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

A statistically significant association between a silent mutation (102T/C) in the serotonin-2A (5-HT2A) receptor gene and schizophrenia has recently been reported in a sample of Japanese patients and healthy controls. This finding suggests that genetic predisposition to schizophrenia may be affected by a functional 5-HT2A receptor variant that is in linkage disequilibrium with 102T/C. In the present study, we have sought to identify genetic variation in the 5-HT2A receptor gene by screening genomic DNA samples from 91 unrelated subjects comprising 45 patients with schizophrenia and 46 healthy controls by using single-strand conformation analysis. We have identified four nucleotide sequence variants. Two sequence changes would result in protein alterations: a substitution of threonine by asparagine at position 25 (Thr25Asn), and a substitution of histidine by tyrosine at position 452 (His452Tyr). In order to test for a possible contribution to the development of schizophrenia, we have determined allele frequencies in extended samples of unrelated patients and healthy controls. The two amino acid substitutions are found with similar frequencies in patients and controls, indicating that the presence of these variants is not causally related to the development of schizophrenia. However, the reported association of the non-coding polymorphism 102T/C with the disease has also been detected in our sample (P=0.041, odds ratio=1.28, 95% confidence interval 1.012-1.623).
 ...
PMID:Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia. 865 41

We have measured the concentrations of glycine and its potential precursors, serine and threonine, in 20 areas of the postmortem brains of chronic schizophrenics and controls using high-performance liquid chromatography by pre-column derivatization with dimethyl-amino-azobenzene sulphonyl chloride. The regional distribution pattern of glycine in the postmortem brains with and without the disease was more similar to that of serine (r = 0.874, P < 0.0001) than to that of threonine (r = 0.476, P < 0.01). A multiple regression analysis with regressor variables including diagnosis, age at death and interval between death and freezing revealed that there is a significant difference between schizophrenics and controls in the contents of these amino acids in a number of brain areas. The level of glycine in the orbitofrontal cortex of schizophrenics was found to be significantly increased in schizophrenics, with a tendency to an increase in that of serine. The increase in glycine was also significantly high in the off-drug group of schizophrenics who had not taken antipsychotics more than 40 days before death. Prominent decreases in both glycine and serine were observed in the somesthetic cortex of the on-drug schizophrenics. Serine was found to be significantly decreased in the putamen of the off-drug schizophrenics. A marked decrease in threonine was also observed in the supramarginal cortex and posterior portion of the lateral occipitotemporal cortex of the off-drug group of schizophrenics and in the putamen of all schizophrenics. The highly similar distribution pattern of glycine and serine in the postmortem brains supports the close coupling of synthesis and metabolism between these chemicals in human brains. The increased content of glycine in the orbitofrontal cortex, the reduced level of serine in the putamen and the decrease in threonine in the cerebral cortices, which were prominent in the off-drug schizophrenics, may be involved in the pathophysiology of schizophrenia.
 ...
PMID:A postmortem study of glycine and its potential precursors in chronic schizophrenics. 888 82

Synapsin III is a new synapsin family gene with the putative function of synaptogenesis regulation and neurotransmitter release in the brain. The gene was mapped to 22q12-q13, a schizophrenia susceptible region gene as suggested by several linkage studies. Hence, the synapsin III gene is considered a candidate gene of schizophrenia. We systematically sequenced the protein coding and 5'-promoter regions of the synapsin III gene to look for mutations in 62 Han Chinese schizophrenic patients from Taiwan with positive family history. Further case-control association study was performed among 163 patients and 151 controls using the genetic polymorphic markers identified from these 62 patients. Three single nucleotide polymorphisms (SNPs) were identified: g.-631C > G and g.-196G>A at 5'-promoter region, and g.69G>A at exon 1. Besides, no other mutations were identified in these patients. The g.69G>A polymorphism does not alter the amino acid threonine at codon 23 (ACG>ACA). Further case-control association studies also did not find significant differences of genotype or allele frequency distributions of these three polymorphisms between 163 patients and 151 non-psychotic comparison individuals. Hence, our data are not in favor of a large effect of synapsin III gene in the pathogenesis of schizophrenia.
 ...
PMID:Mutation analysis of synapsin III gene in schizophrenia. 1184 May 10

Increased cerebrospinal fluid (CSF) tau protein levels are generally considered to provide a sensitive marker of neurodegenerative processes such as Alzheimer's disease (AD). Since a more pronounced cognitive decline has been described in older schizophrenic patients, it has been hypothesized that these patients might be at a higher risk of developing AD. CSF levels of total tau protein and tau protein phosphorylated at threonine 181 (phospho-tau) were determined among 19 older and younger patients with schizophrenia compared to 20 age-matched healthy controls. No significant differences in CSF total tau and phospho-tau levels arose between patients with schizophrenia and controls. Although our results do not exclude a progressive neurodegenerative pathology, they provide evidence against major neuronal degeneration such as an AD-related pathology associated with increased tau levels in schizophrenia.
 ...
PMID:Cerebrospinal fluid tau protein levels in schizophrenia. 1279 49

5-HT(2A) serotonin receptors represent the principal molecular targets for LSD-like hallucinogens and atypical antipsychotic drugs. It has been proposed that a dysregulation of 5-HT(2A) receptor-mediated signaling may contribute to the pathogenesis of schizophrenia and related diseases. A major mechanism for the attenuation of GPCR signaling following agonist activation typically involves the phosphorylation of serine and/or threonine residues by various kinases. Ser/Thr phosphorylation leads to the binding of accessory proteins and the uncoupling of the G proteins, thereby preventing further signaling. The molecular mechanisms by which 5-HT(2A) receptors are desensitized are unknown, and to date, no residues essential for agonist-mediated desensitization have been identified. Thus, we mutated, individually or in groups, all of the 37 serines and threonines in the cytoplasmic domains of the 5-HT(2A) receptor and assessed the effects of these mutations on agonist-mediated desensitization. We discovered that mutation of two residues, S421 in the C-terminal tail and S188 in the second intracellular loop, to alanine resulted in a significant block of agonist-induced desensitization. Intriguingly, a single-nucleotide polymorphism, of unreported frequency, at the S421 locus has been reported (S421F); the S421F mutation, like the S421A mutation, significantly attenuated agonist-mediated desensitization. Taken together, these findings indicate that the process of agonist-mediated desensitization of 5-HT(2A) receptors requires the presence of two nonconserved serine residues located in distinct intracellular loops.
 ...
PMID:Identification of two serine residues essential for agonist-induced 5-HT2A receptor desensitization. 1296 10

We have previously reported a changed mitochondrial (mt) gene expression in brain from patients with schizophrenia [Schizophr. Res. 14 (1995) 203]; now, we describe the distribution in the mtDNA from lymphocytes of a heteroplasmic sequence variation that was originally found in the mtDNA from the postmortem brain of a patient with schizophrenia. The variant is m.12027T>C and results in the change from isoleucine to threonine at position 423 of the ND4 subunit of NADH-ubiquinone reductase. Using a PCR-RFLP method, we have determined the heteroplasmy as the ratio of variant to total (variant ratio) at m.12027 in 184 controls and 181 patients with schizophrenia as well as 24 postmortem brain samples. The distribution of variants is bimodal having peaks at variant ratios of 0.262 and 0.732. The variant-rich fraction is very significantly associated with schizophrenia in males (47%), while there is only 18% in control males. There are significantly more variant-rich control females (36%) than control males (18%), suggesting that the female population is less sensitive to the presence of a variant in terms of liability to schizophrenia. In variant-rich samples from postmortem brain originating from both sexes, there is an increased superoxide production, suggesting that the variation contributes to oxidative stress. Antioxidant glycosides, such as quercetin rutoside, quench the superoxide production without (in contrast to neuroleptic drugs) interfering with the electron transfer activity of the reductase.
 ...
PMID:A mitochondrial DNA sequence variant associated with schizophrenia and oxidative stress. 1462 72

Calcineurin, one of the serine/threonine protein phosphatase, comprises more than 1% of the total protein content in brain. This evidence points towards important roles of calcineurin in neural function. Miyakawa et al. reported that forebrain-specific calcineurin knockout mice showed the behavioral abnormalities that are often observed in schizophrenia patients. Based on this evidence, they suggested that calcineurin dysfunction could be involved in schizophrenia pathogenesis. Thereafter this report, Gerber et al. performed transmission disequilibrium test (TDT) studies and showed an evidence for a nominally significant over-transmission of a common haplotype of the human calcineurin A gamma subunit gene (PPP3CC). We performed association analysis of PPP3CC in Japanese sample of 457 schizophrenia cases and 429 controls. To our regret, we could not confirm the association with Japanese schizophrenia to PPP3CC including core at-risk haplotype. Our result suggests that PPP3CC may not play a major role in Japanese schizophrenia.
 ...
PMID:No association with the calcineurin A gamma subunit gene (PPP3CC) haplotype to Japanese schizophrenia. 1584 70

We identified CAT 53 by cDNA hybridization selection as an expressed sequence tag (EST), located in the vicinity of HLA-C and designated as CAT (for HLA-C associated transcript) 53. CAT 53 encodes a protein described by others and commonly known as phosphatase 1 nuclear targeting subunit (PNUTS). PNUTS is a potent inhibitor of nuclear serine/threonine protein phosphatase 1 (PP1). We present the genomic organization of CAT 53, localize specific sites of mRNA transcription in thin sections of mouse brain by in-situ hybridization, and perform a structural analysis of the peptide domains. We also characterize the protein expression pattern for PNUTS by Western blotting and immunohistochemistry with PNUTS antibody in Alzheimer's disease (AD) brains and age-matched control brains. In-situ hybridization and immunohistochemistry analysis of human and mouse brain show high CAT 53 expression in the olfactory cortex, piriform cortex, and hippocampus. Very high expression of CAT 53 was found mainly in the hippocampus, frontal, and entorhinal cortex of control brains and in the neurofibrillary tangles of AD brain. In the hippocampus, CAT 53 is expressed in CA1 and CA3 cell layers and in the dentate gyrus. The hippocampus is known to play a fundamental role in learning and episodic memories and has been implicated in a number of neurological and psychiatric disorders, including AD, epilepsy, and schizophrenia. Our findings suggest that PNUTS, encoded by CAT 53 on 6p21.3, may have a role in the progression of AD.
 ...
PMID:CAT 53: a protein phosphatase 1 nuclear targeting subunit encoded in the MHC Class I region strongly expressed in regions of the brain involved in memory, learning, and Alzheimer's disease. 1589 2

Calcineurin (CaN), also designated as protein phosphatase 2B, is a major Ca2+/calmodulin-binding protein in the brain and the only serine/threonine phosphatase under the control of Ca2+/calmodulin. CaN activity has been implicated in downstream regulation of dopaminergic signal transduction and in NMDA receptor-dependent synaptic plasticity. Thus, it serves as a point of convergence for the abnormalities of these two neurotransmitter systems in schizophrenia. The aim of the present study was to determine if levels of CaN were altered in two schizophrenia- and CaN-related brain regions--the dorsolateral prefrontal cortex and hippocampus from subjects with schizophrenia compared to that in tissue from age and sex matched controls. CaN protein levels were measured by Western-blot analysis in samples from 15 schizophrenia patients vs. 15 control subjects. No significant differences in CaN protein levels were found either in the prefrontal cortex or in the hippocampus of schizophrenia patients compared to matched control subjects. Our result of lack of difference does not support the concept that brain CaN levels are a pathophysiological factor in this disorder. Further studies with antibodies against specific CaN catalytic subunit isoforms (presently unavailable) are required to resolve this issue.
 ...
PMID:Postmortem brain calcineurin protein levels in schizophrenia patients are not different from controls. 1646 Sep 15

Dopamine- and cyclic AMP-regulated phosphoprotein with a relative molecular weight of 32 kDa (DARPP-32) plays an important role in integrating information of about several neurotransmitters arriving at dopaminoceptive neurons. DARPP-32 is phosphorylated by dopamine D1 receptor at threonine 34 and converted to an inhibitor of protein phosphatase I. It facilitates the phosphorylation of several neurotransmitter receptors, including N-methyl-D-aspartic acid (NMDA)- and alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA)-type glutamate receptors and gamma-aminobutyric acid (GABA)A receptors. In contrast, D2 receptor stimulation induces dephosphorylation of DARPP-32, which results in dephosphorylation of the glutamate and GABAA receptors. Thus, phosphorylation and dephosphorylation of DARPP-32 regulates the functions of neurotransmitter systems. Recent studies from our laboratory and elsewhere have demonstrated that the amount of DARPP-32 in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia is lower than that in the DLPFC of control subjects. Thus, it is plausible that DARPP-32 is associated with the concurrent alterations in dopamine, glutamate, and GABA neurotransmitter systems in subjects with schizophrenia. We have also found reduced levels of DARPP-32 in the DLPFC of subjects with bipolar disorder. Thus, it is important to elucidate the role of DARPP-32 in the pathophysiology of schizophrenia and bipolar disorder.
 ...
PMID:[DARPP-32 in the patients with endogenous psychosis]. 1804 3


1 2 3 4 Next >>