Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

G72 is a strong candidate susceptibility gene for schizophrenia and bipolar disorder, whose function remains enigmatic. Here we show that one splicing isoform of the gene (LG72) encodes for a mitochondrial protein. We also provide convergent lines of evidence that increase of endogenous or exogenous G72 levels promotes robust mitochondrial fragmentation in mammalian cell lines and primary neurons, which proceeds in a manner that does not depend on induction of apoptosis or alteration in mitochondrial transmembrane potential. Finally, we show that increase in G72 levels in immature primary neurons is accompanied by a marked increase in dendritic arborization. By contrast, we failed to confirm the originally proposed functional interaction between G72 and D-amino acid oxidase (DAO) in two tested cell lines. Our results suggest an alternative role for G72 in modulating mitochondrial function.
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PMID:Evidence implicating the candidate schizophrenia/bipolar disorder susceptibility gene G72 in mitochondrial function. 1768 99

The N-methyl-D-aspartate receptor co-agonist d-serine is synthesized by serine racemase and degraded by D-amino acid oxidase. Both D-serine and its metabolizing enzymes are implicated in N-methyl-D-aspartate receptor hypofunction thought to occur in schizophrenia. We studied D-amino acid oxidase and serine racemase immunohistochemically in several brain regions and compared their immunoreactivity and their mRNA levels in the cerebellum and dorsolateral prefrontal cortex in schizophrenia. D-Amino acid oxidase immunoreactivity was abundant in glia, especially Bergmann glia, of the cerebellum, whereas in prefrontal cortex, hippocampus and substantia nigra, it was predominantly neuronal. Serine racemase was principally glial in all regions examined and demonstrated prominent white matter staining. In schizophrenia, D-amino acid oxidase mRNA was increased in the cerebellum, and as a trend for protein. Serine racemase was increased in schizophrenia in the dorsolateral prefrontal cortex but not in cerebellum, while serine racemase mRNA was unchanged in both regions. Administration of haloperidol to rats did not significantly affect serine racemase or D-amino acid oxidase levels. These findings establish the major cell types wherein serine racemase and D-amino acid oxidase are expressed in human brain and provide some support for aberrant D-serine metabolism in schizophrenia. However, they raise further questions as to the roles of D-amino acid oxidase and serine racemase in both physiological and pathophysiological processes in the brain.
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PMID:d-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia. 1788 Mar 99

A series of genetic studies have identified the D-amino acid oxidase (DAO) gene as potentially contributing to schizophrenia susceptibility. An interacting gene, D-amino acid oxidase activator (DAOA) has also been implicated and it has been suggested that variation at these genes may influence the efficiency of glutamate gating at N-methyl-D-aspartate-type (NMDA) receptors. However, recent data suggests that DAOA may influence susceptibility to mood episodes across the spectrum of psychotic disorders rather than contributing to a specific psychosis phenotype. The aim of this study was to determine whether risk variation at DAO is similarly associated with affective or other clinical symptoms in psychosis. We have previously reported association between risk variation at DAO and schizophrenia in an Irish case-control sample. In this study we investigated the relationship between a defined genetic risk variant at DAO and PANSS-derived clinical symptom factors in a sample of 249 patients using principal component and Kruskal-Wallis analyses. Carriers of the DAO risk variant scored significantly higher on the 'depression/anxiety' factor than non-carriers (H=9.02, d.f.=2, p=0.01). These data suggest a potential role for DAO in susceptibility to depressive symptoms in schizophrenia, but a more general role for DAO in affective disorders cannot be excluded.
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PMID:D-amino acid oxidase (DAO) genotype and mood symptomatology in schizophrenia. 1789 6

The flavoprotein D-amino acid oxidase (DAO) degrades the gliotransmitter D-Ser, a potent activator of N-methyl-D-aspartate-type glutamate receptors. A body of evidence suggests that DAO, together with its activator, G72 protein, may play a key role in the pathophysiology of schizophrenia. It has also been suggested that 3,4-dihydroxy-D-phenylalanine (D-DOPA), the stereoisomer of 3,4-dihydroxy-L-phenylalanine (L-DOPA), is oxidized by DAO and converted to dopamine via an alternative biosynthetic pathway. We determined the crystal structures of human DAO in complex with the reaction products of two clinically important substrates, D-Ser and D-DOPA. Kinetic data show that the maximum velocity is much greater for D-DOPA than that for D-Ser, which strongly supports the proposed alternative pathway for dopamine biosynthesis in the treatment of Parkinson's disease. In addition, biochemical characterization of human DAO indicates that it binds FAD more weakly than does porcine D-amino acid oxidase (pDAO) and exists as a stable homodimer, even in the apoprotein form. Determination of the structures of human DAO in various states reveals that, in contrast to pDAO, the hydrophobic-Val-Ala-Ala-Gly-Leu (VAAGL) stretch (residues 47-51, structurally ambivalent peptide) located at the si-face of the flavin ring assumes a uniquely stable conformation, which provides a structural basis for the unique kinetic features of human DAO.
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PMID:Human D-amino acid oxidase: an update and review. 1792 43

D-serine has been shown to be a major endogenous coagonist of the N-methyl D-aspartate (NMDA) type of glutamate receptors. Accumulating evidence suggests that NMDA receptor hypofunction contributes to the symptomatic features of schizophrenia. d-serine degradation can be mediated by the enzyme d-amino acid oxidase (DAAO). An involvement of d-serine in the etiology of schizophrenia is suggested by the association of the disease with single nucleotide polymorphisms in the DAAO and its regulator (G72). The present study aims to further elucidate whether the DAAO activity is altered in schizophrenia. Specific DAAO activity was measured in postmortem cortex samples of bipolar disorder, major depression and schizophrenia patients, and normal controls (n=15 per group). The mean DAAO activity was two-fold higher in the schizophrenia patients group compared with the control group. There was no correlation between DAAO activity and age, age of onset, duration of disease, pH of the tissue and tissue storage time and no effect of gender, cause of death and history of alcohol and substance abuse. The group of neuroleptics users (including bipolar disorder patients) showed significantly higher D-amino acid oxidase activity. However, there was no correlation between the cumulative life-time antipsychotic usage and D-amino acid oxidase levels. In mice, either chronic exposure to antipsychotics or acute administration of the NMDA receptor blocker MK-801, did not change d-amino acid oxidase activity. These findings provide indications that D-serine availability in the nervous system may be altered in schizophrenia because of increased D-amino acid degradation by DAAO.
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PMID:Increased brain D-amino acid oxidase (DAAO) activity in schizophrenia. 1837 21

D-amino acid oxidase (DAO), a potential risk factor for schizophrenia, has been proposed to be involved in the decreased glutamatergic neurotransmission in schizophrenia. Here we show the inhibitory effect of an antipsychotic drug, chlorpromazine, on human DAO, which is consistent with previous reports using porcine DAO, although human DAO was inhibited to a lesser degree (K(i) = 0.7 mM) than porcine DAO. Since chlorpromazine is known to induce phototoxic or photoallergic reactions and also to be transformed into various metabolites, we examined the effects of white light-irradiated chlorpromazine on the enzymatic activity. Analytical methods including high-resolution mass spectrometry revealed that irradiation triggered the oligomerization of chlorpromazine molecules. The oligomerized chlorpromazine showed a mixed type inhibition with inhibition constants of low micromolar range, indicative of enhanced inhibition. Taken together, these results suggest that oligomerized chlorpromazine could act as an active substance that might contribute to the therapeutic effects of this drug.
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PMID:Chlorpromazine oligomer is a potentially active substance that inhibits human D-amino acid oxidase, product of a susceptibility gene for schizophrenia. 1861 85

Schizophrenia is a debilitating lifelong disorder affecting up to 1% of the population worldwide, producing significant financial and emotional hardship for patients and their families. As yet, the causes of schizophrenia and the mechanism of action of antipsychotic drugs are unknown, and many patients do not respond well to currently available medications. Attempts to find risk factors for the disorder using epidemiological methods have shown that schizophrenia is highly heritable, and path analyses predict that the disorder is caused by several genes in combination with nongenetic factors. Therefore, intensive research efforts have been made to identify genes creating vulnerability to schizophrenia and also genes predicting response to treatment. Interactions of the glutamatergic system with dopaminergic and serotonergic circuitry are crucial for normal brain function, and their disruption may be a mechanism by which the pathophysiology of schizophrenia is manifest. Genes within the glutamatergic system are therefore strong candidates for investigation, and these include the glutamate receptor genes in addition to genes encoding neuregulin, dysbindin, D-amino acid oxidase and G72/G30. These genetic studies could eventually reveal new targets for antipsychotic drug treatment, which currently focuses on inhibition of the dopaminergic system. However, a recent breakthrough indicates clinical efficacy of a drug stimulating the metabotropic glutamate receptor II, LY2140023, which has improved efficacy for negative and cognitive symptoms of schizophrenia. Studies of larger patient samples are required to consolidate these data. Further investigation of glutamatergic targets is likely to reinvigorate antipsychotic drug development.
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PMID:Role of glutamate in schizophrenia: integrating excitatory avenues of research. 1875 51

Cognitive deficit is a key feature of schizophrenia. Genetic factors are thought to contribute to cognitive disturbances in schizophrenia patients. However the role of specific-genes in the development of cognitive deficit remains unclear. The article aims at reviewing the current studies devoted to association between gene polymorphisms and cognitive dysfunctions in schizophrenic patients. Main attention is drawn to the association between the Val158Met polymorphism of the COMT gene and cognitive traits that has been consistently replicated and has a biological and neuropsychological support. The association studies on the genes for dopamine and serotonin receptors, brain-derived neurotrophic factor, dysbindin, DISC1, D-amino acid oxidase and D-amino acid oxidase activator are reviewed as well.
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PMID:[Molecular genetics of cognitive deficit in schizophrenia]. 1898 32

Multiple studies indicate that N-methyl-D-aspartate (NMDA) receptor hypofunction underlies some of the deficits associated with schizophrenia. One approach for improving NMDA receptor function is to enhance occupancy of the glycine modulatory site on the NMDA receptor by increasing the availability of the endogenous coagonists D-serine. Here, we characterized a novel D-amino acid oxidase (DAAO) inhibitor, compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and compared it with D-serine. Compound 8 is a moderately potent inhibitor of human (IC(50), 145 nM) and rat (IC(50), 114 nM) DAAO in vitro. In rats, compound 8 (200 mg/kg) decreased kidney DAAO activity by approximately 96% and brain DAAO activity by approximately 80%. This marked decrease in DAAO activity resulted in a significant (p < 0.001) elevation in both plasma (220% of control) and cerebrospinal fluid (CSF; 175% of control) D-serine concentration. However, compound 8 failed to significantly influence amphetamine-induced psychomotor activity, nucleus accumbens dopamine release, or an MK-801 (dizocilpine maleate)-induced deficit in novel object recognition in rats. In contrast, high doses of D-serine attenuated both amphetamine-induced psychomotor activity and dopamine release and also improved performance in novel object recognition. Behaviorally efficacious doses of D-serine (1280 mg/kg) increased CSF levels of D-serine 40-fold above that achieved by the maximal dose of compound 8. These findings demonstrate that pharmacological inhibition of DAAO significantly increases D-serine concentration in the periphery and central nervous system. However, acute inhibition of DAAO appears not to be sufficient to increase D-serine to concentrations required to produce antipsychotic and cognitive enhancing effects similar to those observed after administration of high doses of exogenous D-serine.
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PMID:The behavioral and neurochemical effects of a novel D-amino acid oxidase inhibitor compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and D-serine. 1908

Activation of the N-methyl-D-aspartate receptor (NMDAR) glycine site has been shown to accelerate adaptive forms of learning that may benefit psychopathologies involving cognitive and perseverative disturbances. In this study, the effects of increasing the brain levels of the endogenous NMDAR glycine site agonist D-serine, through the genetic inactivation of its catabolic enzyme D-amino acid oxidase (DAO), were examined in behavioral tests of learning and memory. In the Morris water maze task (MWM), mice carrying the hypofunctional Dao1(G181R) mutation demonstrated normal acquisition of a single platform location but had substantially improved memory for a new target location in the subsequent reversal phase. Furthermore, Dao1(G181R) mutant animals exhibited an increased rate of extinction in the MWM that was similarly observed following pharmacological administration of D-serine (600 mg/kg) in wild-type C57BL/6J mice. In contextual and cued fear conditioning, no alterations were found in initial associative memory recall; however, extinction of the contextual fear memory was facilitated in mutant animals. Thus, an augmented level of D-serine resulting from reduced DAO activity promotes adaptive learning in response to changing conditions. The NMDAR glycine site and DAO may be promising therapeutic targets to improve cognitive flexibility and inhibitory learning in psychiatric disorders such as schizophrenia and anxiety syndromes.
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PMID:Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice. 1911 14


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