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)

AKT-GSK3beta signaling is a target of lithium and as such has been implicated in the pathogenesis of mood disorders. Here, we provide evidence that this signaling pathway also has a role in schizophrenia. Specifically, we present convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK3beta at Ser9 in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype associated with lower AKT1 protein levels; and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency. Our findings support the proposal that alterations in AKT1-GSK3beta signaling contribute to schizophrenia pathogenesis and identify AKT1 as a potential schizophrenia susceptibility gene. Consistent with this proposal, we also show that haloperidol induces a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for an impaired function of this signaling pathway in schizophrenia.
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PMID:Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. 1475 19

The protein kinase glycogen synthase kinase-3 (GSK-3) is highly abundant in brain and involved in signal transduction cascades, particularly during neurodevelopment. We have previously found reduced GSK-3beta mRNA levels, protein levels and GSK-3 total (alpha+beta isoforms) activity in postmortem frontal cortex of schizophrenic patients in the Stanley Medical Research Institute's Brain Collection. To verify and extend these findings, GSK-3 parameters were now measured in the frontal cortex (BA9) and hippocampus obtained from the Rebecca L. Cooper Research Laboratories postmortem brain collection. Fifteen pairs of schizophrenic patients and matched control subjects have been studied. No significant differences in GSK-3alpha and GSK-3beta mRNA levels, GSK-3beta protein levels or total GSK-3 (alpha+beta) activity were found in the frontal cortex of the two diagnostic groups. Hippocampal GSK-3alpha and GSK-3beta mRNA levels were significantly lower (22% and 28%, respectively) in the tissue from the schizophrenic patients compared with the normal controls. Hippocampal GSK-3beta protein levels in the schizophrenic patients were 24% significantly lower than control values only after omission of three outlier subjects. Hippocampal total GSK-3 (alpha+beta) activity in the patients was 31% lower in the schizophrenic patients vs. control subjects. This difference was marginally significant. While our previous data on GSK-3beta in postmortem brain and the recent report that there is impaired AKT1-GSK-3beta signaling in schizophrenia suggest that changes in pathways involving protein kinases such as AKT1 and GSK-3beta in schizophrenia are complex, our present data do not provide strong evidence in support of the involvement of GSK-3beta in schizophrenia. Therefore, further investigation in a greater number of brain samples is warranted to better clarify the possible role of this enzyme in the pathophysiology of schizophrenia.
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PMID:GSK-3 parameters in postmortem frontal cortex and hippocampus of schizophrenic patients. 1547 9

Glycogen Synthase Kinase (GSK)-3 is a ubiquitous serine/threonine protein kinase highly abundant in brain which plays a key role in neural development and neuron survival. We have previously reported that GSK-3beta protein levels and GSK-3 activity are reduced by over 40% in postmortem prefrontal cortex of schizophrenic patients compared to patients with bipolar illness, unipolar depression and to normal controls, and Emamian et al. have recently presented convergent evidence for impaired AKT1-GSK-3beta signaling in schizophrenia. Using specimens of dorsolateral prefrontal cortex tissue obtained from The Stanley Medical Research Institute's Brain Collection, from the same subjects used previously, we now show that GSK-3beta, but not GSK-3alpha, mRNA levels are 36% lower in the patients with schizophrenia compared to all other comparison groups. The present study lends further support to the finding of low GSK-3beta levels in schizophrenia and extends this observation by suggesting that the decrease in GSK-3beta may be due to reduced protein synthesis possibly due to altered transcriptional drive of the GSK-3beta gene.
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PMID:Reduced GSK-3beta mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients. 1556 92

Recent evidence suggests that the AKT1-GSK3beta signalling cascade partially mediates dopamine-dependent behaviours. In relation to the pathophysiology of schizophrenia or methamphetamine (Meth) use disorder, AKT1 is a good candidate gene for such conditions. For schizophrenia, positive associations of SNPs and AKT1 haplotypes were reported in US and Japanese samples. To evaluate the association between AKT1 and Meth-use disorder, we conducted a case-control study of Japanese samples (182 patients and 437 controls). A positive association between a SNP and haplotypes was found, and the 'signal' SNP was the same SNP found to be associated with US schizophrenia, but not with Japanese schizophrenia. Our results indicate that AKT1 may play a possible role in the development of Meth-use disorder. Further investigation of these associations, together with evidence from previous animal studies, may open the way to elucidation of the pathophysiology of this condition.
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PMID:Positive association of AKT1 haplotype to Japanese methamphetamine use disorder. 1598 48

AKT1 (V-akt murine thymoma viral oncogene homolog 1) is a protein kinase isoform of AKT. Five single-nucleotide polymorphisms, rs3803300, rs1130214, rs3730358, rs2498799 and rs2494732, at the genomic region of AKT1 have been reported to be significantly associated with schizophrenia. We tested for the presence of these five single-nucleotide polymorphisms in a Taiwanese population by genotyping 218 co-affected schizophrenia families. Both single locus and haplotypes analyses showed no association of these single-nucleotide polymorphisms with schizophrenia. These findings fail to support AKT1 as a susceptibility gene for schizophrenia in the Taiwanese population.
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PMID:Absence of significant associations between four AKT1 SNP markers and schizophrenia in the Taiwanese population. 1639 29

AKT-glycogen synthase kinase 3beta (GSK3beta) signaling is a target of lithium and has been implicated in the pathogenesis of mood disorders and schizophrenia. AKT1 protein level is decreased in the peripheral lymphocytes and brains of schizophrenic patients. The SNP2/3/4 TCG haplotype of AKT1 was associated with schizophrenia in patients with Northern European origin. In the present study, we genotyped five single nucleotide polymorphisms (SNP1-5) of AKT1 gene according to the original study in Iranians comprising of 321 schizophrenic patients and 383 controls, all residing in Mashhad city, Northeastern Iran. Haplotype analysis showed that the frequency of a five-SNP haplotype (AGCAG) was significantly higher in schizophrenic patients (0.068) than that of controls (0.034) (P = 0.03 after Bonferroni correction, OR = 2.04, CI = 1.2-3.4). In stratified analysis by schizophrenia subtypes, the frequency of the same haplotype was significantly higher in disorganized subtype (n = 78, frequency of haplotype=0.081) when compared with normal controls (P = 0.04 after Bonferroni correction, OR = 2.59, CI = 1.3-5.2). Our findings did not confirm the association of AKT1 SNP2/3/4 TCG haplotype with the risk of schizophrenia as reported in the original study but showed the evidence of association with a different haplotype, AKT1 five-SNP AGCAG haplotype, with the risk of schizophrenia in Iranian population.
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PMID:Association of AKT1 haplotype with the risk of schizophrenia in Iranian population. 1658 35

Neurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function.
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PMID:Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. 1663 32

After years of frustration, the search for genes impacting on schizophrenia is now undergoing some exciting developments. Several proposals of susceptibility genes have been able to be supported by replications. Thus, there are now at least three very strong candidates: the gene for dysbindin (DTNBP1), the gene for neuregulin-1 (NRG1), and a less well-understood gene locus, G72/G30, which are likely to influence manifestations of schizophrenia. Other "hot" candidates such as the disrupted-in-schizophrenia 1 gene (DISC1) and the gene coding for protein kinase B (AKT1) might also prove to be susceptibility genes in the next future. The clinical implications of these findings are not yet fully visible. However, some first insights are possible: most of the genetic findings lack diagnostic specificity, and are also reproduced in bipolar disorder. Strong associations are also obtained on a symptomatic level, not only on a diagnostic level. The pathophysiological role of these hot candidate genes is currently under intensive study.
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PMID:Clinical impact of recently detected susceptibility genes for schizophrenia. 1664 Jan 17

The study of schizophrenia genetics has confirmed the importance of genes in etiology, but has not so far identified the relationship between observed genetic risks and specific DNA variants, protein alterations or biological processes. In spite of many limitations, numerous regions of the human genome give consistent, although by no means unanimous, support for linkage, which is unlikely to occur by chance. Two recent shifts have been evident in the field. First, a series of studies combining linkage and association analyses in the same family sets have identified promising candidate genes (DTNBP1, NRG1, G72/G30, TRAR4). Although a consensus definition of replication for genetic association in a complex trait remains difficult to achieve, the evidence for two of these (dystrobrevin binding protein 1 (DTNBP1), NRG1) is strong. Second, a series of studies combining association with functional investigation of changes in the associated gene in schizophrenia have also identified several candidate genes (COMT, RGS4, PPP3CC, ZDHHC8, AKT1). Somewhat surprisingly, the loci implicated by these studies have proven less robust in replication, although the number of replication studies remains small in several cases. Assessment of the combined evidence for the DTNBP1 gene gives some insight into the nature of the problems remaining to be solved.
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PMID:Molecular genetic studies of schizophrenia. 1672 3

In order to explore the role of noncoding variants in the genetics of schizophrenia, we sequenced 27 kb of noncoding DNA from the gene loci RAC-alpha serine/threonine-protein kinase (AKT1), brain-derived neurotrophic factor (BDNF), dopamine receptor-3 (DRD3), dystrobrevin binding protein-1 (DTNBP1), neuregulin-1 (NRG1) and regulator of G-protein signaling-4 (RGS4) in 37 schizophrenia patients and 25 healthy controls. To compare the allele frequency spectrum between the two samples, we separately computed Tajima's D-value for each sample. The results showed a smaller Tajima's D-value in the case sample, pointing to an excess of rare variants as compared to the control sample. When randomly permuting the affection status of sequenced individuals, we observed a stronger decrease of Tajima's D in 2400 out of 100,000 permutations, corresponding to a P-value of 0.024 in a one-sided test. Thus, rare variants are significantly enriched in the schizophrenia sample, indicating the existence of disease-related sequence alterations. When categorizing the sequenced fragments according to their level of human-rodent conservation or according to their gene locus, we observed a wide range of diversity parameter estimates. Rare variants were enriched in conserved regions as compared to nonconserved regions in both samples. Nevertheless, rare variants remained more common among patients, suggesting an increased number of variants under purifying selection in this sample. Finally, we performed a heuristic search for the subset of gene loci, which jointly produces the strongest difference between controls and cases. This showed a more prominent role of variants from the loci AKT1, BDNF and RGS4. Taken together, our approach provides promising strategy to investigate the genetics of schizophrenia and related phenotypes.
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PMID:A summary statistic approach to sequence variation in noncoding regions of six schizophrenia-associated gene loci. 1673 33


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