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)

Schizophrenia is a heterogenous disorder that is phenomenologically characterised by a combination of negative, positive, and cognitive symptoms with variable expression in the course of illness. Here, we investigated differential gene expression in relation to age to address the heterogeneity of this disorder We used 6000 gene cDNA microarrays to generate gene expression profiles from peripheral blood lymphocytes from 14 individuals with schizophrenia and 14 non-psychiatric controls. Genes showing altered expression were identified and 18 genes with brain-related functions were altered, 4 of which, endothelial differentiation gene 2 (Edg-2), ezrin-radixin-moesin phosphoprotein 50 (EBP50), Myc-associated zinc finger protein (MAZ) and Tumor Necrosis Factor Receptor 2 (TNFR2), were confirmed by relative real-time PCR. Dendrograms were constructed using genes that showed significantly different expression (p<0.05) between groups based on median split of age dividing the matched pairs into distinct subclasses. Our findings suggest that distinct gene expression profiles in peripheral blood lymphocytes associated with schizophrenia phenotypes may provide a first step towards the biological classification of schizophrenia subtypes. The validity of this approach may lead to better methods of defining this enigmatic disease.
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PMID:Preliminary investigation of gene expression profiles in peripheral blood lymphocytes in schizophrenia. 1641 45

Dopamine- and cAMP-regulated phosphoprotein of relative molecular mass 32kDa (DARPP-32) plays a pivotal role in the signal transduction of several neurotransmitters and neuromodulators that are implicated in the pathophysiology of a variety of neuropsychiatric disorders. A postmortem study reported a significantly reduced DARPP-32 expression in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia, suggesting possible involvement of DARPP-32 in the pathophysiology of schizophrenia. Hence, DARPP-32 was considered as a candidate gene for schizophrenia in this study. We first systemically searched for mutations in the DARPP-32 gene in 50 Han Chinese patients with schizophrenia from Taiwan. Five molecular variants were identified, including a C-to-G substitution (g.-2036C>G) in the putative core promoter that obliterated a predictive AP-2 transcription factor binding site, a G deletion in the untranslated exon 2 (g.1238delG), a G-to-A and an A-to-G substitutions in intron 2 (IVS2+31G>A) and intron 6 (IVS6+32A>G), respectively, and a three-base pair deletion of AGA in exon 6 that resulted in deletion of a glutamate at codon 135 (E135del). Further SNP- and haplotype-based association study in 249 patients and 273 control subjects, however, did not detect association of these markers with schizophrenia. Hence, our results suggest that the reduced DARPP-32 protein in patients with schizophrenia is unlikely caused by mutations in the DARPP-32 gene itself and the DARPP-32 gene is also unlikely a major susceptibility gene for schizophrenia. Nevertheless, the identification of these molecular variants should help the study of gene regulation and structure-function relationship of DARPP-32, and the association study of DARPP-32 gene with other neuropsychiatric disorders.
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PMID:Mutation analysis of DARPP-32 as a candidate gene for schizophrenia. 1675 Sep 3

Aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP have been classified as dopamine D(2) receptor partial agonists based largely on their activity in second messenger-based assays of dopamine D(2) receptor signalling. Nevertheless, signal transduction amplification might result in these compounds behaving as dopamine D(2) receptor full agonists at a more downstream level of signalling. We compared the intrinsic activity (E(max), expressed as a percentage of the maximal effect of dopamine) of aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP using second (calcium (Ca(2+)) mobilization) and third (extracellular signal-regulated kinase 2 (ERK2) phosphoprotein expression) messenger readouts of cloned human dopamine D(2long) (hD(2L)) receptor signalling in CHO cells. These compounds were all less potent and displayed lower intrinsic activity in the Ca(2+) assay (aripiprazole = 24.3%, (+)terguride = 56.9%, OPC-4392 = 58.6% and (-)3-PPP = 75.1%), and aripiprazole (E(max) = 54.5%) displayed a substantially lower intrinsic activity than (+)terguride (E(max) = 92.3%), OPC-4392 (E(max) = 93.1%) and (-)3-PPP (E(max) = 101.1%) in the more downstream-based ERK2 phosphoprotein expression assay. These drug effects on Ca(2+) mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD(2L) receptors, as they all were blocked by (-)raclopride, whereas (-)raclopride and other dopamine D(2) receptor antagonists (haloperidol, risperidone, ziprasidone, olanzapine, clozapine and quetiapine) were inactive on their own in both assays. These data are consistent with clinical evidence that only dopamine D(2) receptor partial agonists with a sufficiently low enough intrinsic activity will prove effective against the positive symptoms of schizophrenia, and also highlight the importance of using downstream-based assays in the discovery of novel D(2) receptor partial agonist therapeutics.
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PMID:In vitro functional characteristics of dopamine D2 receptor partial agonists in second and third messenger-based assays of cloned human dopamine D2Long receptor signalling. 1709 71

Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), encoded by PPP1R1B, is a pivotal integrator of information in dopaminoceptive neurons, regulating the response to neuroleptics, psychotomimetics, and drugs of abuse, and affecting striatal function and plasticity. Despite extensive preclinical work, there are almost no data on DARPP-32 function in humans. Here, we identify, through resequencing in 298 chromosomes, a frequent PPP1R1B haplotype predicting mRNA expression of PPP1R1B isoforms in postmortem human brain. This haplotype was associated with enhanced performance on several cognitive tests that depend on frontostriatal function. Multimodal imaging of healthy subjects revealed an impact of the haplotype on neostriatal volume, activation, and the functional connectivity of the prefrontal cortex. The haplotype was associated with the risk for schizophrenia in 1 family-based association analysis. Our convergent results identify a prefrontal-neostriatal system affected by variation in PPP1R1B and suggest that DARPP-32 plays a pivotal role in cognitive function and possibly in the pathogenesis of schizophrenia.
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PMID:Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. 1729 Mar 3

Dopamine and cyclic adenosine 3':5'-monophosphate (AMP)-regulated phosphoprotein, relative molecular mass 32,000 (DARPP-32), plays an important role in modulating the functions of various neurotransmitter systems. To explore the alterations in DARPP-32 in subjects with schizophrenia and bipolar disorder, we employed immunohistochemical and Western blotting techniques and examined the distribution and expression of DARPP-32 in the postmortem dorsolateral prefrontal cortex (DLPFC) from 12 subjects with schizophrenia, 10 subjects with bipolar disorder, and 11 control subjects. Immunohistochemical study demonstrated that DARPP-32 immunolabeling in the neuronal soma from subjects with schizophrenia and bipolar disorder was lower than in that from the controls. The results of the immunoblot analysis were consistent with those of the immunohistochemistry, and the amount of DARPP-32 in subjects with schizophrenia and bipolar disorder was found to be lower than that in the control subjects. The present study suggests that DARPP-32 decreases in the DLPFC of patients with schizophrenia and bipolar disorder, and further suggests that this decrease is associated with dysfunction of dopaminoceptive neurons in the DLPFC of patients affected by these two mental disorders.
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PMID:Immunohistochemical and immunoblot analysis of Dopamine and cyclic AMP-regulated phosphoprotein, relative molecular mass 32,000 (DARPP-32) in the prefrontal cortex of subjects with schizophrenia and bipolar disorder. 1752 92

Schizophrenia has been linked with dysfunctions of glutamatergic, dopaminergic, and serotonergic neurotransmission. Dopamine- and cAMP-regulated phosphoprotein of relative molecular mass 32 kDa (DARPP-32), encoded by PPP1R1B (protein phosphatase 1, regulatory/inhibitor subunit 1B) gene, is enriched in neostriatal medium spiny neurons. It plays a key regulator role in dopaminergic and glutamatergic signaling pathways. The combined evidence from reduced DARPP-32 expression in the dorsolateral prefrontal cortex (DLPFC) in schizophrenic patients and from abnormalities in mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32 suggested that it would be worthwhile to investigate the association between DARPP-32 and schizophrenia. In the present study, we genotyped five single nucleotide polymorphisms (SNPs) in the PPP1R1B gene and conducted a case-control study involving 520 schizophrenic patients and 386 healthy subjects drawn from the Chinese population. No allelic, genotypic or haplotypic association was found. However, our results do not preclude the possibility that the PPP1R1B is a susceptibility gene for schizophrenia in the Chinese population, since, as a central molecular switch, PPP1R1B may contribute to schizophrenia by interacting with other genes. Further functional analysis and genetic association studies are needed to determine the potential roles of PPP1R1B and other related genes in the pathophysiology of schizophrenia.
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PMID:An association study between PPP1R1B gene and schizophrenia in the Chinese population. 1761 27

Several lines of evidence, including genome-wide linkage scans and postmortem brain studies of patients with schizophrenia or bipolar disorder, have suggested that DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa), a key regulatory molecule in the dopaminergic signaling pathway, is involved in these disorders. After evaluating the linkage disequilibrium pattern of the gene encoding DARPP-32 (PPP1R1B; located on 17q12), we conducted association analyses of this gene with schizophrenia and bipolar disorder. Single-marker and haplotypic analyses of four single nucleotide polymorphisms (SNPs; rs879606, rs12601930, rs907094, and rs3764352) in a sample set (subjects with schizophrenia=384, subjects with bipolar disorder=318, control subjects=384) showed that PPP1R1B polymorphisms were not significantly associated with schizophrenia, whereas, even after Bonferroni corrections, significant associations with bipolar disorder were observed for rs12601930 (corrected genotypic p=0.00059) and rs907094 (corrected allelic p=0.040). We, however, could not confirm these results in a second independent sample set (subjects with bipolar disorder=366, control subjects=370). We now believe that the significant association observed with the first sample set was a result of copy number aberrations in the region surrounding these SNPs. Our findings suggest that PPP1R1B SNPs are unlikely to be related to the development of schizophrenia and bipolar disorder in the Japanese population.
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PMID:Genetic analysis of the gene coding for DARPP-32 (PPP1R1B) in Japanese patients with schizophrenia or bipolar disorder. 1805 81

Dopamine-and-cAMP-regulated neuronal phosphoprotein (32 kDa) (DARPP-32), encoded by PPP1R1B, is expressed in brain regions receiving dopaminergic projections, including the prefrontal cortex (PFC), and is implicated in the pathophysiology of schizophrenia. The broad functional capacity of DARPP-32 has potential relevance to both psychotic and negative symptoms of schizophrenia. We wished to determine if DARPP-32 gene expression and variation at selected SNPs correlated significantly with patient phenotypes. We performed RT-PCR to quantify DARPP-32 mRNA from brain samples (Brodmann Area 46) donated by the Stanley Medical Research Institute (SMRI, Array Collection): 35 from unaffected controls (UC), 35 from patients with schizophrenia (SCZ), and 35 with bipolar disorder (BP). Relative mRNA expression was calculated in relation to the housekeeping gene Cyclophilin. SNP genotyping was conducted by PCR on DNA obtained from Brodmann Area 46. We found a significant difference in gene expression levels between SCZ patients who died by suicide (SCZ-S) (n=6) vs. other causes of death (SCZ-NS) (P<0.004), as well as between SCZ-S and UC (P<0.04). We genotyped the intron SNP rs907094 and found that the SCZ-S group was more similar to UC than to the SCZ-NS population. DARPP-32 expression differences between SCZ-S, SCZ-NS, and UC populations are consistent with previous literature suggesting that serotonin system components are also altered in suicide. Work in a larger sample is needed to confirm these findings.
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PMID:Reduced prefrontal cortex DARPP-32 mRNA in completed suicide victims with schizophrenia. 1857 38

The majority of psychopharmaca acts by binding to G-protein coupled receptors and thereby asserts it's action through the regulation of intracellular signaling networks. The convergence and interactions of pathways within these networks make the detailed signaling hard to study experimentally, and the response to a stimuli can be non-intuitive. To approach these problems with systems biology and merging biochemical data in a computer model to do virtual experiments with high time-resolution can shed new light on the functioning of these networks. The phosphoprotein DARPP-32 is regulated by several modulatory neurotransmitters, including dopamine, serotonin and adenosin, and it's function has been proposed to be altered in schizophrenia. Moreover, the well studied regulation of DARPP-32, and the vast amount of biochemical data makes it a model molecule when it comes to intracellular signaling. To better understand the interactions of the pathways that regulate DARPP-32 activation we constructed a computer model based on experimental data. In this work we discovered unexpected responses of DARPP-32 at fast timescales. An equally important outcome of the work was to identify areas where additional work is needed in order to understand intracellular signaling at the systems level, showing the need for close collaborations between theoretical and experimental biologists.
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PMID:Modelling of DARPP-32 regulation to understand intracellular signaling in psychiatric disease. 1875 27

Recent studies on the phosphoprotein synapsin II have revealed reduced expression in postmortem medial prefrontal cortex tissues from subjects with schizophrenia, and chronic antipsychotic drug treatment has resulted in concurrent increases in synapsin II mRNA and protein levels. Collectively, this research suggests a role of synapsin II in the pathophysiology of schizophrenia; however, whether synapsin II plays a causal role in this disease process still remains unclear. Therefore, the goal of this investigation was to examine whether synapsin II knockout mice display behavioral abnormalities commonly expressed in preclinical animal models of schizophrenia, namely deficits in prepulse inhibition (PPI), decreased social behavior, and locomotor hyperactivity. Results indicate that mice with knockout of the synapsin II gene demonstrate deficits in PPI at three prepulse intensities (67, 70, and 73 dB), along with deficits in habituation to startle to a 110 dB acoustic pulse. Knockout animals also expressed decreased social behavior and increased locomotor activity when compared to wildtype and heterozygous populations. Complete knockout of the synapsin II gene was confirmed in postmortem brain tissues via immunoblotting. In conclusion, these results confirm that synapsin II knockout mice display behavioral endophenotypes similar to established preclinical animal models of schizophrenia, and lend support to the notion that abnormalities in synapsin II expression may play a causal role in the underlying pathophysiological mechanisms of schizophrenia.
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PMID:Behavioral abnormalities in synapsin II knockout mice implicate a causal factor in schizophrenia. 1936 Aug 55


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