| 1 | Am. J. Hum. Genet. 2006 Sep 79: 586-92 |
|---|---|
| PMID | 16909399 |
| Title | 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. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Ann. N. Y. Acad. Sci. 2008 Oct 1139: 63-9 |
| PMID | 18991850 |
| Title | Glutamate cysteine ligase modifier (GCLM) subunit gene is not associated with methamphetamine-use disorder or schizophrenia in the Japanese population. |
| Abstract | A recent study showed a significant association between schizophrenia in European samples and the glutamate cysteine ligase modifier (GCLM) subunit gene, which is the key glutathione (GSH)-synthesizing enzyme. Since the symptoms of methamphetamine (METH)-induced psychosis are similar to those of schizophrenia, the GCLM gene is thought to be a good candidate gene for METH-use disorder or related disorders. To evaluate the association between the GCLM gene and METH-use disorder and schizophrenia, we conducted a case-control study of Japanese subjects (METH-use disorder, 185 cases; schizophrenia, 742 cases; and controls, 819). Four SNPs (2 SNPs from an original report and JSNP database, and 2 "tagging SNPs" from HapMap database) in the GCLM gene were examined in this association analysis; one SNP showed an association with both METH-use disorder and METH-induced psychosis. After Bonferroni's correction for multiple testing, however, this significance disappeared. No significant association was found with schizophrenia. Our findings suggest that a common genetic variation in the GCLM gene might not contribute to the risk of METH-use disorder and schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Psychiatr. Genet. 2009 Oct 19: 279-80 |
| PMID | 19584774 |
| Title | Association and expression studies of glutamate-cysteine ligase modifier (GCLM) and schizophrenia in the Chinese Han population. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | J. Neurochem. 2009 Mar 108: 1410-22 |
| PMID | 19183254 |
| Title | Curcumin, quercetin, and tBHQ modulate glutathione levels in astrocytes and neurons: importance of the glutamate cysteine ligase modifier subunit. |
| Abstract | A decrease in GSH levels, the main redox regulator, can be observed in neurodegenerative diseases as well as in schizophrenia. In search for substances able to increase GSH, we evaluated the ability of curcumin (polyphenol), quercetin (flavonoid), and tert-butylhydroquinone (tBHQ) to up-regulate GSH-synthesizing enzymes. The gene expression, activity, and product levels of these enzymes were measured in cultured neurons and astrocytes. In astrocytes, all substances increased GSH levels and the activity of the rate-limiting synthesizing enzyme, glutamate cysteine ligase (GCL). In neurons, curcumin and to a lesser extent tBHQ increased GCL activity and GSH levels, while quercetin decreased GSH and led to cell death. In the two cell types, the gene that showed the greatest increase in its expression was the one coding for the modifier subunit of GCL (GCLM). The increase in mRNA levels of GCLM was 3 to 7-fold higher than that of the catalytic subunit. In astrocytes from GCLM-knock-out mice showing low GSH (-80%) and low GCL activity (-50%), none of the substances succeeded in increasing GSH synthesis. Our results indicate that GCLM is essential for the up-regulation of GCL activity induced by curcumin, quercetin and tBHQ. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Jan 150B: 86-94 |
| PMID | 18449862 |
| Title | Association study between the genetic polymorphisms of glutathione-related enzymes and schizophrenia in a Japanese population. |
| Abstract | Several lines of evidence suggest that oxidative stress plays a role in the pathogenesis of schizophrenia, and that glutathione (GSH) plays a crucial role in antioxidant defense mechanisms. In this study, we performed association studies between GSH-related genes (GSTM1, GSTP1, GSTO1, GSTT1, GSTT2, GPX1, and GCLM) and schizophrenia in a Japanese population. The overall distributions of the genotypes and alleles of each gene were not different between schizophrenic patients and controls. Subjects with residual-type schizophrenia showed different distributions in the analysis of GSTM1 genotype and in the combination analysis of GSTs, GPX1, and GCLM genotypes although the small sample size should be considered as a limitation of this study. In addition, our findings revealed that there were large ethnic differences in the genotype distributions of those GSH-related genes. The present study suggests that GSH-related genes may not play a major role in the pathogenesis of schizophrenia in a Japanese population. However, a dysregulation of GSH metabolism may be one of the vulnerability factors contributing to the development of a certain type of schizophrenia, and it is likely that the ethnic background should be considered in further study for those GSH-related genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Jan 150B: 86-94 |
| PMID | 18449862 |
| Title | Association study between the genetic polymorphisms of glutathione-related enzymes and schizophrenia in a Japanese population. |
| Abstract | Several lines of evidence suggest that oxidative stress plays a role in the pathogenesis of schizophrenia, and that glutathione (GSH) plays a crucial role in antioxidant defense mechanisms. In this study, we performed association studies between GSH-related genes (GSTM1, GSTP1, GSTO1, GSTT1, GSTT2, GPX1, and GCLM) and schizophrenia in a Japanese population. The overall distributions of the genotypes and alleles of each gene were not different between schizophrenic patients and controls. Subjects with residual-type schizophrenia showed different distributions in the analysis of GSTM1 genotype and in the combination analysis of GSTs, GPX1, and GCLM genotypes although the small sample size should be considered as a limitation of this study. In addition, our findings revealed that there were large ethnic differences in the genotype distributions of those GSH-related genes. The present study suggests that GSH-related genes may not play a major role in the pathogenesis of schizophrenia in a Japanese population. However, a dysregulation of GSH metabolism may be one of the vulnerability factors contributing to the development of a certain type of schizophrenia, and it is likely that the ethnic background should be considered in further study for those GSH-related genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Psychiatr. Genet. 2009 Aug 19: 201-8 |
| PMID | 19455074 |
| Title | Mutation screening of the glutamate cysteine ligase modifier (GCLM) gene in patients with schizophrenia. |
| Abstract | Experimental evidences show that glutathione and its rate-limiting synthesizing enzyme, the glutamate-cysteine ligase (GCL), are involved in the pathogenesis of schizophrenia. Furthermore, genetic association has been previously reported between two single nucleotide polymorphisms lying in noncoding regions of glutamate cysteine ligase modifier (GCLM) gene, which specifies for the modifier subunit of GCL and schizophrenia. We wanted to investigate the presence of GCLM true functional mutations, likely in linkage disequilibrium with the previously identified single nucleotide polymorphism alleles, in the same set of cases that allowed the detection of the original association signal. We screened all the coding regions of GCLM and their intronic flanking vicinities in 353 patients with schizophrenia by direct DNA sequencing. Ten sequence variations were identified, five of which were not previously described. None of these DNA changes was within the GCLM coding sequence and in-silico analysis failed to indicate functional impairment induced by these variations. Furthermore, screening of normal controls and downstream statistical analyses revealed no significant relationship of any of these DNA variants with schizophrenia. It is unlikely that functional mutations in the GCLM gene could play a major role in genetic predisposition to schizophrenia and further studies will be required to assess its etiological function in the disease. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Schizophr. Res. 2010 Jun 119: 273-4 |
| PMID | 20061124 |
| Title | Genetic analysis of glutamate cysteine ligase modifier (GCLM) gene and schizophrenia in Han Chinese. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | 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, including schizophrenia and 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, schizophrenic |
| 10 | 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 in schizophrenia and 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-Trøndelag 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 of GCLC, the gene encoding the GCL catalytic subunit. Using the linkage disequilibrium between the GCLC markers 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, r²=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, schizophrenic |
| 11 | Psychiatry Clin. Neurosci. 2011 Feb 65: 39-46 |
| PMID | 21105962 |
| Title | No association between glutathione-synthesis-related genes and Japanese schizophrenia. |
| Abstract | schizophrenia is 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 with schizophrenia. 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 and schizophrenia were 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) and schizophrenia in Japanese individuals. Seventeen single-nucleotide polymorphisms (SNP) in GCLM, GCLC, and GSS were genotyped in 358 patients with schizophrenia and in 359 controls. No SNP showed a significant association between their allelic or genotypic frequencies and schizophrenia. Case-control haplotype association analysis using windows of two or three SNP showed no significant associations with schizophrenia. The case-control haplotype analyses based on the ascertained linkage disequilibrium blocks also showed no significant associations in any genes with schizophrenia. The three primary GSH synthesis genes do not have an apparent degree of association with schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | PLoS ONE 2011 -1 6: e22875 |
| PMID | 21829542 |
| Title | Altered glycogen metabolism in cultured astrocytes from mice with chronic glutathione deficit; relevance for neuroenergetics in schizophrenia. |
| Abstract | Neurodegenerative and psychiatric disorders including Alzheimer's, Parkinson's or Huntington's diseases and schizophrenia have been associated with a deficit in glutathione (GSH). In particular, a polymorphism in the gene of glutamate cysteine ligase modulatory subunit (GCLM) is associated with schizophrenia. GSH is the most important intracellular antioxidant and is necessary for the removal of reactive by-products generated by the utilization of glucose for energy supply. Furthermore, glucose metabolism through the pentose phosphate pathway is a major source of NADPH, the cofactor necessary for the regeneration of reduced glutathione. This study aims at investigating glucose metabolism in cultured astrocytes from GCLM knockout mice, which show decreased GSH levels. No difference in the basal metabolism of glucose was observed between wild-type and knockout cells. In contrast, glycogen levels were lower and its turnover was higher in knockout astrocytes. These changes were accompanied by a decrease in the expression of the genes involved in its synthesis and degradation, including the protein targeting to glycogen. During an oxidative challenge induced by tert-Butylhydroperoxide, wild-type cells increased their glycogen mobilization and glucose uptake. However, knockout astrocytes were unable to mobilize glycogen following the same stress and they could increase their glucose utilization only following a major oxidative insult. Altogether, these results show that glucose metabolism and glycogen utilization are dysregulated in astrocytes showing a chronic deficit in GSH, suggesting that alterations of a fundamental aspect of brain energy metabolism is caused by GSH deficit and may therefore be relevant to metabolic dysfunctions observed in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | 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 in schizophrenia (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, schizophrenic |
| 14 | Biol. Psychiatry 2012 Jun 71: 1006-14 |
| PMID | 21945305 |
| Title | N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development. |
| Abstract | Glutathione (GSH) is the major cellular redox-regulator and antioxidant. Redox-imbalance due to genetically impaired GSH synthesis is among the risk factors for schizophrenia. Here we used a mouse model with chronic GSH deficit induced by knockout (KO) of the key GSH-synthesizing enzyme, glutamate-cysteine ligase modulatory subunit (GCLM). With high-resolution magnetic resonance spectroscopy at 14.1 T, we determined the neurochemical profile of GCLM-KO, heterozygous, and wild-type mice in anterior cortex throughout development in a longitudinal study design. Chronic GSH deficit was accompanied by an elevation of glutamine (Gln), glutamate (Glu), Gln/Glu, N-acetylaspartate, myo-Inositol, lactate, and alanine. Changes were predominantly present at prepubertal ages (postnatal days 20 and 30). Treatment with N-acetylcysteine from gestation on normalized most neurochemical alterations to wild-type level. Changes observed in GCLM-KO anterior cortex, notably the increase in Gln, Glu, and Gln/Glu, were similar to those reported in early schizophrenia, emphasizing the link between redox imbalance and the disease and validating the model. The data also highlight the prepubertal period as a sensitive time for redox-related neurochemical changes and demonstrate beneficial effects of early N-acetylcysteine treatment. Moreover, the data demonstrate the translational value of magnetic resonance spectroscopy to study brain disease in preclinical models. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 15 | Biol. Psychiatry 2013 Mar 73: 574-82 |
| PMID | 23140664 |
| Title | Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine. |
| Abstract | A hallmark of the pathophysiology of schizophrenia is a dysfunction of parvalbumin-expressing fast-spiking interneurons, which are essential for the coordination of neuronal synchrony during sensory and cognitive processing. Oxidative stress as observed in schizophrenia affects parvalbumin interneurons. However, it is unknown whether the deleterious effect of oxidative stress is particularly prevalent during specific developmental time windows. We used mice with impaired synthesis of glutathione (GCLM knockout [KO] mice) to investigate the effect of redox dysregulation and additional insults applied at various periods of postnatal development on maturation and long-term integrity of parvalbumin interneurons in the anterior cingulate cortex. A redox dysregulation, as in GCLM KO mice, renders parvalbumin interneurons but not calbindin or calretinin interneurons vulnerable and prone to exhibit oxidative stress. A glutathione deficit delays maturation of parvalbumin interneurons, including their perineuronal net. Moreover, an additional oxidative challenge in preweaning or pubertal but not in young adult GCLM KO mice reduces the number of parvalbumin-immunoreactive interneurons. This effect persists into adulthood and can be prevented with the antioxidant N-acetylcysteine. In GCLM KO mice, early-life insults inducing oxidative stress are detrimental to immature parvalbumin interneurons and have long-term consequences. In analogy, individuals carrying genetic risks to redox dysregulation would be potentially vulnerable to early-life environmental insults, during the maturation of parvalbumin interneurons. Our data support the need to develop novel therapeutic approaches based on antioxidant and redox regulator compounds such as N-acetylcysteine, which could be used preventively in young at-risk subjects. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 16 | Biomed Rep 2014 Sep 2: 729-736 |
| PMID | 25054019 |
| Title | Meta-analyses of 10 polymorphisms associated with the risk of schizophrenia. |
| Abstract | schizophrenia (SCZ) is a severe complex psychiatric disorder that generates problems for the associated family and society and causes disability with regards to work for patients. The aim of the present study was to assess the contribution of 10 genetic polymorphisms to SCZ susceptibility. Meta-analyses were conducted using the data without a limitation for time or language. A total of 27 studies with 7 genes and 10 polymorphisms were selected for the meta-analyses. Two polymorphisms were found to be significantly associated with SCZ. SNAP25 rs3746544 was shown to increase the SCZ risk by 18% [P=0.01; odds ratio (OR), 1.18; 95% confidence interval (CI), 1.05-1.34] and GRIK3 rs6691840 was found to increase the risk by 30% (P=0.008; OR, 1.30; 95% CI, 1.07-1.58). Significant results were found under the dominant (P=0.001; OR, 1.36; 95% CI, 1.13-1.65) and additive (P=0.02; OR, 1.45; 95% CI, 1.06-1.98) model for the SNAP25 rs3746544 polymorphism and under the additive model for the GRIK3 rs6691840 polymorphism (P=0.03; OR, 1.73; 95% CI, 1.04-2.85). There were no significant results observed for the other eight polymorphisms, which were CCKAR rs1800857, CHRNA7 rs904952, CHRNA7 rs6494223, CHRNA7 rs2337506, DBH Ins>Del, FEZ1 rs559668, FEZ1 rs597570 and GCLM rs2301022. In conclusion, the present meta-analyses indicated that the SNAP25 rs3746544 and GRIK3 rs6691840 polymorphisms were risk factors of SCZ, which may provide valuable information for the clinical diagnosis of SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 17 | Int. J. Neuropsychopharmacol. 2015 -1 19: -1 |
| PMID | 26433393 |
| Title | Glutathione Deficit Affects the Integrity and Function of the Fimbria/Fornix and Anterior Commissure in Mice: Relevance for Schizophrenia. |
| Abstract | Structural anomalies of white matter are found in various brain regions of patients with schizophrenia and bipolar and other psychiatric disorders, but the causes at the cellular and molecular levels remain unclear. Oxidative stress and redox dysregulation have been proposed to play a role in the pathophysiology of several psychiatric conditions, but their anatomical and functional consequences are poorly understood. The aim of this study was to investigate white matter throughout the brain in a preclinical model of redox dysregulation. In a mouse model with impaired glutathione synthesis (GCLM KO), a state-of-the-art multimodal magnetic resonance protocol at high field (14.1 T) was used to assess longitudinally the white matter structure, prefrontal neurochemical profile, and ventricular volume. Electrophysiological recordings in the abnormal white matter tracts identified by diffusion tensor imaging were performed to characterize the functional consequences of fractional anisotropy alterations. Structural alterations observed at peri-pubertal age and adulthood in GCLM KO mice were restricted to the anterior commissure and fornix-fimbria. Reduced fractional anisotropy in the anterior commissure (-7.5%±1.9, P<.01) and fornix-fimbria (-4.5%±1.3, P<.05) were accompanied by reduced conduction velocity in fast-conducting fibers of the posterior limb of the anterior commissure (-14.3%±5.1, P<.05) and slow-conducting fibers of the fornix-fimbria (-8.6%±2.6, P<.05). Ventricular enlargement was found at peri-puberty (+25%±8 P<.05) but not in adult GCLM KO mice. Glutathione deficit in GCLM KO mice affects ventricular size and the integrity of the fornix-fimbria and anterior commissure. This suggests that redox dysregulation could contribute during neurodevelopment to the impaired white matter and ventricle enlargement observed in schizophrenia and other psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 18 | PLoS ONE 2016 -1 11: e0146797 |
| PMID | 26799654 |
| Title | Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. |
| Abstract | Many studies indicate a crucial role for the vitamin B12 and folate-dependent enzyme methionine synthase (MS) in brain development and function, but vitamin B12 status in the brain across the lifespan has not been previously investigated. Vitamin B12 (cobalamin, Cbl) exists in multiple forms, including methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), serving as cofactors for MS and methylmalonylCoA mutase, respectively. We measured levels of five Cbl species in postmortem human frontal cortex of 43 control subjects, from 19 weeks of fetal development through 80 years of age, and 12 autistic and 9 schizophrenic subjects. Total Cbl was significantly lower in older control subjects (> 60 yrs of age), primarily reflecting a >10-fold age-dependent decline in the level of MeCbl. Levels of inactive cyanocobalamin (CNCbl) were remarkably higher in fetal brain samples. In both autistic and schizophrenic subjects MeCbl and AdoCbl levels were more than 3-fold lower than age-matched controls. In autistic subjects lower MeCbl was associated with decreased MS activity and elevated levels of its substrate homocysteine (HCY). Low levels of the antioxidant glutathione (GSH) have been linked to both autism and schizophrenia, and both total Cbl and MeCbl levels were decreased in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice, which exhibit low GSH levels. Thus our findings reveal a previously unrecognized decrease in brain vitamin B12 status across the lifespan that may reflect an adaptation to increasing antioxidant demand, while accelerated deficits due to GSH deficiency may contribute to neurodevelopmental and neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 19 | PLoS ONE 2016 -1 11: e0146797 |
| PMID | 26799654 |
| Title | Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. |
| Abstract | Many studies indicate a crucial role for the vitamin B12 and folate-dependent enzyme methionine synthase (MS) in brain development and function, but vitamin B12 status in the brain across the lifespan has not been previously investigated. Vitamin B12 (cobalamin, Cbl) exists in multiple forms, including methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), serving as cofactors for MS and methylmalonylCoA mutase, respectively. We measured levels of five Cbl species in postmortem human frontal cortex of 43 control subjects, from 19 weeks of fetal development through 80 years of age, and 12 autistic and 9 schizophrenic subjects. Total Cbl was significantly lower in older control subjects (> 60 yrs of age), primarily reflecting a >10-fold age-dependent decline in the level of MeCbl. Levels of inactive cyanocobalamin (CNCbl) were remarkably higher in fetal brain samples. In both autistic and schizophrenic subjects MeCbl and AdoCbl levels were more than 3-fold lower than age-matched controls. In autistic subjects lower MeCbl was associated with decreased MS activity and elevated levels of its substrate homocysteine (HCY). Low levels of the antioxidant glutathione (GSH) have been linked to both autism and schizophrenia, and both total Cbl and MeCbl levels were decreased in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice, which exhibit low GSH levels. Thus our findings reveal a previously unrecognized decrease in brain vitamin B12 status across the lifespan that may reflect an adaptation to increasing antioxidant demand, while accelerated deficits due to GSH deficiency may contribute to neurodevelopmental and neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |