Decreased expression of Fyn protein and disbalanced alternative splicing patterns in platelets from patients with schizophrenia
Decreased expression of Fyn protein and disbalanced alternative splicing patterns in platelets from patients with schizophrenia
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DOI：
10.1016/j.psychres.2008.04.014
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发表时间：
2009-07-30
影响因子：
11.3
通讯作者：
Yagi, Takeshi
中科院分区：
文献类型：
--
作者：
Hattori, Kotaro;Fukuzako, Hiroshi;Yagi, Takeshi
Fyn是Src家族激酶，在脑组织和血细胞中高度表达。在小鼠脑中，Fyn参与脑发育、通过N-甲基-D-天冬氨酸（NMDA）受体亚基磷酸化的突触传递以及情绪行为的调节。最近，我们发现Fyn参与了抗精神病药物氟哌啶醇在纹状体神经元的信号转导。为了确定精神分裂症患者是否存在Fyn异常，我们分析了110名精神分裂症患者，75名患者的一级亲属和130名对照者的血小板样本中的Fyn表达。Western blot分析显示，与对照组相比，精神分裂症患者及其亲属的Fyn蛋白水平显着降低。在mRNA水平上，fyn的剪接模式在患者及其亲属中发生了改变;特别是，fyn Delta 7的比例升高，其中外显子7缺失。在HEK 293 T细胞中的表达研究表明，Fyn Delta 7对Fyn底物的磷酸化具有显性负效应。这些结果表明，在Fyn功能的新缺陷，表现为下调Fyn蛋白或改变转录的Fyn基因，在精神分裂症患者。(C)2008爱思唯尔爱尔兰有限公司保留所有战斗。
Fyn, a Src-family kinase, is highly expressed in brain tissue and blood cells. In the mouse brain, Fyn participates in brain development, synaptic transmission through the phosphorylation of N-methyl-D-aspartate (NMDA) receptor subunits, and the regulation of emotional behavior. Recently, we found that Fyn is required for the signal transduction in striatal neurons that is initiated by haloperidol, an antipsychotic drug. To determine whether Fyn abnormalities are present in patients with schizophrenia, we analyzed Fyn expression in platelet samples from 110 patients with schizophrenia, 75 of the patients' first-degree relatives, and 130 control subjects. A Western blot analysis revealed significantly lower levels of Fyn protein among the patients with schizophrenia and their relatives, compared with the level in the control group. At the mRNA level, the splicing patterns of fyn were altered in the patients and their relatives; specifically, the ratio of fyn Delta 7, in which exon 7 is absent, was elevated. An expression study in HEK293Tcells revealed that Fyn Delta 7 had a dominant-negative effect on the phosphorylation of Fyn's substrate. These results suggest novel deficits in Fyn function, manifested as the downregulation of Fyn protein or the altered transcription of the fyn gene, in patients with schizophrenia. (C) 2008 Elsevier Ireland Ltd. All fights reserved.