), 62 +/- 28% predicted). In the total population, there was a trend toward an association between GCLC genotypes and CF lung disease (linear regression coefficient [SEM], 1.68 [1.0]; p = 0.097). In the stratified analysis, there was a highly significant association between GCLC genotype and CF lung function in subjects with a milder CFTR genotype (linear regression coefficient [SEM], 5.5 (1.7); p = 0.001).ConclusionsIn patients with CF with a milder CFTR genotype, there is a strong association between functional polymorphisms of the GCLC gene and CF lung disease severity.

| S-EPMC2648118 | biostudies-literature

Non-canonical Glutamate-Cysteine Ligase Activity Protects against Ferroptosis.

Project description:Cysteine is required for maintaining cellular redox homeostasis in both normal and transformed cells. Deprivation of cysteine induces the iron-dependent form of cell death known as ferroptosis; however, the metabolic consequences of cysteine starvation beyond impairment of glutathione synthesis are poorly characterized. Here, we find that cystine starvation of non-small-cell lung cancer cell lines induces an unexpected accumulation of γ-glutamyl-peptides, which are produced due to a non-canonical activity of glutamate-cysteine ligase catalytic subunit (GCLC). This activity is enriched in cell lines with high levels of NRF2, a key transcriptional regulator of GCLC, but is also inducible in healthy murine tissues following cysteine limitation. γ-glutamyl-peptide synthesis limits the accumulation of glutamate, thereby protecting against ferroptosis. These results indicate that GCLC has a glutathione-independent, non-canonical role in the protection against ferroptosis by maintaining glutamate homeostasis under cystine starvation.

| S-EPMC7839835 | biostudies-literature

Glutamate-Cysteine Ligase Catalytic Subunit Attenuated Hepatitis C Virus-Related Liver Fibrosis and Suppressed Endoplasmic Reticulum Stress.

Project description:The study aimed to clarify the role and molecular mechanism of glutamate-cysteine ligase catalytic subunit (GCLC) in modulating Hepatitis C virus (HCV)-related liver fibrosis. Twenty patients with HCV-related liver fibrosis and 15 healthy controls were enrolled. Differentially expressed plasma mRNAs were detected by digital gene expression profile analysis and validated by qRT-PCR. Hepatic histopathology was observed by H&E and Masson stained liver sections. The mRNA and protein expression of GCLC, endoplasmic reticulum (ER) stress markers, and inflammatory and fibrogenic factors were detected in liver tissues from patients with HCV-related hepatic fibrosis and HCV core protein-expressing LX-2. The GCLC-overexpressing LX-2 were established by transfecting puc19-GCLC plasmid. Then, glutathione and reactive oxygen species (ROS) levels were measured respectively by spectrophotometric diagnostic kit and dihydrodichlorofluorescein diacetate kit. GCLC were dramatically down-regulated in HCV-related fibrotic livers and activated HSCs, which companied with up-regulation of ER stress-related genes, including inositol-requiring 1 (IRE1) and glucose-regulated protein 78 (GRP78). Also, the proinflammatory and profibrogenic gene, including nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNFα), and transforming growth factor 1(TGFβ1), was highly upregulated. Overexpression of GCLC in hepatic stellate cells could suppress α-SMA and collagen I expression, produce hepatic GSH and reduce ROS, and down-regulate IRE1, GRP78, NF-κB, TNF-α, and TGFβ1 expression. GCLC was a negative regulatory factor in the development of HCV-related liver fibrosis and might be a potential therapeutic target for liver fibrosis.

| S-EPMC7461853 | biostudies-literature

Identification and characterization of gshA, a gene encoding the glutamate-cysteine ligase in the halophilic archaeon Haloferax volcanii.

Project description:Halophilic archaea were found to contain in their cytoplasm millimolar concentrations of gamma-glutamylcysteine (gamma GC) instead of glutathione. Previous analysis of the genome sequence of the archaeon Halobacterium sp. strain NRC-1 has indicated the presence of a sequence homologous to sequences known to encode the glutamate-cysteine ligase GshA. We report here the identification of the gshA gene in the extremely halophilic archaeon Haloferax volcanii and show that H. volcanii gshA directs in vivo the synthesis and accumulation of gamma GC. We also show that the H. volcanii gene when expressed in an Escherichia coli strain lacking functional GshA is able to restore synthesis of glutathione.

| S-EPMC2725602 | biostudies-literature

Differential regulation of glutamate-cysteine ligase subunit expression and increased holoenzyme formation in response to cysteine deprivation.

Project description:GCL (glutamate-cysteine ligase) is a heterodimer of a GCLC (GCL catalytic subunit) that possesses all of the enzymatic activity and a GCLM (GCL modifier subunit) that alters the K(i) of GCLC for GSH. We hypothesized that the expression of GCLM and the association of GCLM with GCLC were responsible for the apparent increase in GCL activity state observed in the liver of rats fed low-protein diets or in hepatocytes cultured in low-sulphur amino acid-containing medium. Therefore we conducted a series of studies using rats and a human hepatoma (HepG2/C3A) cell line to assess the role of GCLM and holoenzyme formation in the regulation of GCL activity in response to sulphur amino acid intake or availability. Increases in GCL activity in rat liver, as well as in HepG2 cells, were due to the additive effects of changes in the amount of GCLC and the kcat for GCLC. The increase in the kcat for GCLC was associated with increased holoenzyme formation, which was associated with an increase in the molar ratio of GCLM to GCLC. Furthermore, our results indicate that the GCLM level in rat liver is always limiting and that up-regulation of the GCLM level results in increased holoenzyme formation and an increase in the kcat. This is the first report demonstrating that the catalytic efficiency of rat GCL is increased by holoenzyme formation and the first demonstration of differential up-regulation of the GCL subunits in response to cysteine deprivation.

| S-EPMC1383676 | biostudies-literature

Glutamate-cysteine ligase catalytic subunit is associated with cisplatin resistance in lung adenocarcinoma.

Project description:Background:Cisplatin is a key drug for treating lung adenocarcinoma, and its sensitivity to cisplatin is directly related to prognosis. We aimed to reveal the roles of genes related to glutathione synthesis (glutamate-cysteine ligase catalytic subunit, GCLC) and cystine uptake (cystine/glutamate transporter, xCT and CD44v8-10) in cisplatin resistance and prognosis in lung adenocarcinoma. Methods:We established cell lines stably expressing GCLC, xCT, standard isoform of CD44, and CD44v8-10, and investigated their sensitivities to cisplatin. We also measured mRNA expression levels of these genes in the tumor tissues from 92 lung adenocarcinoma patients. Patients were divided into high-expression (upper quartile, N = 23) and low-expression groups (remaining patients, N = 69). Recurrence-free survival, overall survival (N = 92), and post-recurrence survival (N = 22) were selected as endpoints. Results:Compared with the control green fluorescent protein-expressing cell line (inhibitory concentration 50:6.9 ?M), all the stable cell lines were more resistant to cisplatin (12.9 ?M, P = 0.025; 13.9 ?M, P = 0.028; 26.7 ?M, P = 0.001; 17.7 ?M, P = 0.008, respectively). In contrast, there was no significant difference in recurrence-free or overall survival between the high- and low-expression groups for any of the genes. However, high expression of GCLC was a risk factor for poorer post-recurrence survival (hazard ratio, 6.26; 95% confidence interval, 1.37-28.7; P = 0.018). Conclusion:High expression levels of genes related to glutathione synthesis and cystine uptake promote cisplatin resistance in lung adenocarcinoma cell lines. High expression of GCLC in tumor tissue may be a potential predictor of treatment failure.

| S-EPMC5892860 | biostudies-literature

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