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)

Compared to healthy controls, unmedicated schizophrenic patients had significantly higher plasma concentrations of taurine, methionine, valine, isoleucine, leucine, phenylalanine, and lysine. Except for taurine, these amino acids share the L-transport system for neutral amino acids. In the patients, homovanillic (HVA) acid levels in CSF were decreased and the plasma levels of the amino acids competing with tyrosine and tryptophan for transport into the brain, were all negatively correlated to the CSF concentrations of HVA and 5-HIAA. These findings could be explained by a change in the affinity of the L-system or by a decrease in its overall capacity in schizophrenia. Raised plasma levels of the competing amino acids may limit the brain uptake of tyrosine, leading to a diminished dopamine turnover, and resulting in a compensatory development of supersensitive dopamine receptors.
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PMID:Plasma amino acids in relation to cerebrospinal fluid monoamine metabolites in schizophrenic patients and healthy controls. 241 98

Among the biochemical theories proposed for schizophrenia the best-founded appears to be the dopaminergic theory. Dopaminergic agonists exacerbate schizophrenic symptoms. Neuroleptics, which are the most effective drugs in schizophrenia, are dopaminergic-blocking agents. Other biochemical disorders have been demonstrated in some cases of schizophrenia but results are not always consonant. The presence of abnormal compounds, i.e. methylated derivatives or phenylethylamine, has often been mentioned. Several disorders of enzymes have also been reported, such as a defect in beta-dopamine hydroxylase or an abnormal activity of the MAO which metabolizes the indolamines and catecholamines. Disorders of the metabolism of noradrenaline and serotonin have also been suggested, mainly on experimental evidence. Other compounds have been incriminated, such as endorphins, gamma-aminobutyric acid, lysine-8 vasopressin or prostaglandins. The action of neuroleptics can be ascribed to dopaminergic respector blockade, as a safe approximation. However, the demonstration of several dopaminergic pathways and of several types of receptors makes the understanding of their mode of action all the more difficult that they interplay with many other neurotransmittors.
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PMID:[Biochemistry of schizophrenia and mechanism of action of neuroleptics]. 613 Jun 4

Sixteen out of 19 patients suffering from chronic anergic schizophrenia completed a placebo-controlled cross-over study with lysine-8-vasopressin (LVP), following a schedule of 1 week of placebo, 3 weeks of LVP, starting with 22.5 IU/day, gradually increased to 67.5 IU/day, and finally 4 weeks of placebo. The psychic state was evaluated with the Brief Psychiatric Rate Scale (BPRS), during weekly live interviews, and following videotaped BPRS interviews at the beginning and end of the LVP period, and at the end of the final placebo period. Symptoms of parkinsonism and tardive dyskinesia were also videotaped during a standardized examination at the same intervals. The videotapes were subsequently randomized and evaluated blindly. The results of liver interviews showed a significant (P less than 0.05) decrease in the BPRS anergic factor after 2 and 3 weeks of LVP treatment, but there were no changes in any single item, other BPRS factors, or the BPRS total score. The results of the videotape evaluations showed that the BPRS thinking disorder factor was significantly (P less than 0.05) decreased after 3 weeks of LVP, whereas the BPRS score was unchanged. No consistent changes in parkinsonism or tardive dyskinesia were found. Although side effects were few, six patients became agitated or aggressive during the LVP treatment. The beneficial effect on thought disorder and anergia, but the absence of global effects on the schizophrenic syndrome, illustrates the need for further research with other vasopressin analogues. The advantages and disadvantages of live and videotaped psychiatric interviews are also discussed.
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PMID:Vasopressin in anergic schizophrenia. A cross-over study with lysine-8-vasopressin and placebo. 679 86

Exposure of food proteins to certain processing conditions induces two major chemical changes: racemization of all L-amino acids to D-isomers and concurrent formation of cross-linked amino acids such as lysinoalanine. Racemization of L-amino acids residues to their D-isomers in food and other proteins is pH-, time-, and temperature-dependent. Although racemization rates of the 18 different L-amino acid residues in a protein vary, the relative rates in different proteins are similar. The diet contains both processing-induced and naturally formed D-amino acids. The latter include those found in microorganisms, plants, and marine invertebrates. Racemization impairs digestibility and nutritional quality. The nutritional utilization of different D-amino acids varies widely in animals and humans. In addition, some D-amino acids may be both beneficial and deleterious. Thus, although D-phenylalanine in an all-amino-acid diet is utilized as a nutritional source of L-phenylalanine, high concentrations of D-tyrosine in such diets inhibit the growth of mice. Both D-serine and lysinoalanine induce histological changes in the rat kidney. The wide variation in the utilization of D-amino acids is illustrated by the fact that whereas D-methionine is largely utilized as a nutritional source of the L-isomer, D-lysine is totally devoid of any nutritional value. Similarly, although L-cysteine has a sparing effect on L-methionine when fed to mice, D-cysteine does not. Because D-amino acids are consumed by animals and humans as part of their normal diets, a need exists to develop a better understanding of their roles in nutrition, food safety, microbiology, physiology, and medicine. To contribute to this effort, this multidiscipline-oriented overview surveys our present knowledge of the chemistry, nutrition, safety, microbiology, and pharmacology of D-amino acids. Also covered are the origin and distribution of D-amino acids in the food chain and in body fluids and tissues and recommendations for future research in each of these areas. Understanding of the integrated, beneficial effects of D-amino acids against cancer, schizophrenia, and infection, and overlapping aspects of the formation, occurrence, and biological functions of D-amino should lead to better foods and improved human health.
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PMID:Chemistry, nutrition, and microbiology of D-amino acids. 1055 72

Recently a new variant of Creutzfeldt-Jakob disease, a human prion disease, with prominent psychiatric manifestations in the early stage was identified, suggesting that human prion disease may be associated with mental disorders. Furthermore, a novel missense mutation with asparagine-to-serine substitution at codon 171 of the human prion gene (N171S) was identified in a family with severe psychiatric symptoms. This finding provides further clue that the prion gene may be a susceptibility gene for certain psychiatric disorders. We systematically sequenced the protein-coding and untranslated exons of prion gene in 62 Han Chinese schizophrenic patients with positive family history from Taiwan. We identified two polymorphisms that alter amino acid sequences, a methionine/valine at codon 129 (M129V) and a glutamate/lysine at codon 219 (E219K), respectively. Further comparison of the genotype, allele and haplotype frequency distributions of these two polymorphisms between 234 schizophrenic patients and 100 non-psychotic controls, however, did not reveal significant differences between two groups. Besides, no other mutations in the prion gene were identified in these 62 patients. Hence, our results suggest that the prion gene may not play a major role in conferring susceptibility to schizophrenia.
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PMID:Lack of evidence to support the association of the human prion gene with schizophrenia. 1124 88

Glutamatergic signaling is regulated, in part, through differential expression of NMDA and AMPA/KA channel subunits and G protein-coupled metabotropic receptors. In human brain, region-specific expression patterns of glutamate receptor genes are maintained over the course of decades, suggesting a role for molecular mechanisms involved in long-term regulation of transcription, including methylation of lysine residues at histone N-terminal tails. Using a native chromatin immunoprecipitation assay, we studied histone methylation marks at proximal promoters of 16 ionotropic and metabotropic glutamate receptor genes (GRIN1,2A-D; GRIA1,3,4; GRIK2,4,5; GRM1,3,4,6,7 ) in cerebellar cortex collected across a wide age range from midgestation to 90 years old. Levels of di- and trimethylated histone H3-lysine 4, which are associated with open chromatin and transcription, showed significant differences between promoters and a robust correlation with corresponding mRNA levels in immature and mature cerebellar cortex. In contrast, levels of trimethylated H3-lysine 27 and H4-lysine 20, two histone modifications defining silenced or condensed chromatin, did not correlate with transcription but were up-regulated overall in adult cerebellum. Furthermore, differential gene expression patterns in prefrontal and cerebellar cortex were reflected by similar differences in H3-lysine 4 methylation at promoters. Together, these findings suggest that histone lysine methylation at gene promoters is involved in developmental regulation and maintenance of region-specific expression patterns of ionotropic and metabotropic glutamate receptors. The association of a specific epigenetic mark, H3-(methyl)-lysine 4, with the molecular architecture of glutamatergic signaling in human brain has potential implications for schizophrenia and other disorders with altered glutamate receptor function.
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PMID:Histone methylation at gene promoters is associated with developmental regulation and region-specific expression of ionotropic and metabotropic glutamate receptors in human brain. 1599 84

Alterations in GABAergic mRNA expression play a key role for prefrontal dysfunction in schizophrenia and other neurodevelopmental disease. Here, we show that histone H3-lysine 4 methylation, a chromatin mark associated with the transcriptional process, progressively increased at GAD1 and other GABAergic gene promoters (GAD2, NPY, SST) in human prefrontal cortex (PFC) from prenatal to peripubertal ages and throughout adulthood. Alterations in schizophrenia included decreased GAD1 expression and H3K4-trimethylation, predominantly in females and in conjunction with a risk haplotype at the 5' end of GAD1. Heterozygosity for a truncated, lacZ knock-in allele of mixed-lineage leukemia 1 (Mll1), a histone methyltransferase expressed in GABAergic and other cortical neurons, resulted in decreased H3K4 methylation at GABAergic gene promoters. In contrast, Gad1 H3K4 (tri)methylation and Mll1 occupancy was increased in cerebral cortex of mice after treatment with the atypical antipsychotic, clozapine. These effects were not mimicked by haloperidol or genetic ablation of dopamine D2 and D3 receptors, suggesting that blockade of D2-like signaling is not sufficient for clozapine-induced histone methylation. Therefore, chromatin remodeling mechanisms at GABAergic gene promoters, including MLL1-mediated histone methylation, operate throughout an extended period of normal human PFC development and play a role in the neurobiology of schizophrenia.
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PMID:Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters. 1794 19

Alterations in RNA levels are frequently reported in brain of subjects diagnosed with autism, schizophrenia, depression, and other psychiatric diseases, but it remains unclear whether the underlying molecular pathology involves changes in gene expression, as opposed to alterations in messenger RNA processing. Pre-clinical studies have revealed that stress, drugs, and a variety of other environmental factors lead to changes in RNA levels in brain via epigenetic mechanisms, including modification of histone proteins. A number of site-specific modifications of the nucleosome core histones-including the trimethylated forms of histone H3 lysines K4, K9, and K27-are of particular interest for postmortem research, because these marks differentiate between active and inactive chromatin and seem to remain relatively stable during tissue autolysis. Therefore, histone methylation profiling at promoter regions could provide important clues about mechanisms of gene expression in human brain during development and in disease. Intriguingly, mutations within the genes encoding the H3K9-specific methyltransferase, EHMT1, and the H3K4-specific histone demethylase, JARID1C/SMCX, have been linked to mental retardation and autism, respectively. In addition, the H3K4-specific methyltransferase, MLL1, is essential for hippocampal synaptic plasticity and might be involved in cortical dysfunction of some cases of schizophrenia. Together, these findings emphasize the potential significance of histone lysine methylation for orderly brain development and also as a molecular toolbox to study chromatin function in postmortem tissue.
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PMID:Epigenetic regulation in human brain-focus on histone lysine methylation. 1881 64

It has been difficult to identify disease-causing alleles in schizophrenia (SZ) and bipolar disorder (BD) candidate genes. One reason is that responsible functional variants may exist in unidentified regulatory domains. With the advent of microarray technology and high throughput sequencing, however, it is now feasible to screen genes for such regulatory domains relatively easily by using chromatin immunoprecipitation-based methodologies, such as ChIP-chip and ChIP-seq. In ChIP-chip, regulatory sequences can be captured from chromatin immunoprecipitates prepared with antibodies against covalently modified histones that mark certain regulatory domains; DNA extracted from such immunoprecipitates can then be used as microarray probes. As a first step toward demonstrating the feasibility of this approach in psychiatric genetics, we used ChIP-chip to identify regulatory domains in several candidate genes: NRG1, DTNBP1, DISC1, DAO, DAOA, PDE4B, and COMT. Immunoprecipitates were generated with antibodies to histone H3 acetylated at lysine 9 (H3K9Ac) and histone H3 monomethylated at lysine 4 (H3K4me1), which mark promoters and some enhancers, using fetal brain chromatin as a substrate. Several novel putative regulatory elements, as well as the core and proximal promoters for each gene, were enriched in the immunoprecipitates. Genetic variants within these regions would be of interest to study as potential disease-associated alleles.
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PMID:Survey of schizophrenia and bipolar disorder candidate genes using chromatin immunoprecipitation and tiled microarrays (ChIP-chip). 1922 52

Studies of peripheral blood leukocytes of schizophrenic patients have shown in electron microscopy (EM) that decondensation of the chromatin constitutes a biological marker indicating increased genomic expression. Since this increase depends on chromatin relaxation by dissociation of lysine-rich histone H1 from nucleosomes, with exposure of arginine residues of core histones, the ratio of arginine to lysine residues in each nucleus represents a reliable measure of activation. Lysine- and arginine-rich proteins are demonstrable in light microscopy (LM), differentially, as yellow and black, respectively, with the ammoniacal silver reaction (ASR). Application of ASR on leukocyte pellets before they are dehydrated and embedded in epoxy resins gives reliable results in semithin sections. In thin sections the ASR method localizes only the amino acid arginine by forming deposits of electron-opaque particles, visualized in the EM. Leukocytes of 12 first-episode schizophrenic patients and 5 controls were used. Light micrographs of the semithin sections were inserted in a personal computer. The percentage of lysine and arginine was measured in 300 nuclei per subject. Morphometry showed that lymphocytes of schizophrenic patients have increased ratios of arginine to lysine, compared to controls, indicating activation; neutrophils of the patients have even a higher ratio, indicating an abnormal condition of the genome. Chromatin conformational changes are also evident by phosphotungstic acid hematoxylin (PTAH) block staining, which reveals condensed chromatin as an electron-lucent area in the nuclei, and decondensed chromatin as an electron-dense area. Because decondensed chromatin is a biological marker of schizophrenia, the efficacy of these methods to demonstrate this particular state offers a tool for early diagnosis, since first-episode schizophrenic patients have a better prognosis when treatment is started promptly, at the beginning of the disease.
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PMID:Chromatin alterations in leukocytes of first-episode schizophrenic patients. 2045 59


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