Glyoxalase 1 Confers Susceptibility to Schizophrenia: From Genetic Variants to Phenotypes of Neural Function

This research aimed to investigate the role of glyoxalase 1 (Glo-1) polymorphisms in the susceptibility of schizophrenia. Using the real-time polymerase chain reaction (PCR) and spectrophotometric assays technology, significant differences in Glo-1 messenger ribonucleic acid (mRNA) expression (P = 3.98 × 10−5) and enzymatic activity (P = 1.40 × 10−6) were found in peripheral blood of first-onset antipsychotic-naïve patients with schizophrenia and controls. The following receiver operating characteristic (ROC) curves analysis showed that Glo-1 could predict the schizophrenia risk (P = 4.75 × 10−6 in mRNA, P = 1.43 × 10−7 in enzymatic activity, respectively). To identify the genetic source of Glo-1 risk in schizophrenia, Glo-1 polymorphisms (rs1781735, rs1130534, rs4746, and rs9470916) were genotyped with SNaPshot technology in 1,069 patients with schizophrenia and 1,023 healthy individuals. Then, the impact of risk polymorphism on the promoter activity, mRNA expression, and enzymatic activity was analyzed. The results revealed significant differences in the distributions of genotype (P = 0.020, false discovery rate (FDR) correction) and allele (P = 0.020, FDR correction) in rs1781735, in which G > T mutation significantly showed reduction in the promoter activity (P = 0.016), mRNA expression, and enzymatic activity (P = 0.001 and P = 0.015, respectively, GG vs. TT, in peripheral blood of patients with schizophrenia) of Glo-1. The expression quantitative trait locus (eQTL) findings were followed up with the resting-state functional magnetic resonance imaging (fMRI) analysis. The TT genotype of rs1781735, associated with lower RNA expression in the brain (P < 0.05), showed decreased neuronal activation in the left middle frontal gyrus in schizophrenia (P < 0.001). In aggregate, this study for the first time demonstrates how the genetic and biochemical basis of Glo-1 polymorphism culminates in the brain function changes associated with increased schizophrenia risk. Thus, establishing a combination of multiple levels of changes ranging from genetic variants, transcription, protein function, and brain function changes is a better predictor of schizophrenia risk.

Download Full-text

Featured Article: Pyruvate preserves antiglycation defenses in porcine brain after cardiac arrest

Experimental Biology and Medicine ◽

10.1177/1535370217703353 ◽

2017 ◽

Vol 242 (10) ◽

pp. 1095-1103 ◽

Cited By ~ 4

Author(s):

Gary F Scott ◽

Anh Q Nguyen ◽

Brandon H Cherry ◽

Roger A Hollrah ◽

Isabella Salinas ◽

...

Keyword(s):

Cardiac Arrest ◽

Glutathione Reductase ◽

Ischemia Reperfusion ◽

Protein Glycation ◽

Carbonyl Stress ◽

Swine Model ◽

Glyoxalase 1 ◽

Cardiocerebral Resuscitation ◽

The Impact ◽

The Brain

Cardiac arrest (CA) and cardiocerebral resuscitation (CCR)-induced ischemia–reperfusion imposes oxidative and carbonyl stress that injures the brain. The ischemic shift to anaerobic glycolysis, combined with oxyradical inactivation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), provokes excessive formation of the powerful glycating agent, methylglyoxal. The glyoxalase (GLO) system, comprising the enzymes glyoxalase 1 (GLO1) and GLO2, utilizes reduced glutathione (GSH) supplied by glutathione reductase (GR) to detoxify methylglyoxal resulting in reduced protein glycation. Pyruvate, a natural antioxidant that augments GSH redox status, could sustain the GLO system in the face of ischemia–reperfusion. This study assessed the impact of CA-CCR on the cerebral GLO system and pyruvate’s ability to preserve this neuroprotective system following CA. Domestic swine were subjected to 10 min CA, 4 min closed-chest CCR, defibrillation and 4 h recovery, or to a non-CA sham protocol. Sodium pyruvate or NaCl control was infused (0.1 mmol/kg/min, intravenous) throughout CCR and the first 60 min recovery. Protein glycation, GLO1 content, and activities of GLO1, GR, and GAPDH were analyzed in frontal cortex biopsied at 4 h recovery. CA-CCR produced marked protein glycation which was attenuated by pyruvate treatment. GLO1, GR, and GAPDH activities fell by 86, 55, and 30%, respectively, after CA-CCR with NaCl infusion. Pyruvate prevented inactivation of all three enzymes. CA-CCR sharply lowered GLO1 monomer content with commensurate formation of higher molecular weight immunoreactivity; pyruvate preserved GLO1 monomers. Thus, ischemia–reperfusion imposed by CA-CCR disabled the brain’s antiglycation defenses. Pyruvate preserved these enzyme systems that protect the brain from glycation stress. Impact statement Recent studies have demonstrated a pivotal role of protein glycation in brain injury. Methylglyoxal, a by-product of glycolysis and a powerful glycating agent in brain, is detoxified by the glutathione-catalyzed glyoxalase (GLO) system, but the impact of cardiac arrest (CA) and cardiocerebral resuscitation (CCR) on the brain’s antiglycation defenses is unknown. This study in a swine model of CA and CCR demonstrated for the first time that the intense cerebral ischemia–reperfusion imposed by CA-resuscitation disabled glyoxalase-1 and glutathione reductase (GR), the source of glutathione for methylglyoxal detoxification. Moreover, intravenous administration of pyruvate, a redox-active intermediary metabolite and antioxidant in brain, prevented inactivation of glyoxalase-1 and GR and blunted protein glycation in cerebral cortex. These findings in a large mammal are first evidence of GLO inactivation and the resultant cerebral protein glycation after CA-resuscitation, and identify novel actions of pyruvate to minimize protein glycation in postischemic brain.

Download Full-text

Over 400 million years of cooperation: Untangling the chondrocranium-dermatocranium connection

10.1101/2021.11.24.469914 ◽

2021 ◽

Author(s):

Susan M. Motch Perrine ◽

M Kathleen Pitirri ◽

Emily L Durham ◽

Mizuho Kawasaki ◽

Hao Zheng ◽

...

Keyword(s):

Genetic Variants ◽

Endochondral Ossification ◽

Cell Function ◽

Postnatal Growth ◽

Mouse Embryos ◽

Fibroblast Growth ◽

Direct Effects ◽

Dorsal Aspect ◽

The Impact ◽

The Brain

The cranial endo- and dermal skeletons, which comprise the vertebrate skull, evolved independently and form separately during embryogenesis. In mammals, the mostly cartilaginous cranial endoskeleton forms prior to the bony dermatocranium. Many features of the chondrocranium are transient, undergoing endochondral ossification or disappearing, so its role in skull morphogenesis is not understood The fibroblast growth factor (FGF) and receptor (FGFR) signaling pathway contributes significantly to the regulation of osteochondroprogenitor cell function. Mutations in FGFR genes are associated with diseases that impact the skull including dwarfing chondrodyplasia and craniosynostosis syndromes. We investigate the developing chondrocranium and dermatocranium using a mouse model for craniosynostosis carrying a gain of function mutation in Fgfr2 to assess development of these cranial skeleton systems. Dermatocrania and chondrocrania of Fgfr2cC342Y/+ mice and their Fgfr2c+/+ littermates were quantified in 3D from microcomputed tomography images of mouse embryos. Chondrocrania of embryonic mice carrying the Fgfr2 mutation are larger than their Fgfr2c+/+ littermates and include novel extensions of cartilage over the lateral and dorsal aspect of the brain. Like the forming chondrocranium, the embryonic dermatocranium is larger in Fgfr2cC342Y/+ mice throughout embryogenesis but after disappearance of much of the chondrocranium, the dermatocranium becomes progressively smaller relative to Fgfr2c+/+ littermates during postnatal growth. Results reveal the direct effects of this Fgfr2c mutation on embryonic cranial cartilage, the impact of chondrocranial structure on developing dermatocranial elements, the importance of the chondrocranium in decoding the impact of specific genetic variants on head morphogenesis, and the potential for harnessing these effects as therapeutic targets.

Download Full-text

Current Paradigms to Explore the Gut Microbiota Linkage to Neurological Disorders

EMJ Neurology ◽

10.33590/emjneurol/20-00068 ◽

2020 ◽

pp. 68-79

Author(s):

Varruchi Sharma ◽

Atul Sankhyan ◽

Anshika Varshney ◽

Renuka Choudhary ◽

Anil K. Sharma

Keyword(s):

Gut Microbiota ◽

Neurological Disorders ◽

Brain Function ◽

Intervention Strategy ◽

Neurological Complications ◽

Communication Link ◽

Brain Functions ◽

Current Review ◽

The Impact ◽

The Brain

It has been suggested that an intricate communication link exists between the gut microbiota and the brain and its ability to modulate behaviour of an individual governing homeostasis. Metabolic activity of the microbiota is considered to be relatively constant in healthy individuals, despite differences in the composition of microbiota. The metabolites produced by gut microbiota and their homeostatic balance is often perturbed as a result of neurological complications. Therefore, it is of paramount importance to explore the link between gut microbiota and brain function and behaviour through neural, endocrine, and immune pathways. This current review focusses on the impact of altered gut microbiota on brain functions and how microbiome modulation by use of probiotics, prebiotics, and synbiotics might prove beneficial in the prevention and/or treatment of neurological disorders. It is important to carefully understand the complex mechanisms underlying the gut–brain axis so as to use the gut microbiota as a therapeutic intervention strategy for neurological disorders.

Download Full-text

The impact of diet-based glycaemic response and glucose regulation on cognition: evidence across the lifespan

Proceedings of The Nutrition Society ◽

10.1017/s0029665117000829 ◽

2017 ◽

Vol 76 (4) ◽

pp. 466-477 ◽

Cited By ~ 13

Author(s):

Sandra I. Sünram-Lea ◽

Lauren Owen

Keyword(s):

Blood Glucose ◽

Cognitive Function ◽

Brain Function ◽

Healthy Lifestyle ◽

Glucose Deprivation ◽

Glucose Regulation ◽

Glycaemic Response ◽

Glucose Levels ◽

The Impact ◽

The Brain

The brain has a high metabolic rate and its metabolism is almost entirely restricted to oxidative utilisation of glucose. These factors emphasise the extreme dependence of neural tissue on a stable and adequate supply of glucose. Whereas initially it was thought that only glucose deprivation (i.e. under hypoglycaemic conditions) can affect brain function, it has become apparent that low-level fluctuations in central availability can affect neural and consequently, cognitive performance. In the present paper the impact of diet-based glycaemic response and glucose regulation on cognitive processes across the lifespan will be reviewed. The data suggest that although an acute rise in blood glucose levels has some short-term improvements of cognitive function, a more stable blood glucose profile, which avoids greater peaks and troughs in circulating glucose is associated with better cognitive function and a lower risk of cognitive impairments in the longer term. Therefore, a habitual diet that secures optimal glucose delivery to the brain in the fed and fasting states should be most advantageous for the maintenance of cognitive function. Although the evidence to date is promising, it is insufficient to allow firm and evidence-based nutritional recommendations. The rise in obesity, diabetes and metabolic syndrome in recent years highlights the need for targeted dietary and lifestyle strategies to promote healthy lifestyle and brain function across the lifespan and for future generations. Consequently, there is an urgent need for hypothesis-driven, randomised controlled trials that evaluate the role of different glycaemic manipulations on cognition.

Download Full-text

Exploring the mRNA expression level of RELN in peripheral blood of schizophrenia patients before and after antipsychotic treatment

10.21203/rs.3.rs-62941/v3 ◽

2020 ◽

Author(s):

Jiajun Yin ◽

Yana Lu ◽

Shui Yu ◽

Zhanzhan Dai ◽

Fuquan Zhang ◽

...

Keyword(s):

Mrna Expression ◽

Peripheral Blood ◽

Antipsychotic Treatment ◽

Mrna Levels ◽

Healthy Controls ◽

Quantitative Real Time Pcr ◽

Expression Levels ◽

Before And After ◽

The Brain

Abstract Background: The Reelin (RELN) gene encodes the protein reelin, which is a large extracellular matrix glycoprotein that plays a key role in brain development. Additionally, this protein may be involved in memory formation, neurotransmission, and synaptic plasticity, which have been shown to be disrupted in schizophrenia (SCZ). A decreasing trend in the expression of RELN mRNA in the brain and peripheral blood of SCZ patients has been observed. There is a need to determine whether changes in RELN mRNA expression in SCZ patients are the result of long-term antipsychotic treatment rather than the etiological characteristics of schizophrenia. The expression levels of RELN mRNA in the peripheral blood of 48 healthy controls and 30 SCZ patients before and after 12-weeks of treatment were measured using quantitative real-time PCR.Results: The expression levels of RELN mRNA in the SCZ group were significantly lower than that of healthy controls; however, after 12-weeks of antipsychotic treatment, RELN mRNA levels were significantly increased in the SCZ group.Conclusion: The up-regulation of RELN mRNA expression was current in SCZ patients after antipsychotic treatment, suggesting that the changes in RELN mRNA expression were related to the effect of the antipsychotic treatment.

Download Full-text

Effects of Long-Term Exposure to L-Band High-Power Microwave on the Brain Function of Male Mice

BioMed Research International ◽

10.1155/2021/2237370 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Yanyun Lin ◽

Peng Gao ◽

Yichen Guo ◽

Qin Chen ◽

Haiyang Lang ◽

...

Keyword(s):

Nervous System ◽

Power Density ◽

High Power ◽

Brain Function ◽

High Power Microwave ◽

L Band ◽

The Impact ◽

The Brain ◽

Power Microwave

Currently, the impact of electromagnetic field (EMF) exposure on the nervous system is an increasingly arousing public concern. The present study was designed to explore the effects of continuous long-term exposure to L-band high-power microwave (L-HPM) on brain function and related mechanisms. Forty-eight male Institute of Cancer Research (ICR) mice were exposed to L-HPM at various power densities (0.5, 1.0, and 1.5 W/m2) and the brain function was examined at different time periods after exposure. The morphology of the brain was examined by hematoxylin-eosin (HE) and deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. Furthermore, cholinergic markers, oxidative stress markers, and the expression of c-fos were evaluated to identify a “potential” mechanism. The results showed that exposure to L-HPM at 1.5 W/m2 can cause generalized injuries in the hippocampus (CA1 and CA3) and cerebral cortex (the first somatosensory cortex) of mice, including cell apoptosis, cholinergic dysfunction, and oxidative damage. Moreover, the deleterious effects were closely related to the power density and exposure time, indicating that long-term and high-power density exposure may be detrimental to the nervous system.

Download Full-text

Peripherally expressed misfolded proteins remotely disrupt brain function and aggravate stroke-induced brain injury

10.1101/785477 ◽

2019 ◽

Author(s):

Yanying Liu ◽

Kalpana Subedi ◽

Aravind Baride ◽

Svetlana Romanova ◽

Christa C. Huber ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Function ◽

Small Heat Shock Protein ◽

Brain Dysfunction ◽

Misfolded Proteins ◽

Wild Type ◽

Mouse Blood ◽

Αb Crystallin ◽

The Impact ◽

The Brain

AbstractImpaired proteostasis has been linked to various diseases, whereas little is known about the impact of peripherally misfolded proteins on the brain. We here studied the brain of mice with cardiomyocyte-restricted overexpression of a missense (R120G) mutant small heat shock protein, αB-crystallin (CryABR120G). At baseline, the CryABR120G mice showed impaired cognitive and motor functions, aberrant protein aggregates, neuroinflammation, impaired blood-brain barrier, and reduced proteasome activity in the brain compared with their non-transgenic (Ntg) littermates. Ischemic stroke dramatically exacerbated these pathological alterations and caused more severe brain dysfunction in CryABR120G mice than in the Ntg mice. Intravenously injecting the exosomes isolated from CryABR120G mouse blood into wild-type mice caused the similar phenotypes seen from CryABR120G mice. Importantly, the CryABR120G protein showed the prion-like properties. These results suggest that peripherally misfolded proteins in the heart remotely disrupt brain function through prion-like neuropathology, which may represent an underappreciated mechanism underlying heart-brain crosstalk.

Download Full-text

Exploring the mRNA expression level of RELN in peripheral blood of schizophrenia patients before and after antipsychotic treatment

Hereditas ◽

10.1186/s41065-020-00158-6 ◽

2020 ◽

Vol 157 (1) ◽

Author(s):

Jiajun Yin ◽

Yana Lu ◽

Shui Yu ◽

Zhanzhan Dai ◽

Fuquan Zhang ◽

...

Keyword(s):

Mrna Expression ◽

Peripheral Blood ◽

Antipsychotic Treatment ◽

Mrna Levels ◽

Healthy Controls ◽

Quantitative Real Time Pcr ◽

Expression Levels ◽

Before And After ◽

The Brain

Abstract Background The Reelin (RELN) gene encodes the protein reelin, which is a large extracellular matrix glycoprotein that plays a key role in brain development. Additionally, this protein may be involved in memory formation, neurotransmission, and synaptic plasticity, which have been shown to be disrupted in schizophrenia (SCZ). A decreasing trend in the expression of RELN mRNA in the brain and peripheral blood of SCZ patients has been observed. There is a need to determine whether changes in RELN mRNA expression in SCZ patients are the result of long-term antipsychotic treatment rather than the etiological characteristics of schizophrenia. The expression levels of RELN mRNA in the peripheral blood of 48 healthy controls and 30 SCZ patients before and after 12-weeks of treatment were measured using quantitative real-time PCR. Results The expression levels of RELN mRNA in the SCZ group were significantly lower than that of healthy controls; however, after 12-weeks of antipsychotic treatment, RELN mRNA levels were significantly increased in the SCZ group. Conclusion The up-regulation of RELN mRNA expression was current in SCZ patients after antipsychotic treatment, suggesting that the changes in RELN mRNA expression were related to the effect of the antipsychotic treatment.

Download Full-text

Exploring the mRNA Expression Level of RELN in Peripheral Blood of Schizophrenia Patients Before and After Antipsychotic Treatment

10.21203/rs.3.rs-62941/v1 ◽

2020 ◽

Author(s):

Jiajun Yin ◽

Yana Lu ◽

Shui Yu ◽

Zhanzhan Dai ◽

Fuquan Zhang ◽

...

Keyword(s):

Mrna Expression ◽

Peripheral Blood ◽

Antipsychotic Treatment ◽

Mrna Levels ◽

Healthy Controls ◽

Quantitative Real Time Pcr ◽

Expression Levels ◽

Before And After ◽

The Brain

Abstract Background: The Reelin (RELN) gene encodes the protein reelin, which is a large extracellular matrix glycoprotein that plays a key role in brain development. Additionally, this protein may be involved in memory formation, neurotransmission, and synaptic plasticity, which have been shown to be disrupted in schizophrenia (SCZ). A decreasing trend in the expression of RELN mRNA in the brain and peripheral blood of SCZ patients has been observed. There is a need to determine whether changes in RELN mRNA expression in SCZ patients are the result of long-term antipsychotic treatment rather than the etiological characteristics of schizophrenia. The expression levels of RELN mRNA in the peripheral blood of 48 healthy controls and 30 SCZ patients before and after 12-weeks of treatment were measured using quantitative real-time PCR. Results: The expression levels of RELN mRNA in the SCZ group were significantly lower than that of healthy controls; however, after 12-weeks of antipsychotic treatment, RELN mRNA levels were significantly increased in the SCZ group.Conclusion: The up-regulation of RELN mRNA expression was concurrent with the improvement of symptoms in SCZ patients after antipsychotic treatment, suggesting that the changes in RELN mRNA expression were related to the effect of the antipsychotic treatment.

Download Full-text