Distinctively higher plasma G72 protein levels in patients with schizophrenia than in healthy individuals

Lin, Chieh‐Hsin; Chang, Hsiang-Kuang; Chen, Y. J.; Huang, Chieh-Liang; Tun, R. Y. M.; Tsai, Guochuan E.; Lane, Hsien‐Yuan

doi:10.1038/mp.2013.80

Cited by 33 publications

(41 citation statements)

References 10 publications

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“…Based on their biochemical study, they assumed that the brain level of pLG72 is lower in patients with schizophrenia, resulting in the activation of DAAO and finally a decreased level of D-serine concentration in synapsis. Although our study demonstrated that the serum pLG72 level is higher in patients with schizophrenia [ 10 ] and supported the finding that pLG72 can activate DAAO [ 11 ], the function of pLG72 is still controversial. In this paper, we aim to predict the biological function of pLG72 by employing systems biology approaches and to demonstrate our hypothesis using cell biology methods.…”

Section: Introductionsupporting

confidence: 83%

Identification of pLG72-Induced Oxidative Stress Using Systemic Approaches

Wang

Chen

Zhang

et al. 2015

BioMed Research International

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G72 is a schizophrenia-susceptible gene encoding a polypeptide with 153 amino acids. In 2002, it was originally proposed as an activator of D-amino acid oxidase (DAOA) that could enhance the activity of DAAO and subsequently reduce the neurotransmission of N-methyl-D-aspartate receptors. However, several controversial findings have been reported recently. Due to a number of inconsistent descriptions of pLG72's biofunctions, this study aims to identify the cellular effects induced by pLG72 in U87 cells using systems biology approaches. The analyses of transcriptomics and biological networks showed that pLG72 might be involved in the induction of oxidative stress. To confirm the in silico prediction, we tested and discovered that overexpression of pLG72 effectively enhanced reactive oxygen species (ROS) in U87 cells and, furthermore, this induction can be quenched by Tempol, a general ROS scavenger. Therefore, G72-transgenic mice presenting some psychiatric symptoms, along with the pLG72 level being significantly increased in the serum of patients with schizophrenia, have led us to propose that the ROS enhancement in mental diseases may be from the overexpression of pLG72 in brain cells.

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Section: Introductionsupporting

confidence: 83%

Identification of pLG72-Induced Oxidative Stress Using Systemic Approaches

Wang

Chen

Zhang

et al. 2015

BioMed Research International

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“…37 In addition to genetic evidence, altered pLG72 protein levels have been found in the plasma of patients with SCZ, compared to control subjects. 38 Unlike DAAO, the existence of putative modulators of DDO has never been investigated so far. Therefore, in the light of the dysfunctional DDO activity found in the DLPFC of SCZ patients, future studies will be mandatory to assess the occurrence of regulatory molecules and cellular factors that could tune the metabolic control played by DDO over d -Asp under physiological and pathologic conditions.…”

Section: Discussionmentioning

confidence: 99%

Decreased free d-aspartate levels are linked to enhanced d-aspartate oxidase activity in the dorsolateral prefrontal cortex of schizophrenia patients

et al. 2017

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It is long acknowledged that the N-methyl d-aspartate receptor co-agonist, d-serine, plays a crucial role in several N-methyl d-aspartate receptor-mediated physiological and pathological processes, including schizophrenia. Besides d-serine, another free d-amino acid, d-aspartate, is involved in the activation of N-methyl d-aspartate receptors acting as an agonist of this receptor subclass, and is abundantly detected in the developing human brain. Based on the hypothesis of N-methyl d-aspartate receptor hypofunction in the pathophysiology of schizophrenia and considering the ability of d-aspartate and d-serine to stimulate N-methyl d-aspartate receptor-dependent transmission, in the present work we assessed the concentration of these two d-amino acids in the post-mortem dorsolateral prefrontal cortex and hippocampus of patients with schizophrenia and healthy subjects. Moreover, in this cohort of post-mortem brain samples we investigated the spatiotemporal variations of d-aspartate and d-serine. Consistent with previous work, we found that d-aspartate content was selectively decreased by around 30% in the dorsolateral prefrontal cortex, but not in the hippocampus, of schizophrenia-affected patients, compared to healthy subjects. Interestingly, such selective reduction was associated to greater (around 25%) cortical activity of the enzyme responsible for d-aspartate catabolism, d-aspartate oxidase. Conversely, no significant changes were found in the methylation state and transcription of DDO gene in patients with schizophrenia, compared to control individuals, as well as in the expression levels of serine racemase, the major enzyme responsible for d-serine biosynthesis, which also catalyzes aspartate racemization. These results reveal the potential involvement of altered d-aspartate metabolism in the dorsolateral prefrontal cortex as a factor contributing to dysfunctional N-methyl d-aspartate receptor-mediated transmission in schizophrenia.

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“…Meta-analyses provided evidence of significant association between G72/G30 genes and schizophrenia353637. Interestingly, there are two reports showing increased G72 protein levels in the blood of patients with schizophrenia3839. A subsequent largest GWAS study of schizophrenia demonstrated the SRR gene as a susceptible gene40.…”

mentioning

confidence: 99%

Supplementation with D-serine prevents the onset of cognitive deficits in adult offspring after maternal immune activation

Fujita

Ishima

Hashimoto

2016

Sci Rep

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Prenatal maternal infection contributes to the etiology of schizophrenia, with D-serine, an endogenous co-agonist of the N-methyl-D-aspartate (NMDA) receptor, playing a role in the pathophysiology of this disease. We examined whether supplementation with D-serine during juvenile and adolescent stages could prevent the onset of cognitive deficits, prodromal and the core symptoms of schizophrenia in adult offspring after maternal immune activation (MIA). Juvenile offspring exposed prenatally to poly(I:C) showed reduced expression of NMDA receptor subunits in the hippocampus. Supplementing drinking water with D-serine (600 mg/L from P28 to P56) prevented the onset of cognitive deficits in adult offspring after MIA, in a significant manner. This study shows that supplementing offspring with D-serine during juvenile and adolescent stages could prevent the onset of psychosis in adulthood, after MIA. Therefore, early intervention with D-serine may prevent the occurrence of psychosis in high-risk subjects.

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Distinctively higher plasma G72 protein levels in patients with schizophrenia than in healthy individuals

Cited by 33 publications

References 10 publications

Identification of pLG72-Induced Oxidative Stress Using Systemic Approaches

Identification of pLG72-Induced Oxidative Stress Using Systemic Approaches

Decreased free d-aspartate levels are linked to enhanced d-aspartate oxidase activity in the dorsolateral prefrontal cortex of schizophrenia patients

Supplementation with D-serine prevents the onset of cognitive deficits in adult offspring after maternal immune activation

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