| 1 | Mol. Psychiatry 2000 Jul 5: 443-7 |
|---|---|
| PMID | 10889557 |
| Title | Function of the C-36 to T polymorphism in the human cholecystokinin gene promoter. |
| Abstract | Cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain, and in man significant quantities are expressed in all regions of the brain.1,2 Therefore, CCK has been implicated in a variety of CNS functions-such as feeding behavior, anxiety, analgesia and memory functions as well as psychiatric disease like panic disorder and schizophrenia (for review, see2,3). Recently, a number of studies have indicated that a C-36 to T transition in the CCK gene promoter SP1 element4 (Figure 1) is associated with alcoholism and withdrawal symptoms as well as panic disorder.5-7 Moreover, it has been proposed that the polymorphism plays a direct role in the pathogenesis of the disorders by decreasing the expression and synthesis of CCK peptides. The significance of these findings is still unclear and other studies have failed to demonstrate linkage between the polymorphism and alcoholism.8 In this study we examined the function of the C-36 to T transition in transcription of the human CCK gene. We demonstrate that substitution of the C-36 residue causes a slight reduction of SP1 and Sp3 binding, but this has no effect on transcription in vivo. Moreover, no difference in the response to physiological stimuli was observed. Taken together the results show that the C to T polymorphism does not play a direct role in the pathogenesis of either alcoholism or panic disorder and that a putative association to these disorders is likely to be the result of co-segregation with a linked mutation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Schizophr. Res. 2002 Nov 58: 83-6 |
| PMID | 12363394 |
| Title | Polymorphism analysis of the upstream region of the human N-methyl-D-aspartate receptor subunit NR1 gene (GRIN1): implications for schizophrenia. |
| Abstract | Dysfunction of the gene for the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor (GRIN1) has been implicated in the pathogenesis of schizophrenia. In support of this hypothesis are behavioral abnormalities reminiscent of schizophrenia in mice with an attenuated expression of the NR1 subunit receptor and the reduced level of NR1 mRNA in postmortem brains of patients with schizophrenia. We screened single nucleotide polymorphisms (SNPs) in the upstream region between +51 and -941 from the translation initiation codon of GRIN1 and identified 17 SNPs, 10 of which were located within the region containing the SP1 motif and the GSG motifs. As genotyping of 191-196 Japanese patients with schizophrenia and 202-216 controls revealed no significant association between schizophrenia and the SNPs in the upstream region of GRIN1, these SNPs apparently do not play a critical role in the pathogenesis of schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Mol. Psychiatry 2002 -1 7: 1101-6 |
| PMID | 12476325 |
| Title | Identification of a novel variant of the human NR2B gene promoter region and its possible association with schizophrenia. |
| Abstract | N-methyl-D-aspartate (NMDA) receptor dysfunction is involved in the pathogenesis of schizophrenia. We determined the nucleotide sequence of the 5'-upstream region of the human NMDA receptor 2B (NR2B) subunit gene and identified a novel T-200G variant located in one of the SP1 binding sites. To investigate the effect of this variant on the transcriptional activity of the hNR2B gene, we performed gene reporter assays using PC12 pheochromocytoma cells transiently transfected with luciferase reporter plasmids. In the absence of nerve growth factor (NGF), luciferase activities did not significantly differ between the two alleles and the control plasmid. However, luciferase reporter activity of the T allele was significantly up-regulated compared to that of the G allele in the presence of NGF (P = 0.0013), indicating that this polymorphic site is a critical region for NR2B gene regulation through NGF-induced SP1-binding. A case control study showed that the frequency of the G allele (P = 0.0164) was significantly higher in 100 schizophrenics than in 100 controls. These findings suggest that the T-200G variant causes dysfunction of NMDA receptors consisting of the NR2B subunit and may be involved in the development of schizophrenia. Replication studies of independent samples and family-based association studies are necessary to further evaluate the significance of our findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Mol. Psychiatry 2002 -1 7: 1101-6 |
| PMID | 12476325 |
| Title | Identification of a novel variant of the human NR2B gene promoter region and its possible association with schizophrenia. |
| Abstract | N-methyl-D-aspartate (NMDA) receptor dysfunction is involved in the pathogenesis of schizophrenia. We determined the nucleotide sequence of the 5'-upstream region of the human NMDA receptor 2B (NR2B) subunit gene and identified a novel T-200G variant located in one of the SP1 binding sites. To investigate the effect of this variant on the transcriptional activity of the hNR2B gene, we performed gene reporter assays using PC12 pheochromocytoma cells transiently transfected with luciferase reporter plasmids. In the absence of nerve growth factor (NGF), luciferase activities did not significantly differ between the two alleles and the control plasmid. However, luciferase reporter activity of the T allele was significantly up-regulated compared to that of the G allele in the presence of NGF (P = 0.0013), indicating that this polymorphic site is a critical region for NR2B gene regulation through NGF-induced SP1-binding. A case control study showed that the frequency of the G allele (P = 0.0164) was significantly higher in 100 schizophrenics than in 100 controls. These findings suggest that the T-200G variant causes dysfunction of NMDA receptors consisting of the NR2B subunit and may be involved in the development of schizophrenia. Replication studies of independent samples and family-based association studies are necessary to further evaluate the significance of our findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Nucleic Acids Res. 2002 Jul 30: 2930-9 |
| PMID | 12087179 |
| Title | On the epigenetic regulation of the human reelin promoter. |
| Abstract | Reln mRNA and protein levels are reduced by approximately 50% in various cortical structures of post-mortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. To study mechanisms responsible for this down-regulation, we have analyzed the promoter of the human reelin gene. We show that the reelin promoter directs expression of a reporter construct in multiple human cell types: neuroblastoma cells (SHSY5Y), neuronal precursor cells (NT2), differentiated neurons (hNT) and hepatoma cells (HepG2). Deletion constructs confirmed the presence of multiple elements regulating Reln expression, although the promoter activity is promiscuous, i.e. activity did not correlate with expression of the endogenous gene as reflected in terms of reelin mRNA levels. Co-transfection of the -514 bp human reelin promoter with either SP1 or Tbr1 demonstrated that these transcription factors activate reporter expression by 6- and 8.5-fold, respectively. Within 400 bp of the RNA start site there are 100 potential CpG targets for DNA methylation. Retinoic acid (RA)-induced differentiation of NT2 cells to hNT neurons was accompanied by increased reelin expression and by the appearance of three DNase I hypersensitive sites 5' to the RNA start site. RA-induced differentiation was also associated with demethylation of the reelin promoter. To test if methylation silenced reelin expression, we methylated the promoter in vitro prior to transfection. In addition, we treated NT2 cells with the methylation inhibitor aza-2'-deoxycytidine and observed a 60-fold increase in reelin mRNA levels. The histone deacetylase inhibitors trichostatin A (TSA) and valproic acid also induced expression of the endogenous reelin promoter, although TSA was considerably more potent. These findings indicate that one determinant responsible for regulating reelin expression is the methylation status of the promoter. Our data also raise the interesting possibility that the down-regulation of reelin expression documented in psychiatric patients might be the consequence of inappropriate promoter hypermethylation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Psychiatr. Genet. 2003 Dec 13: 205-9 |
| PMID | 14639047 |
| Title | A possible association between an insertion/deletion polymorphism of the NQO2 gene and schizophrenia. |
| Abstract | Glutathione-S-transferases, NAD(P)H: quinone oxidoreductase1 (NQO1) and NRH: quinone oxidoreductase2 (NQO2) provide important cellular defences against the neurotoxicity induced by catecholamine-derived o-quinones and oxidative stress during redox cycling. In this study, we investigated the association between polymorphisms of the NQO2 gene and schizophrenia. We analysed the promoter and coding regions of the NQO2 gene for 102 patients with schizophrenia and for 234 controls using single-strand conformational change polymorphism and PCR direct-sequencing analyses and the RNA concentration of NQO2 in white blood cells isolated from peripheral blood was measured. We identified 12 variants including the insertion/deletion (I/D) polymorphism of the 29 base pair nucleotide sequence in the promoter region. The frequency of the D allele was significantly higher in the schizophrenic group than in the control group (P=0.0109). Especially, in patients with the episodic type as course specifiers, this value was highly significant (P=0.0016) and the significance remained after the Bonferroni correction. The 29 base pair nucleotide sequence contains four repeats of the putative core sequence of the SP1-binding cis-element that is important in the activation of gene expression. Our preliminary data, although sample size was not enough, demonstrated that the RNA concentration of NQO2 in white blood cells isolated from peripheral blood was higher in individuals homozygous (II) for the I allele than in those heterozygous (ID) or homozygous (DD) for the D allele. The present data suggest that individuals with the deletion of the 29 base pair sequence in the promoter region of the NQO2 gene may confer susceptibility to a certain form of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Psychiatr. Genet. 2003 Dec 13: 205-9 |
| PMID | 14639047 |
| Title | A possible association between an insertion/deletion polymorphism of the NQO2 gene and schizophrenia. |
| Abstract | Glutathione-S-transferases, NAD(P)H: quinone oxidoreductase1 (NQO1) and NRH: quinone oxidoreductase2 (NQO2) provide important cellular defences against the neurotoxicity induced by catecholamine-derived o-quinones and oxidative stress during redox cycling. In this study, we investigated the association between polymorphisms of the NQO2 gene and schizophrenia. We analysed the promoter and coding regions of the NQO2 gene for 102 patients with schizophrenia and for 234 controls using single-strand conformational change polymorphism and PCR direct-sequencing analyses and the RNA concentration of NQO2 in white blood cells isolated from peripheral blood was measured. We identified 12 variants including the insertion/deletion (I/D) polymorphism of the 29 base pair nucleotide sequence in the promoter region. The frequency of the D allele was significantly higher in the schizophrenic group than in the control group (P=0.0109). Especially, in patients with the episodic type as course specifiers, this value was highly significant (P=0.0016) and the significance remained after the Bonferroni correction. The 29 base pair nucleotide sequence contains four repeats of the putative core sequence of the SP1-binding cis-element that is important in the activation of gene expression. Our preliminary data, although sample size was not enough, demonstrated that the RNA concentration of NQO2 in white blood cells isolated from peripheral blood was higher in individuals homozygous (II) for the I allele than in those heterozygous (ID) or homozygous (DD) for the D allele. The present data suggest that individuals with the deletion of the 29 base pair sequence in the promoter region of the NQO2 gene may confer susceptibility to a certain form of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Apr 134B: 60-6 |
| PMID | 15717292 |
| Title | Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. |
| Abstract | DNA methylation changes could provide a mechanism for DNA plasticity and dynamism for short-term adaptation, enabling a type of cell memory to register cellular history under different environmental conditions. Some environmental insults may also result in pathological methylation with corresponding alteration of gene expression patterns. Evidence from several studies has suggested that in schizophrenia and bipolar disorder, mRNA of the reelin gene (RELN), which encodes a protein necessary for neuronal migration, axonal branching, synaptogenesis, and cell signaling, is severely reduced in post-mortem brains. Therefore, we investigated the methylation status of the RELN promoter region in schizophrenic patients and normal controls as a potential mechanism for down regulation of its expression. Ten post-mortem frontal lobe brain samples from male schizophrenic patients and normal controls were obtained from the Harvard Brain Tissue Resources Center. DNA was extracted using a standard phenol-chloroform DNA extraction protocol. To evaluate differences between patients and controls, we applied methylation specific PCR (MSP) using primers localized to CpG islands flanking a potential cyclic AMP response element (CRE) and a stimulating protein-1 (SP1) binding site located in the promoter region. For each sample, DNA extraction, bisulfite treatment, and MSP were independently repeated at least four times to accurately determine the methylation status of the target region. Forty-three PCR trials were performed on the test and control samples. MSP analysis of the RELN promoter revealed an unmethylated signal in all reactions (43 of 43) using DNA from the frontal brain tissue, derived from either the schizophrenic patients or normal controls indicating that this region of the RELN promoter is predominantly unmethylated. However, we observed a distinct methylated signal in 73% of the trials (16 of 22) in schizophrenic patients compared with 24% (5 of 21) of controls. Thus, the hypermethylation of the CpG islands flanking a CRE and SP1 binding site observed at a significantly higher level (t = -5.07, P = 0.001) may provide a mechanism for the decreased RELN expression, frequently observed in post-mortem brains of schizophrenic patients. We also found an inverse relationship between the level of DNA methylation using MSP analysis and the expression of the RELN gene using semi-quantitative RT-PCR. Despite the small sample size, these studies indicate that promoter hypermethylation of the RELN gene could be a significant contributor in effecting epigenetic alterations and provides a molecular basis for the RELN gene hypoactivity in schizophrenia. Further studies with a larger sample set would be required to validate these preliminary observations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Apr 134B: 60-6 |
| PMID | 15717292 |
| Title | Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. |
| Abstract | DNA methylation changes could provide a mechanism for DNA plasticity and dynamism for short-term adaptation, enabling a type of cell memory to register cellular history under different environmental conditions. Some environmental insults may also result in pathological methylation with corresponding alteration of gene expression patterns. Evidence from several studies has suggested that in schizophrenia and bipolar disorder, mRNA of the reelin gene (RELN), which encodes a protein necessary for neuronal migration, axonal branching, synaptogenesis, and cell signaling, is severely reduced in post-mortem brains. Therefore, we investigated the methylation status of the RELN promoter region in schizophrenic patients and normal controls as a potential mechanism for down regulation of its expression. Ten post-mortem frontal lobe brain samples from male schizophrenic patients and normal controls were obtained from the Harvard Brain Tissue Resources Center. DNA was extracted using a standard phenol-chloroform DNA extraction protocol. To evaluate differences between patients and controls, we applied methylation specific PCR (MSP) using primers localized to CpG islands flanking a potential cyclic AMP response element (CRE) and a stimulating protein-1 (SP1) binding site located in the promoter region. For each sample, DNA extraction, bisulfite treatment, and MSP were independently repeated at least four times to accurately determine the methylation status of the target region. Forty-three PCR trials were performed on the test and control samples. MSP analysis of the RELN promoter revealed an unmethylated signal in all reactions (43 of 43) using DNA from the frontal brain tissue, derived from either the schizophrenic patients or normal controls indicating that this region of the RELN promoter is predominantly unmethylated. However, we observed a distinct methylated signal in 73% of the trials (16 of 22) in schizophrenic patients compared with 24% (5 of 21) of controls. Thus, the hypermethylation of the CpG islands flanking a CRE and SP1 binding site observed at a significantly higher level (t = -5.07, P = 0.001) may provide a mechanism for the decreased RELN expression, frequently observed in post-mortem brains of schizophrenic patients. We also found an inverse relationship between the level of DNA methylation using MSP analysis and the expression of the RELN gene using semi-quantitative RT-PCR. Despite the small sample size, these studies indicate that promoter hypermethylation of the RELN gene could be a significant contributor in effecting epigenetic alterations and provides a molecular basis for the RELN gene hypoactivity in schizophrenia. Further studies with a larger sample set would be required to validate these preliminary observations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Apr 144B: 332-40 |
| PMID | 17192956 |
| Title | Synaptotagmin XI as a candidate gene for susceptibility to schizophrenia. |
| Abstract | Synaptotagmin XI (Syt11) is a member of the synaptotagmin family, which is localized in cells either in synaptic vesicles or the cellular membrane, and is known to act as a calcium sensor. The Syt11 gene is located on chromosome locus 1q21-q22, which was previously reported as a major susceptibility locus of familial schizophrenia. Here, we present evidence for an association between the number of 33-bp repeats in the promoter region of the Syt11 gene and schizophrenia. We found that the transcriptional activity of the gene is affected by the number of 33-bp repeats, which include an SP1 binding site, suggesting that the excessive expression of Syt11 can be associated with schizophrenia. Another (single nucleotide) polymorphism in the Syt11 5'UTR region, where the potent transcription factor YY1 can bind, also affects the transcriptional activity of Syt11. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | PLoS ONE 2007 -1 2: e817 |
| PMID | 17786189 |
| Title | Sp1 expression is disrupted in schizophrenia; a possible mechanism for the abnormal expression of mitochondrial complex I genes, NDUFV1 and NDUFV2. |
| Abstract | The prevailing hypothesis regards schizophrenia as a polygenic disease, in which multiple genes combine with each other and with environmental stimuli to produce the variance of its clinical symptoms. We investigated whether the ubiquitous transcription factor SP1 is abnormally expressed in schizophrenia, and consequently can affect the expression of genes implicated in this disorder. mRNA of SP1 and of mitochondrial complex I subunits (NDUFV1, NDUFV2) was analyzed in three postmortem brain regions obtained from the Stanley Foundation Brain Collection, and in lymphocytes of schizophrenic patients and controls. SP1 role in the transcription of these genes was studied as well. SP1 was abnormally expressed in schizophrenia in both brain and periphery. Its mRNA alteration pattern paralleled that of NDUFV1 and NDUFV2, decreasing in the prefrontal cortex and the striatum, while increasing in the parieto-occipital cortex and in lymphocytes of schizophrenic patients as compared with controls. Moreover, a high and significant correlation between these genes existed in normal subjects, but was distorted in patients. SP1 role in the regulation of complex I subunits, was demonstrated by the ability of the SP1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, SP1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin. These findings suggest that abnormality in SP1, which can be the main activator/repressor or act in combination with additional transcription factors and is subjected to environmental stimuli, can contribute to the polygenic and clinically heterogeneous nature of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | PLoS ONE 2007 -1 2: e817 |
| PMID | 17786189 |
| Title | Sp1 expression is disrupted in schizophrenia; a possible mechanism for the abnormal expression of mitochondrial complex I genes, NDUFV1 and NDUFV2. |
| Abstract | The prevailing hypothesis regards schizophrenia as a polygenic disease, in which multiple genes combine with each other and with environmental stimuli to produce the variance of its clinical symptoms. We investigated whether the ubiquitous transcription factor SP1 is abnormally expressed in schizophrenia, and consequently can affect the expression of genes implicated in this disorder. mRNA of SP1 and of mitochondrial complex I subunits (NDUFV1, NDUFV2) was analyzed in three postmortem brain regions obtained from the Stanley Foundation Brain Collection, and in lymphocytes of schizophrenic patients and controls. SP1 role in the transcription of these genes was studied as well. SP1 was abnormally expressed in schizophrenia in both brain and periphery. Its mRNA alteration pattern paralleled that of NDUFV1 and NDUFV2, decreasing in the prefrontal cortex and the striatum, while increasing in the parieto-occipital cortex and in lymphocytes of schizophrenic patients as compared with controls. Moreover, a high and significant correlation between these genes existed in normal subjects, but was distorted in patients. SP1 role in the regulation of complex I subunits, was demonstrated by the ability of the SP1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, SP1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin. These findings suggest that abnormality in SP1, which can be the main activator/repressor or act in combination with additional transcription factors and is subjected to environmental stimuli, can contribute to the polygenic and clinically heterogeneous nature of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Schizophr. Res. 2008 Dec 106: 229-36 |
| PMID | 18790604 |
| Title | Levels of [(3)H]pirenzepine binding in Brodmann's area 6 from subjects with schizophrenia is not associated with changes in the transcription factor SP1 or BACE1. |
| Abstract | Decreased muscarinic M1 receptor (CHRM1) mRNA has been reported in Brodmann's area (BA) 6 from subjects with schizophrenia. We have extended this study by measuring levels of CHRM1 ([(3)H]pirenzepine binding), CHRM3 ([(3)H]4-DAMP binding), the transcription factor SP1 and the CHRM1 downstream target beta-site APP-cleaving enzyme 1 (BACE1) in BA 6 from 19 subjects with schizophrenia and 19 control subjects. Radioligand binding was quantified using either in situ radioligand binding with autoradiography or, in cohorts of 10 control subjects and 10 subjects with schizophrenia, membrane enriched fraction (MEF) CNS ([(3)H]pirenzepine binding only). Levels of SP1 and BACE1 were measured by Western blotting. [(3)H]pirenzepine binding to tissue sections was in two layers, binding to tissue sections (Binding layer 1: p<0.01; Binding layer 2: p<0.001) and MEF (p<0.05) were decreased in schizophrenia. Levels of [(3)H]4-DAMP binding, SP1 and BACE1 were not altered in subjects with the disorder. This study shows a decrease in levels of CHRM1 in BA 6 from subjects with schizophrenia; as CHRM1 and BA 6 are important in maintaining normal cognitive function, these data support the hypothesis that decreased levels of cortical CHRM1 may contribute to the cognitive deficits associated with schizophrenia. Our findings on BACE1 suggest that the schizophrenia phenotype reported in BACE(-/-) mice is not simply due to lack of that protein in the cortex. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | J. Neurochem. 2008 Apr 105: 512-23 |
| PMID | 18194215 |
| Title | SP1 regulates a human SNAP-25 gene expression. |
| Abstract | The synaptosomal-associated protein of 25 kDa (SNAP-25) is a pre-synaptic plasma membrane protein. SNAP-25 plays an important role in synaptic vesicle membrane docking and fusion, which is involved in the regulation of neurotransmitter release. SNAP-25 has been implicated in the pathogenesis of neuropsychiatric disorders including schizophrenia, attention-deficit hyperactivity disorder and Alzheimer's disease. We cloned a 1584 bp segment of the 5' flanking region of the human SNAP-25 gene. A series of nested deletions of the 5' flanking region fragment were subcloned into the pGL3-basic luciferase reporter plasmid. N2A cells were transfected with the SNAP-25 promoter constructs and luciferase activity was measured as an indication of promoter activity. We identified a 188 bp fragment containing the transcription initiation site as the minimal region necessary for promoter activity. Several putative cis-acting elements including SP1, hypoxia inducible factor (HIF), cAMP-response element binding protein, T-cell factor/lymphocyte enhancer factor 1 (TCF/LEF1), AP1 and the signal transducer and activator of transcription-6 (STAT6) are found in the 5' flanking region of SNAP-25 gene. Transcriptional activation and gel shift assays showed that the human SNAP-25 gene promoter contains functional SP1 response elements. Over-expression of SP1 increased SNAP-25 gene expression and inhibition of SP1-mediated transcriptional activation reduced SNAP-25 gene expression. These results suggest that SP1 plays an important role in regulation of the human SNAP-25 gene expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | J Neural Transm (Vienna) 2009 Nov 116: 1383-96 |
| PMID | 19784753 |
| Title | The interplay between mitochondrial complex I, dopamine and Sp1 in schizophrenia. |
| Abstract | schizophrenia is currently believed to result from variations in multiple genes, each contributing a subtle effect, which combines with each other and with environmental stimuli to impact both early and late brain development. At present, schizophrenia clinical heterogeneity as well as the difficulties in relating cognitive, emotional and behavioral functions to brain substrates hinders the identification of a disease-specific anatomical, physiological, molecular or genetic abnormality. Mitochondria play a pivotal role in many essential processes, such as energy production, intracellular calcium buffering, transmission of neurotransmitters, apoptosis and ROS production, all either leading to cell death or playing a role in synaptic plasticity. These processes have been well established as underlying altered neuronal activity and thereby abnormal neuronal circuitry and plasticity, ultimately affecting behavioral outcomes. The present article reviews evidence supporting a dysfunction of mitochondria in schizophrenia, including mitochondrial hypoplasia, impairments in the oxidative phosphorylation system (OXPHOS) as well as altered mitochondrial-related gene expression. Abnormalities in mitochondrial complex I, which plays a major role in controlling OXPHOS activity, are discussed. Among them are schizophrenia specific as well as disease-state-specific alterations in complex I activity in the peripheral tissue, which can be modulated by DA. In addition, CNS and peripheral abnormalities in the expression of three of complex I subunits, associated with parallel alterations in their transcription factor, specificity protein 1 (SP1) are reviewed. Finally, this review discusses the question of disease specificity of mitochondrial pathologies and suggests that mitochondria dysfunction could cause or arise from anomalities in processes involved in brain connectivity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Am J Psychiatry 2011 Dec 168: 1318-25 |
| PMID | 21890790 |
| Title | Allelic differences between Han Chinese and Europeans for functional variants in ZNF804A and their association with schizophrenia. |
| Abstract | ZNF804A is a schizophrenia risk gene that was recently identified by genome-wide association studies as well as subsequent replications. Although the results are consistent among studies in European populations, there have been conflicting reports in Chinese populations. The authors conducted both association and functional analyses to test whether ZNF804A is a risk gene for schizophrenia in Chinese populations. The authors recruited two case-control samples of independent Han Chinese (a total of 2,207 participants) from southwestern China. A total of six single-nucleotide polymorphisms (SNPs), including the key SNP (rs1344706) that showed significant association with schizophrenia in European populations and the other five promoter SNPs of ZNF804A, were tested. Based on the results of the association analysis, the authors performed two functional assays to test the impact of the risk SNP on transcriptional factor binding affinity and promoter activity. The SNP rs1344706 was not associated with schizophrenia in either of the two Han Chinese groups, and this result was confirmed by meta-analyses in five Han Chinese samples. However, the authors identified two ZNF804A promoter SNPs that were significantly associated with schizophrenia in both samples, and the significance was strengthened in the combined samples and further supported by haplotype analysis. The functional assays demonstrated that the risk SNP (rs359895) can influence SP1 binding affinity, resulting in a higher promoter activity of the risk allele. Our results suggest that ZNF804A is a common risk gene for schizophrenia in world populations and that the newly identified functional SNP (rs359895) is likely a risk SNP for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | J Psychiatr Res 2013 Jul 47: 926-34 |
| PMID | 23540600 |
| Title | Analysis of Sp transcription factors in the postmortem brain of chronic schizophrenia: a pilot study of relationship to negative symptoms. |
| Abstract | Negative symptoms are the most resilient manifestations in schizophrenia. An imbalance in dopamine and glutamate pathways has been proposed for the emergence of these symptoms. SP1, SP3 and SP4 transcription factors regulate genes in these pathways, suggesting a possible involvement in negative symptoms. In this study, we characterized Sp factors in the brains of subjects with schizophrenia and explored a possible association with negative symptoms. We also included analysis of NR1, NR2A and DRD2 as Sp target genes. Postmortem cerebellum and prefrontal cortex from an antemortem clinically well-characterized and controlled collection of elderly subjects with chronic schizophrenia (n = 16) and control individuals (n = 14) were examined. We used the Positive and Negative Syndrome and the Clinical Global Impression schizophrenia scales, quantitative PCR and immunoblot. SP1 protein and mRNA were reduced in the prefrontal cortex in schizophrenia whereas none of Sp factors were altered in the cerebellum. However, we found that SP1, SP3 and SP4 protein levels inversely correlated with negative symptoms in the cerebellum. Furthermore, NR2A and DRD2 mRNA levels correlated with negative symptoms in the cerebellum. In the prefrontal cortex, SP1 mRNA and NR1 and DRD2 inversely correlated with these symptoms while Sp protein levels did not. This pilot study not only reinforces the involvement of SP1 in schizophrenia, but also suggests that reduced levels or function of SP1, SP4 and SP3 may participate in negative symptoms, in part through the regulation of NMDA receptor subunits and/or Dopamine D2 receptor, providing novel information about the complex negative symptoms in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | J Psychiatr Res 2013 Nov 47: 1608-14 |
| PMID | 23941741 |
| Title | Reduced expression of SP1 and SP4 transcription factors in peripheral blood mononuclear cells in first-episode psychosis. |
| Abstract | Alterations of transcription factor specificity protein 4 (SP4) and 1 (SP1) have been linked to different neuropsychiatric diseases. Reduced SP4 and SP1 protein levels in the prefrontal cortex have been associated with bipolar disorder and schizophrenia, respectively, suggesting that both factors could be involved in the pathogenesis of disorders with psychotic features. The aim of this study was to investigate whether the reduction of SP1, SP4 and SP3 protein and mRNA expression in peripheral blood mononuclear cells in the early stages of psychosis may act as a potential biomarker of these disorders. A cross-sectional study of first-episode psychosis patients (n = 14) compared to gender- and age-matched healthy controls (n = 14) was designed. Patients were recruited through the adult mental health services of Parc Sanitari Sant Joan de Déu. Protein and gene expression levels of SP1, SP4 and SP3 were assessed in peripheral blood mononuclear cells of patients with first-episode psychosis and healthy control subjects. We report that protein levels of SP1 and SP4, but not SP3, are significantly reduced in patients compared to controls. In contrast, we did not observe any differences in expression levels for SP1, SP4 or SP3 genes between patient and control groups. In patients, SP4 protein levels were significantly associated with SP1 protein levels. No association was found, however, between protein and gene expression levels for each factor. Our study shows reduced SP1 and SP4 protein levels in first-episode psychosis in lymphocytes, suggesting that these transcription factors are potential peripheral biomarkers of psychotic spectrum disorders in the early stages. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Schizophr. Res. 2014 Sep 158: 247-54 |
| PMID | 25037527 |
| Title | An investigation of the factors that regulate muscarinic receptor expression in schizophrenia. |
| Abstract | We previously identified a group of subjects with schizophrenia who, on average, have a 75% decrease in cholinergic receptor, muscarinic 1 (CHRM1) in Brodmann's area (BA) 9. To extend this finding, we determined i) if the decrease in CHRM1 was present in another functionally related CNS region (BA6), ii) whether the marked decrease in CHRM1 was accompanied by changes in levels of other CHRMs and iii) potential factors responsible for the decreased CHRM1 expression. We measured CHRM1 and CHRM3 using in situ radioligand binding with [(3)H]pirenzepine and [(3)H]4-DAMP respectively in BA6 from 20 subjects with schizophrenia who had low levels of CHRM1 in BA9 (SzLow[(3)H]PZP), 18 subjects with schizophrenia whose levels of CHRM1 were similar to controls (SzNormal[(3)H]PZP) and 20 control subjects. Levels of CHRM1, 3 and 4 mRNA were measured using qPCR and levels of the transcription factors, SP1 and SP3, were determined using Western blots. In BA6, the density of [(3)H]pirenzepine binding was decreased in subjects with SzLow[(3)H]PZP (p<0.001) compared to controls. The density of [(3)H]4-DAMP binding, levels of CHRM1, 3 and 4 mRNA and levels of SP1 and SP3 was not significantly different between the three groups. This study shows that the previously identified decrease in CHRM1 expression is not confined to the dorsolateral prefrontal cortex but is present in other cortical areas. The effect shows some specificity to CHRM1, with no change in levels of binding to CHRM3. Furthermore, this decrease in CHRM1 does not appear to be associated with low levels of CHRM1 mRNA or to simply be regulated by the transcription factors, SP1 and SP3, suggesting that other mechanisms are responsible for the decreased CHRM1 in these subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | J Psychiatr Res 2014 Nov 58: 189-96 |
| PMID | 25175639 |
| Title | Increased SP4 and SP1 transcription factor expression in the postmortem hippocampus of chronic schizophrenia. |
| Abstract | Altered levels of transcription factor specificity protein 4 (SP4) and 1 (SP1) in the cerebellum, prefrontal cortex and/or lymphocytes have been reported in severe psychiatric disorders, including early psychosis, bipolar disorder, and chronic schizophrenia subjects who have undergone long-term antipsychotic treatments. SP4 transgenic mice show altered hippocampal-dependent psychotic-like behaviours and altered development of hippocampal dentate gyrus. Moreover, NMDAR activity regulates SP4 function. The aim of this study was to investigate SP4 and SP1 expression levels in the hippocampus in schizophrenia, and the possible effect of antipsychotics and NMDAR blockade on SP protein levels in rodent hippocampus. We analysed SP4 and SP1 expression levels in the postmortem hippocampus of chronic schizophrenia (n = 14) and control (n = 11) subjects by immunoblot and quantitative RT-PCR. We tested the effect of NMDAR blockade on SP factors in the hippocampus of mouse treated with an acute dose of MK801. We also investigated the effect of subacute treatments with haloperidol and clozapine on SP protein levels in the rat hippocampus. We report that SP4 protein and both SP4 and SP1 mRNA expression levels are significantly increased in the hippocampus in chronic schizophrenia. Likewise, acute treatment with MK801 increased both SP4 and SP1 protein levels in mouse hippocampus. In contrast, subacute treatment with haloperidol and clozapine did not significantly alter SP protein levels in rat hippocampus. These results suggest that SP4 and SP1 upregulation may be part of the mechanisms deregulated downstream of glutamate signalling pathways in schizophrenia and might be contributing to the hippocampal-dependent cognitive deficits of the disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | FEBS Open Bio 2014 -1 4: 542-53 |
| PMID | 25061554 |
| Title | Systematic analysis of transcription-level effects of neurodegenerative diseases on human brain metabolism by a newly reconstructed brain-specific metabolic network. |
| Abstract | Network-oriented analysis is essential to identify those parts of a cell affected by a given perturbation. The effect of neurodegenerative perturbations in the form of diseases of brain metabolism was investigated by using a newly reconstructed brain-specific metabolic network. The developed stoichiometric model correctly represents healthy brain metabolism, and includes 630 metabolic reactions in and between astrocytes and neurons, which are controlled by 570 genes. The integration of transcriptome data of six neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia) with the model was performed to identify reporter features specific and common for these diseases, which revealed metabolites and pathways around which the most significant changes occur. The identified metabolites are potential biomarkers for the pathology of the related diseases. Our model indicated perturbations in oxidative stress, energy metabolism including TCA cycle and lipid metabolism as well as several amino acid related pathways, in agreement with the role of these pathways in the studied diseases. The computational prediction of transcription factors that commonly regulate the reporter metabolites was achieved through binding-site analysis. Literature support for the identified transcription factors such as USF1, SP1 and those from FOX families are known from the literature to have regulatory roles in the identified reporter metabolic pathways as well as in the neurodegenerative diseases. In essence, the reconstructed brain model enables the elucidation of effects of a perturbation on brain metabolism and the illumination of possible machineries in which a specific metabolite or pathway acts as a regulatory spot for cellular reorganization. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Dec 168: 687-96 |
| PMID | 26285059 |
| Title | Antipsychotic drugs attenuate aberrant DNA methylation of DTNBP1 (dysbindin) promoter in saliva and post-mortem brain of patients with schizophrenia and Psychotic bipolar disorder. |
| Abstract | Due to the lack of genetic association between individual genes and schizophrenia (SCZ) pathogenesis, the current consensus is to consider both genetic and epigenetic alterations. Here, we report the examination of DNA methylation status of DTNBP1 promoter region, one of the most credible candidate genes affected in SCZ, assayed in saliva and post-mortem brain samples. The Illumina DNA methylation profiling and bisulfite sequencing of representative samples were used to identify methylation status of the DTNBP1 promoter region. Quantitative methylation specific PCR (qMSP) was employed to assess methylation of DTNBP1 promoter CpGs flanking a SP1 binding site in the saliva of SCZ patients, their first-degree relatives and control subjects (30, 15, and 30/group, respectively) as well as in post-mortem brains of patients with SCZ and bipolar disorder (BD) versus controls (35/group). qRT-PCR was used to assess DTNBP1 expression. We found DNA hypermethylation of DTNBP1 promoter in the saliva of SCZ patients (?12.5%, P?=?0.036), particularly in drug-naïve patients (?20%, P?=?0.011), and a trend toward hypermethylation in their first-degree relatives (P?=?0.085) versus controls. Analysis of post-mortem brain samples revealed an inverse correlation between DTNBP1 methylation and expression, and normalization of this epigenetic change by classic antipsychotic drugs. Additionally, BD patients with psychotic depression exhibited higher degree of methylation versus other BD patients (?80%, P?=?0.025). DTNBP1 promoter DNA methylation may become a key element in a panel of biomarkers for diagnosis, prevention, or therapy in SCZ and at risk individuals pending confirmatory studies with larger sample sizes to attain a higher degree of significance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |