Publications (10) View all
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Article: Mitochondrial DNA (mtDNA) in brain samples from patients with major psychiatric disorders: Gene expression profiles, MtDNA content and presence of the MtDNA common deletion.
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ABSTRACT: Several lines of evidence support a mitochondrial dysfunction in major psychiatric disorders. The objective of this study was to determine whether mitochondrial DNA (mtDNA) expression or content are implicated in the mitochondrial dysfunction observed in schizophrenia (SCH), bipolar disorder (BD), and major depressive disorder (MDD). MtDNA gene expression and mtDNA content (including the MT-ND4 deletion) were measured by RT-qPCR and qPCR, respectively. Post-mortem brain tissue from 60 subjects, divided evenly into four diagnostic groups (SCH, BD, MDD, and control (C)), was analyzed. MT-ND1 gene expression was significantly increased in the BD group compared with the C group. MDD and SCH patients showed a similar pattern of mtDNA expression, which was different from that in BD patients. Similarly, a larger number of MDD and SCH patients tended to have the MT-ND4 gene deleted compared with BD and C subjects. However, no other significant differences were observed in mtDNA gene expression and mtDNA content. Notably, high variability was observed in the mtDNA gene expression and content in each diagnostic group. Previous studies and the present work provide evidence for a role of mtDNA in SCH, BD and MDD. However, further studies with larger patient and control groups as well as by analyzing distinct brain regions are needed to elucidate the role of mtDNA in major psychiatric disorders. © 2013 Wiley Periodicals, Inc.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2013; · 3.70 Impact Factor -
Article: Increased expression of the spliced DDR1c isoform in brain tissues from schizophrenia patients.
Journal of psychiatric research 03/2012; 46(6):825-7. · 3.72 Impact Factor -
Article: RT-qPCR study on post-mortem brain samples from patients with major psychiatric disorders: reference genes and specimen characteristics.
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ABSTRACT: Gene expression studies conducted in post-mortem human brain samples have the potential to identify relevant genes implicated in psychiatric disorders. Although reverse transcription quantitative real-time PCR (RT-qPCR) has emerged as the method of choice for specific gene expression studies, it requires the use of stable reference genes, and it is necessary to control for pre- and post-mortem factors to obtain reliable data. The aim of this study was to identify suitable reference genes and specimen characteristics that can be taken into account when comparing mRNA expression data between post-mortem brain specimens from psychiatric patients and controls. We used a selection of suitably matched occipital cortex specimens from subjects in each of the following groups: schizophrenia (N = 15), bipolar disorder (N = 13), major depressive disorder (N = 15), and control (N = 15). Quantitative and qualitative RNA analyses were performed prior to RT-qPCR and gene expression stability was evaluated with geNorm and NormFinder. We identified GAPDH, RPS17, RPL30, RPLP0, and TFRC as potential reference genes from a sample plate containing 32 candidates commonly used as reference genes. Further analyses of these 5 genes highlighted that 1) they are suitable reference genes for RT-qPCR studies in these post-mortem brain samples from psychiatric patients, and 2) the RNA quality index is highly correlated with gene expression values (r = -0.681, p < 0.0001). In addition to controlling for pre- and post-mortem factors and selecting stable reference genes for normalization, sample sets should be matched with regard to RNA quality.Journal of psychiatric research 06/2011; 45(11):1411-8. · 3.72 Impact Factor -
Article: Expression of the tyrosine kinase discoidin domain receptor 1 (DDR1) in human central nervous system myelin.
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ABSTRACT: During development of the mouse brain, the protein kinase discoidin domain receptor 1 (DDR1) is present prenatally in neurons of the proliferative areas, and postnatally, DDR1 expression is no longer detected in neurons, but a spatial-temporal expression pattern in oligodendrocytes that overlaps with the dynamics of the myelination process is detected. Notably, oligodendrocytic DDR1 expression is upregulated in mice during experimentally induced remyelination. Recently, we demonstrated that DDR1 expression is high in human brain and that there is an association between the gene and schizophrenia in a case-control study. However, data regarding expression of DDR1 in the human brain are scarce. Here, we describe the expression pattern of DDR1 in the human adult cerebral cortex. Using several immunohistological techniques and in situ hybridization, we identified DDR1 in the following: a) myelin, b) capillary endothelial cells in the gray as well as white matter, and c) in the soma of some oligodendrocytes and astrocytes in the white matter. The most important overall finding in this study was that DDR1 is present in myelin and is expressed by oligodendrocyte cells. We detected the presence of DDR1 mRNA and protein in myelin and observed that DDR1 co-localized with the classical myelin basic protein (MBP). Moreover, we found a strong positive correlation between expression levels of DDR1 and two myelin-associated genes, myelin-associated glycoprotein (MAG) and oligodendrocyte transcription factor 2 (OLIG2). These observations suggest that DDR1 could be an important constituent of myelin. Because defects in myelination are linked to several mental disorders such as schizophrenia, the function of DDR1 in the process of myelination warrants further investigation.Brain research 04/2010; 1336:22-9. · 2.46 Impact Factor -
Article: The discoidin domain receptor 1 as a novel susceptibility gene for schizophrenia.
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ABSTRACT: Evidence suggests that myelin alterations could predispose to schizophrenia. Reduced expression of several myelin genes has been observed in schizophrenia patients. Recently, we identified the discoidin domain receptor 1 (DDR1; located at human chromosome 6p21.3) as a myelin gene in the mouse model and in a human oligodendroglial cell line. In the present study we screened for single nucleotide polymorphisms (SNPs) in the DNA from 100 schizophrenia patients. We identified a novel mutation within exon 10 that produces the amino-acid substitution N502S in the a-d isoforms, and M475V in the e isoform. However the frequency of the mutation (2%) was similar in schizophrenia patients and in control subjects. In a case-control assessment with 389 schizophrenic patients and 615 controls, we identified one SNP (SNP9, rs1049623) associated with schizophrenia (odds ratio=1.44, 95% confidence interval: 1.15-1.79, adjusted P=0.0016). This association was confirmed in haplotype analysis; the SNPs 9-10-11 (rs1049623, rs2267641 and rs2239518) haplotype remaining significant even after adjustment for multiple testing (adjusted P=0.0136). Of note was a strong gender dependence in the association, that is, statistical significance restricted to men (adjusted P-value=0.0002). Regression analysis of DDR1 mRNA expression in peripheral blood lymphocytes from schizophrenia patients showed that the presence of the G allele significantly decreased the relative number of mRNA copies in a dose-dependent manner (P=0.003). These data suggest that the risk haplotype tags a cis-acting variant involved in the transcription regulation system of the gene. In conclusion, we propose the DDR1 as a new susceptibility gene for schizophrenia.Molecular Psychiatry 10/2007; 12(9):833-41. · 13.67 Impact Factor
