| 1 | Arch. Gen. Psychiatry 2010 Jun 67: 589-97 |
|---|---|
| PMID | 20530008 |
| Title | Enhanced carbonyl stress in a subpopulation of schizophrenia. |
| Abstract | Various factors are involved in the pathogenesis of schizophrenia. Accumulation of advanced glycation end products, including pentosidine, results from carbonyl stress, a state featuring an increase in reactive carbonyl compounds (RCOs) and their attendant protein modifications. Vitamin B(6) is known to detoxify RCOs, including advanced glycation end products. Glyoxalase I (GLO1) is one of the enzymes required for the cellular detoxification of RCOs. To examine whether plasma levels of pentosidine and serum vitamin B(6) are altered in patients with schizophrenia and to evaluate the functionality of GLO1 variations linked to concomitant carbonyl stress. An observational biochemical and genetic analysis study. Multiple centers in Japan. One hundred six individuals (45 schizophrenic patients and 61 control subjects) were recruited for biochemical measurements. Deep resequencing of GLO1 derived from peripheral blood or postmortem brain tissue was performed in 1761 patients with schizophrenia and 1921 control subjects. Pentosidine and vitamin B(6) concentrations were determined by high-performance liquid chromatographic assay. Protein expression and enzymatic activity were quantified in red blood cells and lymphoblastoid cells using Western blot and spectrophotometric techniques. We found that a subpopulation of individuals with schizophrenia exhibit high plasma pentosidine and low serum pyridoxal (vitamin B(6)) levels. We also detected genetic and functional alterations in GLO1. Marked reductions in enzymatic activity were associated with pentosidine accumulation and vitamin B(6) depletion, except in some healthy subjects. Most patients with schizophrenia who carried the genetic defects exhibited high pentosidine and low vitamin B(6) levels in contrast with control subjects with the genetic defects, suggesting the existence of compensatory mechanisms. Our findings suggest that GLO1 deficits and carbonyl stress are linked to the development of a certain subtype of schizophrenia. Elevated plasma pentosidine and concomitant low vitamin B(6) levels could be the most cogent and easily measurable biomarkers in schizophrenia and should be helpful for classifying heterogeneous types of schizophrenia on the basis of their biological causes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Arch. Gen. Psychiatry 2010 Jun 67: 589-97 |
| PMID | 20530008 |
| Title | Enhanced carbonyl stress in a subpopulation of schizophrenia. |
| Abstract | Various factors are involved in the pathogenesis of schizophrenia. Accumulation of advanced glycation end products, including pentosidine, results from carbonyl stress, a state featuring an increase in reactive carbonyl compounds (RCOs) and their attendant protein modifications. Vitamin B(6) is known to detoxify RCOs, including advanced glycation end products. Glyoxalase I (GLO1) is one of the enzymes required for the cellular detoxification of RCOs. To examine whether plasma levels of pentosidine and serum vitamin B(6) are altered in patients with schizophrenia and to evaluate the functionality of GLO1 variations linked to concomitant carbonyl stress. An observational biochemical and genetic analysis study. Multiple centers in Japan. One hundred six individuals (45 schizophrenic patients and 61 control subjects) were recruited for biochemical measurements. Deep resequencing of GLO1 derived from peripheral blood or postmortem brain tissue was performed in 1761 patients with schizophrenia and 1921 control subjects. Pentosidine and vitamin B(6) concentrations were determined by high-performance liquid chromatographic assay. Protein expression and enzymatic activity were quantified in red blood cells and lymphoblastoid cells using Western blot and spectrophotometric techniques. We found that a subpopulation of individuals with schizophrenia exhibit high plasma pentosidine and low serum pyridoxal (vitamin B(6)) levels. We also detected genetic and functional alterations in GLO1. Marked reductions in enzymatic activity were associated with pentosidine accumulation and vitamin B(6) depletion, except in some healthy subjects. Most patients with schizophrenia who carried the genetic defects exhibited high pentosidine and low vitamin B(6) levels in contrast with control subjects with the genetic defects, suggesting the existence of compensatory mechanisms. Our findings suggest that GLO1 deficits and carbonyl stress are linked to the development of a certain subtype of schizophrenia. Elevated plasma pentosidine and concomitant low vitamin B(6) levels could be the most cogent and easily measurable biomarkers in schizophrenia and should be helpful for classifying heterogeneous types of schizophrenia on the basis of their biological causes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Seishin Shinkeigaku Zasshi 2011 -1 113: 672-8 |
| PMID | 21882541 |
| Title | [Molecular pathophysiology of schizophrenia and preventive strategy in pubertal period]. |
| Abstract | A novel frameshift mutation in glyoxalase 1 (GLO1) gene was detected in a patient with schizophrenia of a pedigree with multiple affected individuals. The patient carrying the mutation showed decreased enzymatic activity by 50%, 3.7 times high level of advanced glycation end products (AGEs) that is substrate of GLO1 and 20% of serum vitamin B6 compared to controls. Case-control study of GLO1 gene suggested that Ala allele of Glu111Ala was associated with schizophrenia. In vitro study using COS-7 cells transfected with cDNA of GLO1 yielded that enzymatic activity is lower in GLO1 with Ala111 than that of Glu111. The homozygotes of Ala111 showed 16% decreased GLO1 activities in RBC as compared with that of Glu111/Ala111 and Glu111/Glu111. Plasma AGEs levels were significantly high and serum vitamin B6 was significantly low in 45 schizophrenics than that of 61 control subjects. Supplementation of vitamin B6 to cases with the genetic defect of GLO1 before onset of psychosis is suggested to be possible strategy for prevention of schizophrenia until pubertal stage since such mutation carriers could have been exposed by high level of AGEs for a long time before disease onset. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Seishin Shinkeigaku Zasshi 2011 -1 113: 672-8 |
| PMID | 21882541 |
| Title | [Molecular pathophysiology of schizophrenia and preventive strategy in pubertal period]. |
| Abstract | A novel frameshift mutation in glyoxalase 1 (GLO1) gene was detected in a patient with schizophrenia of a pedigree with multiple affected individuals. The patient carrying the mutation showed decreased enzymatic activity by 50%, 3.7 times high level of advanced glycation end products (AGEs) that is substrate of GLO1 and 20% of serum vitamin B6 compared to controls. Case-control study of GLO1 gene suggested that Ala allele of Glu111Ala was associated with schizophrenia. In vitro study using COS-7 cells transfected with cDNA of GLO1 yielded that enzymatic activity is lower in GLO1 with Ala111 than that of Glu111. The homozygotes of Ala111 showed 16% decreased GLO1 activities in RBC as compared with that of Glu111/Ala111 and Glu111/Glu111. Plasma AGEs levels were significantly high and serum vitamin B6 was significantly low in 45 schizophrenics than that of 61 control subjects. Supplementation of vitamin B6 to cases with the genetic defect of GLO1 before onset of psychosis is suggested to be possible strategy for prevention of schizophrenia until pubertal stage since such mutation carriers could have been exposed by high level of AGEs for a long time before disease onset. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Br J Psychiatry 2011 Sep 199: 245-6 |
| PMID | 21881099 |
| Title | Schizophrenia with the 22q11.2 deletion and additional genetic defects: case history. |
| Abstract | The 22q11.2 deletion is the most prominent known genetic risk factor for schizophrenia, but its penetrance is at most approximately 50% suggesting that additional risk factors are required for disease progression. We examined a woman with schizophrenia with this deletion for such risk factors. She had high plasma pentosidine levels ('carbonyl stress') and a frameshift mutation in the responsible gene, GLO1. She also had a constant exotropia, so we examined the PHOX2B gene associated with both schizophrenia and strabismus, and detected a 5-alanine deletion. We propose that the combination of these genetic defects may have exceeded the threshold for the manifestation of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Brain Nerve 2011 Mar 63: 223-31 |
| PMID | 21386123 |
| Title | [Studies on pathophysiology of schizophrenia with a rare variant as a clue]. |
| Abstract | schizophrenia is a relatively common and severe mental disorder with complex inheritance patterns; its main manifestations are hallucinations, delusions, and disorganized speech and thinking. The exact etiology of schizophrenia remains unsolved, although pharmacological and biological studies have proposed several hypothetical disease mechanisms and plausible candidate genes for susceptibility. Since the early nineties, extensive genetic studies have been performed on this illness, but there has been no marked progress in the research, and reproducible results have not yet been obtained. Such difficulties in genetic studies of schizophrenia arise from the heterogeneity of this disease. Candidate gene approaches are based on the common disease-common variant hypothesis. However, there is no guarantee that a common variant is shared by patients with heterogeneous pathophysiologies of this disorder. We studied a rare mutation with a major alteration in genetic function based on the common disease-rare variant hypothesis. We detected a novel frameshift mutation of glyoxalase 1 (GLO1) accompanied by a 50% reduction in enzymatic activities in a male schizophrenic patient belonging to a pedigree with multiple affected individuals. GLO1 detoxifies toxic carbonyl compounds that produce advanced glycation end products (AGEs) such as pentosidine by Maillard reaction. AGEs accumulate because of carbonyl stress caused by an increase in reactive carbonyl compounds and their attendant protein modifications. A significant increase in plasma AGEs and a low serum pyridoxal level was seen in our patient. In addition, we found other patients with schizophrenia characterized by the presence of homozygotes of the Ala allele of Glu111Ala in the GLO1 gene and a 16% reduction in the activities that showed high plasma AGEs. As compared to that of the 61 control patients, 45 patients with schizophrenia yielded significantly high levels of AGEs in the plasma and low serum pyridoxal levels. Our findings suggest that GLO1 deficits and carbonyl stress are linked to the development of a certain subtype of schizophrenia. Elevated plasma pentosidine and concomitant low vitamin B? levels can be the most cogent and easily measurable biomarkers in schizophrenia and can prove to be helpful for classifying heterogeneous schizophrenia on the basis of biological causes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Brain Nerve 2011 Mar 63: 223-31 |
| PMID | 21386123 |
| Title | [Studies on pathophysiology of schizophrenia with a rare variant as a clue]. |
| Abstract | schizophrenia is a relatively common and severe mental disorder with complex inheritance patterns; its main manifestations are hallucinations, delusions, and disorganized speech and thinking. The exact etiology of schizophrenia remains unsolved, although pharmacological and biological studies have proposed several hypothetical disease mechanisms and plausible candidate genes for susceptibility. Since the early nineties, extensive genetic studies have been performed on this illness, but there has been no marked progress in the research, and reproducible results have not yet been obtained. Such difficulties in genetic studies of schizophrenia arise from the heterogeneity of this disease. Candidate gene approaches are based on the common disease-common variant hypothesis. However, there is no guarantee that a common variant is shared by patients with heterogeneous pathophysiologies of this disorder. We studied a rare mutation with a major alteration in genetic function based on the common disease-rare variant hypothesis. We detected a novel frameshift mutation of glyoxalase 1 (GLO1) accompanied by a 50% reduction in enzymatic activities in a male schizophrenic patient belonging to a pedigree with multiple affected individuals. GLO1 detoxifies toxic carbonyl compounds that produce advanced glycation end products (AGEs) such as pentosidine by Maillard reaction. AGEs accumulate because of carbonyl stress caused by an increase in reactive carbonyl compounds and their attendant protein modifications. A significant increase in plasma AGEs and a low serum pyridoxal level was seen in our patient. In addition, we found other patients with schizophrenia characterized by the presence of homozygotes of the Ala allele of Glu111Ala in the GLO1 gene and a 16% reduction in the activities that showed high plasma AGEs. As compared to that of the 61 control patients, 45 patients with schizophrenia yielded significantly high levels of AGEs in the plasma and low serum pyridoxal levels. Our findings suggest that GLO1 deficits and carbonyl stress are linked to the development of a certain subtype of schizophrenia. Elevated plasma pentosidine and concomitant low vitamin B? levels can be the most cogent and easily measurable biomarkers in schizophrenia and can prove to be helpful for classifying heterogeneous schizophrenia on the basis of biological causes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Front Genet 2012 -1 3: 250 |
| PMID | 23181072 |
| Title | Role of Glyoxalase 1 (Glo1) and methylglyoxal (MG) in behavior: recent advances and mechanistic insights. |
| Abstract | Glyoxalase 1 (GLO1) is a ubiquitous cellular enzyme that participates in the detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis that induces protein modification (advanced glycation end-products, AGEs), oxidative stress, and apoptosis. The concentration of MG is elevated under high-glucose conditions, such as diabetes. As such, GLO1 and MG have been implicated in the pathogenesis of diabetic complications. Recently, findings have linked GLO1 to numerous behavioral phenotypes, including psychiatric diseases (anxiety, depression, schizophrenia, and autism) and pain. This review highlights GLO1's association with behavioral phenotypes, describes recent discoveries that have elucidated the underlying mechanisms, and identifies opportunities for future research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Seishin Shinkeigaku Zasshi 2012 -1 114: 101-7 |
| PMID | 22568112 |
| Title | [Schizophrenia and carbonyl stress]. |
| Abstract | Glyoxalase I (GLO1) is an enzyme essential for the cellular detoxification of reactive carbonyl compounds. Its impairment leads to carbonyl stress and the eventual formation of advanced glycation end products (AGEs) including pentosidine. In the present study, we provide for the first time evidence of genetic abnormalities in GLO1 with their attendant derangements of biochemistry in a small population of schizophrenia. We found that seventeen schizophrenia (approximately 17.4%) showed increases in plasma pentosidine content although they have no physical complications, and concomitantly marked decrease of pyridoxal levels was found in schizophrenia. Vitamin B6 exists in three forms, i.e., pyridoxine, pyridoxal and pyridoxamine. Pyridoxamine has potent ability to entrap RCOs and prevent their toxicity. Further study of profiling of metabolomics and clinical manifestations in schizophrenia could pave the way for novel, better therapeutic/preventive measures for this devastating disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Biochem. Soc. Trans. 2014 Apr 42: 468-72 |
| PMID | 24646262 |
| Title | Carbonyl stress in schizophrenia. |
| Abstract | We have identified idiopathic carbonyl stress in a subpopulation of schizophrenic patients. We first identified a patient with a mutation in GLO1 (glyoxalase I) who showed increased AGE (advanced glycation end-product) levels and decreased vitamin B6 levels. By applying the observations from this rare case to the general schizophrenic population, we were able to identify a subset of patients (20%) for whom carbonyl stress may represent a causative pathophysiological process. Genetic defects in GLO1 increase the risk of carbonyl stress 5-fold, and the resulting increased AGE levels correlate significantly with PANSS (Positive and Negative Syndrome Scale) scored negative symptoms. Pyridoxamine, an active form of vitamin B6 and scavenger for carbonyl stress, could represent a novel and efficacious therapeutic agent for these treatment-resistant symptoms. In the present article, we describe a unique research approach to identify the causative process in the pathophysiology of a subset of schizophrenia. Our findings could form the basis of a schizophrenia subtype classification within this very heterogeneous disease and ultimately lead to better targeted therapy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Biochem. Soc. Trans. 2014 Apr 42: 468-72 |
| PMID | 24646262 |
| Title | Carbonyl stress in schizophrenia. |
| Abstract | We have identified idiopathic carbonyl stress in a subpopulation of schizophrenic patients. We first identified a patient with a mutation in GLO1 (glyoxalase I) who showed increased AGE (advanced glycation end-product) levels and decreased vitamin B6 levels. By applying the observations from this rare case to the general schizophrenic population, we were able to identify a subset of patients (20%) for whom carbonyl stress may represent a causative pathophysiological process. Genetic defects in GLO1 increase the risk of carbonyl stress 5-fold, and the resulting increased AGE levels correlate significantly with PANSS (Positive and Negative Syndrome Scale) scored negative symptoms. Pyridoxamine, an active form of vitamin B6 and scavenger for carbonyl stress, could represent a novel and efficacious therapeutic agent for these treatment-resistant symptoms. In the present article, we describe a unique research approach to identify the causative process in the pathophysiology of a subset of schizophrenia. Our findings could form the basis of a schizophrenia subtype classification within this very heterogeneous disease and ultimately lead to better targeted therapy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2015 Jun 59: 105-10 |
| PMID | 25645869 |
| Title | Genetic analysis of the glyoxalase system in schizophrenia. |
| Abstract | Recent reports suggest that carbonyl stress might affect a subset of schizophrenia patients suffering from severe symptoms. Carbonyl stress protection is achieved by the glyoxalase system consisting of two enzymes, glyoxalase 1 and 2, which in humans are encoded by the genes GLO1 and HAGH, respectively. Glyoxalase 1 and 2 catalyze the detoxification of reactive alpha-oxoaldehydes such as glyoxal and methylglyoxal, which are particularly damaging components of carbonyl stress. Here, we investigated the role of the glyoxalase system in schizophrenia by performing association analyses of common genetic variants (n=12) in GLO1 and HAGH in a Japanese sample consisting of 2012 schizophrenia patients and 2170 healthy controls. We detected a nominally significant association with schizophrenia (p=0.020) of rs11859266, a SNP in the intronic region of HAGH. However, rs11859266 did not survive multiple testing (empirical p=0.091). The variants in HAGH, rs11859266 and rs3743852, showed significant associations with schizophrenia in males at allelic and genotype levels, which remained persistent after multiple testing with the exception of rs3743852 for the genotype model. We further measured the mRNA expression of both genes in postmortem brain, but did not detect any changes in transcript expression levels between case and control samples or in sex-specific comparisons. Therefore, our findings suggest that an explanation of elevated carbonyl stress in a substantial part (reported as ~20%) of patients with schizophrenia will require the examination of a much larger cohort to detect risk alleles with weak effect size and/or other risk factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |