| 1 | Proc. Natl. Acad. Sci. U.S.A. 2007 Oct 104: 16621-6 |
|---|---|
| PMID | 17921251 |
| Title | Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. |
| Abstract | schizophreniais a complex multifactorial brain disorder with a genetic component. Convergent evidence has implicated oxidative stress and glutathione (GSH) deficits in the pathogenesis of this disease. The aim of the present study was to test whetherschizophreniais associated with a deficit of GSH synthesis. Cultured skin fibroblasts fromschizophrenia患者和对照组的挑战oxidative stress, and parameters of the rate-limiting enzyme for the GSH synthesis, the glutamate cysteine ligase (GCL), were measured. Stressed cells of patients had a 26% (P = 0.002) decreased GCL activity as compared with controls. This reduction correlated with a 29% (P < 0.001) decreased protein expression of the catalytic GCL subunit (GCLC). Genetic analysis of a trinucleotide repeat (TNR) polymorphism in theGCLCgene showed a significant association withschizophreniain two independent case-control studies. The most common TNR genotype 7/7 was more frequent in controls [odds ratio (OR) = 0.6, P = 0.003], whereas the rarest TNR genotype 8/8 was three times more frequent in patients (OR = 3.0, P = 0.007). Moreover, subjects with disease-associated genotypes had lowerGCLC蛋白表达(P = 0.017), GCL活动(P =0.037), and GSH contents (P = 0.004) than subjects with genotypes that were more frequent in controls. Taken together, the study provides genetic and functional evidence that an impaired capacity to synthesize GSH under conditions of oxidative stress is a vulnerability factor forschizophrenia. |
| SCZ Keywords | schizophrenia |
| 2 | Brain Res. Bull. 2009 Apr 79: 46-52 |
| PMID | 19041695 |
| Title | Skin fibroblast model to study an impaired glutathione synthesis: consequences of a genetic polymorphism on the proteome. |
| Abstract | An impaired glutathione (GSH) synthesis was observed in several multifactorial diseases, includingschizophreniaand myocardial infarction. Genetic studies revealed an association betweenschizophreniaand a GAG trinucleotide repeat (TNR) polymorphism in the catalytic subunit (GCLC) of the glutamate cysteine ligase (GCL). Disease-associated genotypes of this polymorphism correlated with a decrease inGCLCprotein expression, GCL activity and GSH content. To clarify consequences of a decreased GCL activity at the proteome level, threeschizophreniapatients and three controls have been selected based on theGCLCGAG TNR多态性。纤维母细胞文化were obtained by skin biopsy and were challenged with tert-butylhydroquinone (t-BHQ), a substance known to induce oxidative stress. Proteome changes were analyzed by two dimensional gel electrophoresis (2-DE) and results revealed 10 spots that were upregulated in patients following t-BHQ treatment, but not in controls. Nine corresponding proteins could be identified by MALDI mass spectrometry and these proteins are involved in various cellular functions, including energy metabolism, oxidative stress response, and cytoskeletal reorganization. In conclusion, skin fibroblasts of subjects with an impaired GSH synthesis showed an altered proteome reaction in response to oxidative stress. Furthermore, the study corroborates the use of fibroblasts as an additional mean to study vulnerability factors of psychiatric diseases. |
| SCZ Keywords | schizophrenia |
| 3 | Bipolar Disord 2010 Aug 12: 550-6 |
| PMID | 20712757 |
| Title | Assessing oxidative pathway genes as risk factors for bipolar disorder. |
| Abstract | There is a growing body of evidence implicating oxidative stress and the glutathione system in the pathogenesis of major psychiatric illnesses, includingschizophreniaand bipolar disorder. Here we investigate whether genes involved in oxidative stress regulation are associated with increased risk for bipolar disorder. Four candidate genes were selected a priori from two different steps in the oxidative stress pathway, specifically the synthesis of glutathione [catalytic subunit of glutamate cysteine ligase (GCLC) and regulatory subunit of glutamate cysteine ligase (GCLM)] and the removal of reactive oxygen species [superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3)]. Haplotype tagging and functional nucleotide polymorphisms were selected in each gene and tested for association with bipolar disorder under narrow (n = 240) and broad (n = 325) phenotypic models, compared to healthy controls (n = 392, comprising 166 psychiatrically assessed unaffected controls plus 226 healthy individuals). Single marker association analysis did not reveal significant association with bipolar disorder; however, haplotypes in the SOD2 gene showed nominal association (global chi(2) = 8.94, p = 0.03; broad model). Interaction analysis revealed a significant interaction between SOD2 and GPX3 haplotypes, which further increases risk for bipolar disorder (odds ratio = 2.247, chi(2) = 9.526, p = 0.002, corrected p = 0.029). Further characterization of the SOD2 and GPX3 interaction using larger cohorts is required to determine the role of these oxidative pathway genes as risk factors for bipolar disorder. |
| SCZ Keywords | schizophrenia |
| 4 | J Affect Disord 2011 Jun 131: 207-13 |
| PMID | 21277635 |
| Title | Glutamate cysteine ligase (GCL) and self reported depression: an association study from the HUNT. |
| Abstract | There is increasing evidence suggesting oxidative stress may play a role in the aetiology of depression. Glutathione is the brain's predominant free radical scavenger, and associated polymorphisms of the glutamate cysteine ligase (GCL) gene have been reported for related psychiatric disorders. The aim of the study was to investigate candidate polymorphisms of GCL validated inschizophreniaand their association with current state depression, as measured by the Hospital Anxiety and Depression Scale (HADS). Polymorphisms were genotyped on 983 cases and 967 controls selected from a population sample of adults participating in the Nord-Tr�ndelag Health Study. Cases were the top scoring individuals (98.5th percentile) on the HADS depression subscale while the controls were randomly selected from below this cut-off. The polymorphisms comprised three SNPs from GCLM, the gene encoding the GCL modifier and 9 SNPs plus a trinucleotide repeat (TNTR) from intron 1 and the 5'UTR ofGCLC, the gene encoding the GCL catalytic subunit. Using the linkage disequilibrium between theGCLCmarkers we also tested whether SNPs could represent the variation of the TNTR. The candidate polymorphisms showed no evidence for association with depression. The C allele of SNP rs9474592 is coupled with the 9 GAG repeats allele of the TNTR, r�=0.81. None of the other SNPs either individually or as two or three-SNP haplotypes was associated with the TNTR alleles. Depression was self-reported and measured at one time point. This study provides no evidence to suggest that polymorphisms of GCL are associated with self-reported depression. |
| SCZ Keywords | schizophrenia |
| 5 | Psychiatry Clin. Neurosci. 2011 Feb 65: 39-46 |
| PMID | 21105962 |
| Title | No association between glutathione-synthesis-related genes and Japanese schizophrenia. |
| Abstract | schizophreniais a major psychiatric disorder with complex genetic, environmental, and psychological causes, and oxidative stress may be involved in the pathogenesis of the disease. Glutathione (GSH), one of the main cellular non-protein antioxidants and redox regulators, and altered GSH levels have been reported in various regions in patients withschizophrenia. Three enzymes are responsible for GSH synthesis: glutamate cysteine ligase modifier (GCLM), glutamate cysteine ligase catalytic subunit (GCLC), and glutathione synthetase (GSS). Previously, positive associations between GCLM andschizophreniawere reported in Europeans, but not in the Japanese population. Thus, in this study, we investigated the association between the GSH synthesis genes (GCLM,GCLC, and GSS) andschizophreniain Japanese individuals. Seventeen single-nucleotide polymorphisms (SNP) in GCLM,GCLC, and GSS were genotyped in 358 patients withschizophreniaand in 359 controls. No SNP showed a significant association between their allelic or genotypic frequencies andschizophrenia. Case-control haplotype association analysis using windows of two or three SNP showed no significant associations withschizophrenia. The case-control haplotype analyses based on the ascertained linkage disequilibrium blocks also showed no significant associations in any genes withschizophrenia. The three primary GSH synthesis genes do not have an apparent degree of association withschizophreniain the Japanese population. |
| SCZ Keywords | schizophrenia |
| 6 | Antioxid. Redox Signal. 2011 Oct 15: 2003-10 |
| PMID | 20673128 |
| Title | Genetic dysregulation of glutathione synthesis predicts alteration of plasma thiol redox status in schizophrenia. |
| Abstract | Genetic studies have shown an association betweenschizophreniaand a GAG trinucleotide repeat (TNR) polymorphism in the catalytic subunit (GCLC) of the glutamate cysteine ligase (GCL), the key enzyme for glutathione (GSH) synthesis. The present study was aimed at analyzing the influence of a GSH dysregulation of genetic origin on plasma thiols (total cysteine, homocysteine, and cysteine-glycine) and other free amino acid levels as well as fibroblast cultures GSH levels. Plasma thiols levels were also compared between patients and controls. As compared with patients with a low-riskGCLCGAG TNR genotype, patients with a high-risk genotype, having an impaired GSH synthesis, displayed a decrease of fibroblast GSH and plasma total cysteine levels, and an increase of the oxidized form of cysteine (cystine) content. Increased levels of plasma free serine, glutamine, citrulline, and arginine were also observed in the high-risk genotype. Taken together, the high-risk genotypes were associated with a subgroup ofschizophreniacharacterized by altered plasma thiols and free amino acid levels that reflect a dysregulation of redox control and an increased susceptibility to oxidative stress. This altered pattern potentially contributes to the development of a biomarker profile useful for early diagnosis and monitoring the effectiveness of novel drugs targeting redox dysregulation inschizophrenia. |
| SCZ Keywords | schizophrenia |
| 7 | Behav. Brain Res. 2012 Jan 226: 563-70 |
| PMID | 22033334 |
| Title | Behavioral phenotyping of glutathione-deficient mice: relevance to schizophrenia and bipolar disorder. |
| Abstract | Redox-dysregulation represents a common pathogenic mechanism inschizophrenia(SZ) and bipolar disorder (BP). It may in part arise from a genetically compromised synthesis of glutathione (GSH), the major cellular antioxidant and redox-regulator. Allelic variants of the genes coding for the rate-limiting GSH synthesizing enzyme glutamate-cysteine-ligase modifier (GCLM) and/or catalytic (GCLC) subunit have been associated with SZ and BP. Using mice knockout (KO) for GCLM we have previously shown that impaired GSH synthesis is associated with morphological, functional and neurochemical anomalies similar to those in patients. Here we asked whether GSH deficit is also associated with SZ- and BP-relevant behavioral and cognitive anomalies. Accordingly, we subjected young adult GCLM-wildtype (WT), heterozygous and KO males to a battery of standard tests. Compared to WT, GCLM-KO mice displayed hyperlocomotion in the open field and forced swim test but normal activity in the home cage, suggesting that hyperlocomotion was selective to environmental novelty and mildly stressful situations. While spatial working memory and latent inhibition remained unaffected, KO mice showed a potentiated hyperlocomotor response to an acute amphetamine injection, impaired sensorymotor gating in the form of prepulse inhibition and altered social behavior compared to WT. These anomalies resemble important aspects of both SZ and the manic component of BP. As such our data support the notion that redox-dysregulation due to GSH deficit is implicated in both disorders. Moreover, our data propose the GCLM-KO mouse as a valuable model to study the behavioral and cognitive consequences of redox dysregulation in the context of psychiatric disease. |
| SCZ Keywords | schizophrenia |
| 8 | Schizophr Bull 2016 Apr -1: -1 |
| PMID | 27069063 |
| Title | Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis. |
| Abstract | Oxidative stress and glutathione (GSH) metabolism dysregulation has been implicated in the pathophysiology ofschizophrenia. GAG-trinucleotide repeat (TNR) polymorphisms in the glutamate-cysteine ligase catalytic gene (GCLC), the rate-limiting enzyme for GSH synthesis, are associated withschizophrenia. In addition, GSH may serve as a reserve pool for neuronal glutamate (Glu) through the ?-glutamyl cycle. The aim of this study is to investigate brain [GSH] and its association withGCLCpolymorphism, peripheral redox indices and brain Glu. Magnetic resonance spectroscopy was used to measure [GSH] and [Glu] in the medial prefrontal cortex (mPFC) of 25 early-psychosis patients and 33 controls.GCLCpolymorphism was genotyped, glutathione peroxidases (GPx) and glutathione reductase (GR) activities were determined in blood cells. Significantly lower [GSHmPFC] inGCLChigh-risk genotype subjects were revealed as compared to low-risk genotype subjects independent of disease status. In male subjects, [GSHmPFC] and blood GPx activities correlate positively in controls (P = .021), but negatively in patients (P = .039). InGCLClow-risk genotypes, [GlumPFC] are lower in patients, while it is not the case for high-risk genotypes. GCLChigh-risk genotypes are associated with low [GSHmPFC], highlighting thatGCLCpolymorphisms should be considered in pathology studies of cerebral GSH. Low brain GSH levels are related to low peripheral oxidation status in controls but with high oxidation status in patients, pointing to a dysregulated GSH homeostasis in early psychosis patients.GCLCpolymorphisms and disease associated correlations between brain GSH and Glu levels may allow patients stratification. |
| SCZ Keywords | schizophrenia |