Failure to support a genetic contribution of AKT1 polymorphisms and altered AKT signaling in schizophrenia
Failure to support a genetic contribution of AKT1 polymorphisms and altered AKT signaling in schizophrenia
复制标题
DOI：
10.1111/j.1471-4159.2006.04033.x
复制
发表时间：
2006-10-01
影响因子：
4.7
通讯作者：
Yoshikawa, Takeo
中科院分区：
文献类型：
--
作者：
Ide, Masayuki;Ohnishi, Tetsuo;Yoshikawa, Takeo
蛋白激酶v-akt鼠胸腺瘤病毒癌基因同源物（AKT）基因家族包括磷酸化和磷酸化糖原合成酶激酶3 β（GSK 3 β）的三种人类同源物。研究报告了AKT 1与精神分裂症的遗传关联。此外，在这种疾病中报告了AKT 1蛋白表达减少和GSK 3 β磷酸化减少，导致了精神分裂症发病机制中AKT 1-GSK 3 β信号减弱的新理论。我们通过进行遗传和蛋白质表达分析来评估这一理论。一个基于家庭的关联测试AKT 1没有显示与精神分裂症在日本的主题。在来自两个不同脑库的精神分裂症患者脑中检测到的总AKT、AKT 1和磷酸化GSK 3 β的表达水平也未能支持这一理论。此外，在日本精神分裂症患者的淋巴细胞中没有观察到减弱的AKT-GSK 3 β信号传导，与以前的研究结果形成对比。重要的是，我们发现Ser 9的磷酸化GSK 3 β水平往往与死后时间呈负相关，AKT的磷酸化水平与大脑pH值呈负相关，这些问题在以前的研究中没有评估。这些数据在估计死后大脑中GSK 3 β和AKT的磷酸化水平时引入了一个注意事项。总的来说，这项研究未能支持精神分裂症中AKT-GSK 3 β分子级联信号的减少。
The protein kinase v-akt murine thymoma viral oncogene homolog (AKT) gene family comprises three human homologs that phosphorylate and inactivate glycogen synthase kinase 3 beta (GSK3 beta). Studies have reported the genetic association of AKT1 with schizophrenia. Additionally, decreased AKT1 protein expression and the reduced phosphorylation of GSK3 beta were reported in this disease, leading to a new theory of attenuated AKT1-GSK3 beta signaling in schizophrenia pathogenesis. We have evaluated this theory by performing both genetic and protein expression analyses. A family based association test of AKT1 did not show association with schizophrenia in Japanese subjects. The expression levels of total AKT, AKT1 and phosphorylated GSK3 beta detected in the schizophrenic brains from two different brain banks also failed to support the theory. In addition, no attenuated AKT-GSK3 beta signaling was observed in the lymphocytes from Japanese schizophrenics, contrasting with previous findings. Importantly, we found that the level of phosphorylated GSK3 beta at Ser9 tended to be inversely correlated with postmortem intervals, and that the phosphorylation levels of AKT were inversely correlated with brain pH, issues not assessed in the previous study. These data introduce a note of caution when estimating the phosphorylation levels of GSK3 beta and AKT in postmortem brains. Collectively, this study failed to support reduced signaling of the AKT-GSK3 beta molecular cascade in schizophrenia.