Genetic analysis of the glyoxalase system in schizophrenia

Bangel, Fabian N.; Yamada, Kazuo; Arai, Makoto; Iwayama, Yoshimi; Balan, Shabeesh; Toyota, Tomoko; Iwata, Yasuhide; Suzuki, Katsuaki; Kikuchi, Mitsuru; Hashimoto, Tasuku; Kanahara, Nobuhisa; Mori, Norio; Itokawa, Masanari; Stork, Oliver; Yoshikawa, Takeo

doi:10.1016/j.pnpbp.2015.01.014

Cited by 15 publications

(9 citation statements)

References 38 publications

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“…As far as we know, data about the MGO concentration in patients with schizophrenia patients are not available (32). In contrast to the above-mentioned genetic study, in a large sample of 2012 schizophrenia patients and 2170 healthy controls, no associations were found between common genetic variants of Glo1 and also the mRNA expression of Glo1 in post mortem brain did not show any changes in transcript expression levels between case and control samples (40). Although add-on treatment with a high dose of the MGO scavenger pyridoxamine was, in part, effective for a subpopulation of schizophrenia patients with enhanced carbonyl stress (254), additional studies are needed to study the impact of MGO in schizophrenia.…”

Section: Schizophreniamentioning

confidence: 85%

Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

Schalkwijk

Stehouwer

2020

Physiological Reviews

362

330

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The formation and accumulation of methylglyoxal (MGO), a highly reactive dicarbonyl compound, has been implicated in the pathogenesis of type 2 diabetes, vascular complications of diabetes, and several other age-related chronic inflammatory diseases such as cardiovascular disease, cancer and disorders of the central nervous system. MGO is mainly formed as a byproduct of glycolysis and, under physiological circumstances, detoxified by the glyoxalase system. MGO is the major precursor of non-enzymatic glycation of proteins and DNA, subsequently leading to the formation of advanced glycation endproducts (AGEs). MGO and MGO-derived AGEs can impact on organs and tissues affecting their functions and structure. This review summarizes the mechanisms through which MGO is formed, its detoxification by the glyoxalase system, and its effect on biochemical pathways in relation to the development of diabetes, vascular complications of diabetes and other age-related diseases. Although therapies to treat MGO-associated complications are not yet available for application in clinical practice, several strategies to lower MGO have been developed over the years. We will summarize several new directions to target MGO stress including glyoxalase inducers and MGO scavengers. Diminishing MGO burden can potentially form the basis for new treatment strategies for age-related disorders in which MGO plays a pivotal role.

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Section: Schizophreniamentioning

confidence: 85%

Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

Schalkwijk

Stehouwer

2020

Physiological Reviews

362

330

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“…Only a single subject, in the EOBP group, was African-American and all the others were Caucasians; therefore, the effects of ethnicity were not examined in the present study. The presently used post-mortem specimens were judged to preserve the acceptable quality for the qRT-PCR assay of mRNAs because (i) their pH values are within the ranges that have been recognized as being reliable (for example, references 23 , 24 , 25 , 26 ), although there is variation within this range, as indicated by the analysis of variance analysis, which showed significant differences in the pH values between the control (CT) and non-EOS groups, and (ii) similar expression levels of the housekeeping genes, GAPDH, ACTB, PGK1 , 18S and 28S rRNA, observed across all the diagnostic groups, suggest that the samples maintain the homogeneity of their RNA quality of the current sample set.…”

Section: Methodsmentioning

confidence: 99%

Reduced cortical expression of a newly identified splicing variant of the DLG1 gene in patients with early-onset schizophrenia

et al. 2015

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The human discs, large homolog 1 gene (DLG1) is mapped to the schizophrenia-susceptibility locus 3q29, and it encodes a scaffold protein that interacts with the N-methyl-D-aspartate receptor presumably dysregulated in schizophrenia. In the current study, we have newly identified a splicing variant of DLG1, which is transcribed from an unreported 95-base-pair exon (exon 3b) and is labeled 3b(+). We investigated the mRNA expression of 3b(+) in the post-mortem dorsolateral prefrontal cortices of patients with psychiatric disorders, obtained from The Stanley Medical Research Institute, and examined the potential association of the expression with the genotype of the single-nucleotide polymorphism (SNP) rs3915512 located within exon 3b. A real-time quantitative reverse transcriptase-polymerase chain reaction revealed that the mRNA levels of 3b(+) were significantly reduced in patients with early-onset schizophrenia (onset at <18 years old, P=0.0003) but not in those with non-early-onset schizophrenia, early-onset or non-early-onset bipolar disorder or in the controls. Furthermore, the genotype at the rs3915512 SNP was closely associated with the levels of 3b(+) mRNA expression. It is inferred that the T allele fails to meet the exonic splicing enhancer consensus, thus resulting in skipping of exon 3b, leading to the expression of 3b(−) (the previously known DLG1 variant) but not 3b(+). Because all the subjects with early-onset schizophrenia in the current study possess the T/T genotype, the reduced level of the DLG1 3b(+) transcript may be involved in the susceptibility and/or pathophysiology of early-onset schizophrenia.

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“…Demographic studies showed a higher distribution of GLO 1 in Alaska and a lower GLO 1 allocation in southern and eastern Europe, America, Africa, and India [ 78 ]. Furthermore, associations of distinct Glo-I phenotypes and Glo-I SNPs with diabetes [ 79 ], cardiovascular diseases [ 80 ], schizophrenia [ 81 ], autism [ 82 , 83 ], multiple sclerosis [ 84 ], anxiety [ 85 ], and cancer [ 86 , 87 , 88 ] were observed. These findings led to preliminary anti-tumor effects of Glo-I knockout by siRNA or enzymatic enzyme inhibition in different cancer models [ 89 , 90 , 91 , 92 ].…”

Section: Glyoxalase-system Mgo Ages and Ragementioning

confidence: 99%

The Role of Glyoxalase-I (Glo-I), Advanced Glycation Endproducts (AGEs), and Their Receptor (RAGE) in Chronic Liver Disease and Hepatocellular Carcinoma (HCC)

Hollenbach¹

2017

IJMS

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Glyoxalase-I (Glo-I) and glyoxalase-II (Glo-II) comprise the glyoxalase system and are responsible for the detoxification of methylglyoxal (MGO). MGO is formed non-enzymatically as a by-product, mainly in glycolysis, and leads to the formation of advanced glycation endproducts (AGEs). AGEs bind to their receptor, RAGE, and activate intracellular transcription factors, resulting in the production of pro-inflammatory cytokines, oxidative stress, and inflammation. This review will focus on the implication of the Glo-I/AGE/RAGE system in liver injury and hepatocellular carcinoma (HCC). AGEs and RAGE are upregulated in liver fibrosis, and the silencing of RAGE reduced collagen deposition and the tumor growth of HCC. Nevertheless, data relating to Glo-I in fibrosis and cirrhosis are preliminary. Glo-I expression was found to be reduced in early and advanced cirrhosis with a subsequent increase of MGO-levels. On the other hand, pharmacological modulation of Glo-I resulted in the reduced activation of hepatic stellate cells and therefore reduced fibrosis in the CCl4-model of cirrhosis. Thus, current research highlighted the Glo-I/AGE/RAGE system as an interesting therapeutic target in chronic liver diseases. These findings need further elucidation in preclinical and clinical studies.

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Genetic analysis of the glyoxalase system in schizophrenia

Cited by 15 publications

References 38 publications

Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

Reduced cortical expression of a newly identified splicing variant of the DLG1 gene in patients with early-onset schizophrenia

The Role of Glyoxalase-I (Glo-I), Advanced Glycation Endproducts (AGEs), and Their Receptor (RAGE) in Chronic Liver Disease and Hepatocellular Carcinoma (HCC)

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