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)

Covalent modifications of DNA and its surrounding chromatin constitute an essential and powerful regulatory mechanism for gene transcription. Epigenetics is the study of this regulatory system. There is now strong albeit indirect evidence that epigenetic mechanisms contribute to the pathophysiology of schizophrenia. Furthermore, the discovery that valproic acid, a widely used psychotropic, has powerful epigenetic effects in clinically relevant concentrations suggests new therapeutic possibilities, i.e., drugs that act on chromatin structure. Fortunately, many proteins engaged in these processes, particularly chromatin remodeling, are accessible to pharmacological agents that have a high likelihood of crossing the blood brain barrier. This review will first summarize the essentials of the epigenetic regulatory system, then address the molecular evidence for altered epigenetic mechanisms in schizophrenia, and finally focus on the retinoic acid family of ligand-activated nuclear transcription factors as a likely system for new drug development in the management of schizophrenia-related symptoms.
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PMID:Schizophrenia, epigenetics and ligand-activated nuclear receptors: a framework for chromatin therapeutics. 1556 Sep 54

Mounting evidence suggests that schizophrenia is a neurodevelopmental disease resulting in dysfunctional connectivity between various brain regions. Retinoid pathway dysregulation has been proposed as a potentially important factor in the etiology of schizophrenia. Retinoid signaling plays a central role in many aspects of development, ranging from neurogenesis to activity-dependent plasticity, and regulates the expression of many candidate genes for schizophrenia. The retinoid pathway acts through two families of nuclear receptors highly expressed in the hippocampus, the retinoic acid (RAR) and retinoid X (RXR) receptors, both existing in three different subtypes (alpha, beta and gamma) and several isoforms. The present study examines the expression of the retinoid receptors in the dentate gyrus of schizophrenia and nonpsychiatric controls. The proportion of granule cells of the dentate gyrus expressing RAR(alpha) is increased by twofold in schizophrenia, while the proportion of cells expressing RAR(gamma)1 and 2, as well as RXR(beta) and gamma, is unchanged. These results demonstrate a dysregulation in the expression of at least one member of the RAR family of retinoid receptors in schizophrenia. Understanding the basis for this and how it affects downstream molecular pathways associated with hippocampal plasticity may provide insight into the dysfunctional connectivity of schizophrenia.
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PMID:The expression of retinoic acid receptor alpha is increased in the granule cells of the dentate gyrus in schizophrenia. 1569 73

Vitamin A (all-trans-retinol) is the parent compound of a family of natural and synthetic compounds, the retinoids. Retinoids regulate gene transcription in numerous cells and tissues by binding to nuclear retinoid receptor proteins, which act as transcription factors. Much of the research conducted on retinoid signalling in the nervous system has focussed on developmental effects in the embryonic or early postnatal brain. Here, we review the increasing body of evidence indicating that retinoid signalling plays an important role in the function of the mature brain. Components of the metabolic pathway for retinoids have been identified in adult brain tissues, suggesting that all-trans-retinoic acid (ATRA) can be synthesized in discrete regions of the brain. The distribution of retinoid receptor proteins in the adult nervous system is different from that seen during development; and suggests that retinoid signalling is likely to have a physiological role in adult cortex, amygdala, hypothalamus, hippocampus, striatum and associated brain regions. A number of neuronal specific genes contain recognition sequences for the retinoid receptor proteins and can be directly regulated by retinoids. Disruption of retinoid signalling pathways in rodent models indicates their involvement in regulating synaptic plasticity and associated learning and memory behaviours. Retinoid signalling pathways have also been implicated in the pathophysiology of Alzheimer's disease, schizophrenia and depression. Overall, the data underscore the likely importance of adequate nutritional Vitamin A status for adult brain function and highlight retinoid signalling pathways as potential novel therapeutic targets for neurological diseases.
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PMID:Role of retinoid signalling in the adult brain. 1588 77

Phenotypic discordance for schizophrenia in monozygotic twins clearly indicates involvement of environmental factors as key determinants in disease development. Positive findings from genome scans, linkage and association studies apply in only a minority of those affected, while post-mortem brain investigations reveal altered expression of genes and proteins involved in numerous neurodevelopmental, metabolic and neurotransmitter pathways. Such altered expressions could result, on the one hand, from mutations in coding regions or polymorphisms in the promoter and regulatory regions in genes within those areas identified by gene searches or, on the other hand, from inadequate amounts of modulators, transporters and synthesizers of transcription factors necessary for regulation of the putative genes. Hormones and vitamins are such modulators. They could serve as bridges between genes and environment in schizophrenia. Multiple evidence supports the suggestion of retinoids and thyroid hormones as plausible actors in these roles. Both are not only essential for normal development of the central nervous system but also regulate the expression of many neurotransmitters, their synthesizing enzymes and receptors, and other genes in broader signaling transduction cascades affecting pathways that are altered in response to treatment. Functional and positional candidate genes include retinoic acid and thyroid hormone receptors, retinaldehyde dehydrogenases and deiodinases, which synthesize the powerful morphogens, retinoic acid and triiodothyronine, and the enzymes involved in their inactivation. This review highlights selective evidence supporting the retinoid and thyroid hormone hypotheses of schizophrenia.
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PMID:Thyroid hormones and retinoids: a possible link between genes and environment in schizophrenia. 1632 58

Schizophrenia is associated with a number of pathological changes, including alterations in levels of specific proteins. Calprotectin is a novel 36 kDa calcium-binding protein of the S100 family and appears to be a nonspecific marker of inflammation. Calprotectin has not previously been investigated in brain tissue. Samples of post-mortem brain tissue from Brodmann area 9 were obtained from prefrontal cortex from subjects with schizophrenia, bipolar affective disorder, major depression, and from controls. Calprotectin levels were determined by ELISA. To determine cellular localization, immunocytochemical and fluorescent double-labelling analyses were performed. Exogenous calprotectin was added to retinoic acid-differentiated human SH-SY5Y neuroblastoma cell cultures in order to investigate mechanisms of action of calprotectin. Calprotectin was detectable in all samples, and mean levels were noted to be highest in schizophrenic brains (P < 0.05) and lowest in controls. Levels were intermediate in bipolar affective disorder and major depression. Exogenous calprotectin appeared to induce dendritic extension in SH-SY5Y cell culture in a dose-dependent manner. Calprotectin was found to be localized to microglia. These findings suggest that increased levels of calprotecitn in the brain may reflect inflammatory processes, which play a role in the pathogenesis of major psychiatric disorders. Furthermore, calprotectin may influence dendritic plasticity.
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PMID:Calprotectin in microglia from frontal cortex is up-regulated in schizophrenia: evidence for an inflammatory process? 1722 4

Abnormalities of striatal dopaminergic neurotransmission play a significant role in the pathophysiology of central nervous system disorders such as movement disorders, addictions and schizophrenia. The striatum appears to be exposed to intrinsically high levels of oxidative stress (OS). Little is known, however, on the effect of OS on the regulation of the dopamine D2 receptor (DRD2), a key component of striatal dopaminergic neurotransmission. We report here on the effects of H2O2 (a canonical oxidant and non conventional messenger) and polyinosinic-polycytidylic acid (poly(IC) which elicits schizophrenia-like behaviors in newborn rodents and disrupts dopaminergic system development), on DRD2 levels in retinoic acid differentiated SH-SY5Y neuroblastoma. H2O2 elicited a significant increase in DRD2 mRNA and protein levels. Conversely, poly(IC) did not regulate DRD2 levels, although SH-SY5Y cells were confirmed to express TLR3 receptors. Under our conditions, H2O2, but not poly(IC), increased NFkappaB activation (as assessed by p65 nuclear translocation), which paralleled their effects on DRD2 levels regulation.
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PMID:Subacute H2O2, but not poly(IC), upregulates dopamine D2 receptors in retinoic acid differentiated SH-SY5Y neuroblastoma. 1796 Jul 67

The dystrobrevin-binding protein 1 (DTNBP1) gene has been one of the most studied and promising schizophrenia susceptibility genes since it was first reported to be associated with schizophrenia in the Irish Study of High Density Schizophrenia Families (ISHDSF). Although many studies have been performed both at the functional level and in association with psychiatric disorders, there has been no systematic review of the features of the DTNBP1 gene, protein or the relationship between function and phenotype. Using a bioinformatics approach, we identified the DTNBP1 gene in 13 vertebrate species. The comparison of these genes revealed a conserved gene structure, protein-coding sequence and dysbindin domain, but a diverse noncoding sequence. The molecular evolutionary analysis suggests the DTNBP1 gene probably originated in chordates and matured in vertebrates. No signature of recent positive selection was seen in any primate lineage. The DTNBP1 gene likely has many more alternative transcripts than the current three major isoforms annotated in the NCBI database. Our examination of risk haplotypes revealed that, although the frequency of a single nucleotide polymorphism (SNP) or haplotype might be significantly different in cases from controls, difference between major geographic populations was even larger. Finally, we constructed the first DTNBP1 interactome and explored its network features. Besides the biogenesis of lysosome-related organelles complex 1 and dystrophin-associated protein complex, several molecules in the DTNBP1 network likely provide insight into the role of DTNBP1 in biological systems: retinoic acid, beta-estradiol, calmodulin and tumour necrosis factor. Studies of these subnetworks and pathways may provide opportunities to deepen our understanding of the mechanisms of action of DTNBP1 variants.
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PMID:The dystrobrevin-binding protein 1 gene: features and networks. 1866 67

Retinoic acid (Ra) is crucial for the patterning and neuronal differentiation in the central nervous system (CNS). Ra deficiency in animals disrupts the motor activities and memory abilities. The molecular mechanisms underlying these behavior abnormalities remain largely unknown. In the current study, we treated the astrocytoma cells with citral, an inhibitor of Ra synthesis. We analyzed the differences in the protein concentrations between the treated and untreated astrocytoma cells by two-dimensional gel electrophoresis (2-DE), Imagemaster software, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). In total, 39 of 46 altered protein spots with significant mascot scores were identified representing 36 proteins, that were involved in significantly altered glutamate metabolism, lipid metabolism, mitochondrial function, and oxidative stress response by Ingenuity Pathway Analysis (IPA). Altered 3-phosphoglycerate dehydrogenase (PHGDH) was also observed in western blot. These data provide some clues for explaining the behavioral changes caused by Ra deficiency, and support the hypothesis that Ra signaling is associated with some symptoms of neurodegenerative disorders and schizophrenia.
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PMID:Proteome alteration of U251 human astrocytoma cell after inhibiting retinoic acid synthesis. 1908 18

Vitamin A (retinol), in the biologically active form of retinoic acid (RA), has been proposed as involved in the pathogenesis of schizophrenia. We hypothesized that genetic basis of genes encoding RA metabolism enzymes, which control the cellular RA level, might be associated with this disease. This cascade genetic association model, using markers in genes of synthesis and degradation enzymes within the retinoid cascade, would better fit the biological character of the retinoid hypothesis than the single gene strategy. In the present study we chose to investigate 7 genes involved in the synthesis, degradation and transportation of RA, ALDH1A1, ALDH1A2, ALDH1A3, CYP26A1, CYP26B1, CYP26C1 and Transthyretin (TTR), for their roles in the development of schizophrenia. We genotyped 18 single nucleotide polymorphisms (SNPs) in the regulatory and coding regions of these 7 genes using LDR technology in the 617 Chinese Han subjects. Case-control analyses were performed to detect association of these 7 genes with schizophrenia. Association analyses using both allelic and genotypic single-locus tests revealed no significant association between the risk for each of investigated gene and schizophrenia. However, analyses of multiple-locus haplotypes indicated that the overall frequency of rs4646642-rs4646580 of ALDH1A2 gene showed significant difference between patients and control subjects (p=0.0055). We also employed multifactor dimensionality reduction method to detect multilocus effects. In summary, in this work we show multiple candidate genes involved in retinoid cascade in schizophrenics. In addition, our results suggest a positive association between ALDH1A2 and schizophrenics in the Chinese population and support the retinoid hypothesis of schizophrenia.
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PMID:Positive association between ALDH1A2 and schizophrenia in the Chinese population. 1970 8

Human alpha-fetoprotein is a pregnancy-associated protein with an undetermined physiological role. As human alpha-fetoprotein binds retinoids and inhibits estrogen-dependent cancer cell proliferation, and because retinoic acid (a retinol metabolite) and estradiol (an estrogen) can both initiate cellular gene transcription, it is hypothesized here that alpha-fetoprotein functions during critical gestational periods to prevent retinoic acid and maternal estradiol from inappropriately stimulating gene expression in developing brain regions which are sensitive to these chemicals. Prenatal/maternal factors linked to increased autism risk include valproic acid, thalidomide, alcohol, rubella, cytomegalovirus, depression, schizophrenia, obsessive-compulsive disorder, autoimmune disease, stress, allergic reaction, and hypothyroidism. It will be shown how each of these risk factors may initiate expression of genes which are sensitive to retinoic acid and/or estradiol - whether by direct promotion or by reducing production of alpha-fetoprotein. It is thus hypothesized here that autism is not a genetic disorder, but is rather an epigenetic disruption in brain development caused by gestational exposure to chemicals and/or conditions which either inhibit alpha-fetoprotein production or directly promote retinoic acid-sensitive or estradiol-sensitive gene expression. This causation model leads to potential chemical explanations for autistic brain morphology, the distinct symptomatology of Asperger's syndrome, and the differences between high-functioning and low-functioning autism with regard to mental retardation, physical malformation, and sex ratio. It will be discussed how folic acid may cause autism under the retinoic acid/estradiol model, and the history of prenatal folic acid supplementation will be shown to coincide with the history of what is popularly known as the autism epidemic. It is thus hypothesized here that prenatal folic acid supplementation has contributed to the post-1980 increase in US autism diagnoses. In addition to explaining the epidemic within the wider retinoic acid/estradiol model of causation, this theory leads to potential explanations for certain genetic findings in autism, autistic regression, and changing trends in autism symptomatology with regard to mental retardation, wheat allergy, and gastrointestinal problems.
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PMID:A novel embryological theory of autism causation involving endogenous biochemicals capable of initiating cellular gene transcription: a possible link between twelve autism risk factors and the autism 'epidemic'. 2138 46


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