Gene expression analysis implicates a death receptor pathway in schizophrenia pathology.
Gene expression analysis implicates a death receptor pathway in schizophrenia pathology.
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DOI：
10.1371/journal.pone.0035511
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Weickert CS
中科院分区：
文献类型：
--
作者：
Catts VS;Weickert CS
凋亡事件的增加可能是精神分裂症神经病理学的基础。通过数据挖掘方法，我们确定了精神分裂症患者背外侧前额叶皮层（DLPFC）死亡受体信号通路的显著表达变化，特别是涉及肿瘤坏死因子超家族成员6（FAS）受体和肿瘤坏死因子[配体]超家族成员13（TNFSF 13）。我们试图用定量实时RT-PCR在一个独立的组织收集中确认和复制所注意到的mRNA变化。为了测试区域和诊断特异性，检查了眼眶额叶皮质（OFC）的组织，并包括双相情感障碍组。在精神分裂症中，我们证实并复制了DLPFC中TNFSF 13 mRNA表达的显著增加。此外，与未受影响的对照组相比，精神分裂症组中有显著更大比例的受试者DLPFC中FAS受体表达升高。在双相情感障碍组中没有观察到这些变化。在OFC中，TNFSF 13或FAS受体mRNA表达无显著差异。在精神分裂症和双相情感障碍组中发现BH 3相互作用结构域死亡激动剂（BID）mRNA转录水平降低，影响DLPFC和OFC。我们测试了TNFSF 13 mRNA表达是否与DLPFC中的神经元mRNA相关，发现与中间神经元标记物小白蛋白和生长抑素呈显著负相关，与PPP 1 R9 B（spinophilin）呈正相关，但与DLG 4（PSD-95）无关。DLPFC中TNFSF 13 mRNA的表达与组织pH值呈负相关，但培养细胞中pH值的降低不会导致TNFSF 13 mRNA的增加，外源性TNFSF 13也不会降低pH值。我们得出结论，TNFSF 13表达的增加可能是导致精神分裂症脑病理学的几种细胞死亡细胞因子异常之一，而TNFSF 13的增加可能与脑pH值降低有关，这种变化不一定与脑pH值有因果关系。
An increase in apoptotic events may underlie neuropathology in schizophrenia. By data-mining approaches, we identified significant expression changes in death receptor signaling pathways in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia, particularly implicating the Tumor Necrosis Factor Superfamily member 6 (FAS) receptor and the Tumor Necrosis Factor [ligand] Superfamily member 13 (TNFSF13) in schizophrenia. We sought to confirm and replicate in an independent tissue collection the noted mRNA changes with quantitative real-time RT-PCR. To test for regional and diagnostic specificity, tissue from orbital frontal cortex (OFC) was examined and a bipolar disorder group included. In schizophrenia, we confirmed and replicated significantly increased expression of TNFSF13 mRNA in the DLPFC. Also, a significantly larger proportion of subjects in the schizophrenia group had elevated FAS receptor expression in the DLPFC relative to unaffected controls. These changes were not observed in the bipolar disorder group. In the OFC, there were no significant differences in TNFSF13 or FAS receptor mRNA expression. Decreases in BH3 interacting domain death agonist (BID) mRNA transcript levels were found in the schizophrenia and bipolar disorder groups affecting both the DLPFC and the OFC. We tested if TNFSF13 mRNA expression correlated with neuronal mRNAs in the DLPFC, and found significant negative correlations with interneuron markers, parvalbumin and somatostatin, and a positive correlation with PPP1R9B (spinophilin), but not DLG4 (PSD-95). The expression of TNFSF13 mRNA in DLPFC correlated negatively with tissue pH, but decreasing pH in cultured cells did not cause increased TNFSF13 mRNA nor did exogenous TNFSF13 decrease pH. We concluded that increased TNFSF13 expression may be one of several cell-death cytokine abnormalities that contribute to the observed brain pathology in schizophrenia, and while increased TNFSF13 may be associated with lower brain pH, the change is not necessarily causally related to brain pH.
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作者：
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通讯作者：
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