Sp1 Expression Is Disrupted in Schizophrenia; A Possible Mechanism for the Abnormal Expression of Mitochondrial Complex I Genes, NDUFV1 and NDUFV2

• Published in: PloS one Vol. 2; no. 9; p. e817
• Main Authors: Ben-Shachar, Dorit, Karry, Rachel
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.09.2007; Public Library of Science (PLoS)
• Subjects: 5' Flanking Region - genetics; Analysis; Binding; Binding sites; Bipolar disorder; Brain; Cell Adhesion Molecules, Neuronal - genetics; Cell Adhesion Molecules, Neuronal - metabolism; Cell Line, Tumor; Cortex (occipital); Cortex (parietal); Deoxyribonucleic acid; DNA; DNA binding proteins; Electron transport chain; Electron Transport Complex I - genetics; Electron Transport Complex I - metabolism; Environmental effects; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Female; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genetic aspects; Genetic research; Glucose; Growth factors; Humans; Hypotheses; Kinases; Laboratories; Lymphocytes; Male; Medical research; Medicine; Mental disorders; Mental Health/Schizophrenia and Other Psychoses; Middle Aged; Mitochondria; NADH Dehydrogenase - genetics; NADH Dehydrogenase - metabolism; NADH-ubiquinone oxidoreductase; Neostriatum; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neuroblastoma; Neuroblastoma cells; Neuroblasts; Occipital lobe; Organ Specificity - drug effects; Organ Specificity - genetics; Patients; Phosphorylation; Plicamycin - pharmacology; Prefrontal cortex; Promoter Regions, Genetic - genetics; Protein Binding - drug effects; Protein expression; Protein Subunits - genetics; Protein Subunits - metabolism; Proteins; Psychiatry; Psychobiology; Reelin Protein; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Schizophrenia; Schizophrenia - genetics; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Sp1 protein; Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - metabolism; Stimuli; Transcription (Genetics); Transcription factors; Transcription, Genetic - drug effects; Israel
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0000817

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.