Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
PLoS One. 2007 Sep 5;2(9):e817. 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.
METHODOLOGY/PRINCIPAL FINDINGS: 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.
CONCLUSIONS/SIGNIFICANCE: 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.
目前的假说认为精神分裂症是一种多基因疾病，多个基因相互作用，并与环境刺激共同作用，导致其临床表现的差异。我们研究了普遍存在的转录因子 Sp1 是否在精神分裂症中异常表达，以及是否会因此影响该疾病相关基因的表达。
方法/主要发现：我们分析了 Stanley 基金会脑库获得的三个死后大脑区域以及精神分裂症患者和对照组的淋巴细胞中的 Sp1 和线粒体复合物 I 亚基（NDUFV1、NDUFV2）的 mRNA。我们还研究了 Sp1 对这些基因转录的作用。Sp1 在精神分裂症患者的大脑和外周组织中均异常表达。其 mRNA 改变模式与 NDUFV1 和 NDUFV2 的改变模式相似，在前额叶皮层和纹状体中减少，而在顶枕叶皮层和精神分裂症患者的淋巴细胞中增加。此外，在正常受试者中这些基因之间存在高度显著的相关性，但在患者中这种相关性发生了扭曲。Sp1 通过 Sp1/DNA 结合抑制剂米托霉素抑制神经母细胞瘤细胞中 NDUFV1 和 NDUFV2 的转录，从而证明了其在调节复合物 I 亚基中的作用。此外，Sp1 通过结合其三个 GC 盒激活 NDUFV2 启动子。米托霉素抑制了这两种激活和结合作用。
结论/意义：这些发现表明，Sp1 的异常可能是多基因和临床表现异质性的精神分裂症的主要激活剂/抑制剂，或与其他转录因子共同作用，并受到环境刺激的影响。
