Dysregulation of DPYSL2 expression by mTOR signaling in schizophrenia: Multi-level study of postmortem brain
Dysregulation of DPYSL2 expression by mTOR signaling in schizophrenia: Multi-level study of postmortem brain
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DOI：
10.1016/j.neures.2021.09.004
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发表时间：
2022-02-01
影响因子：
2.9
通讯作者：
Yabe, Hirooki
中科院分区：
文献类型：
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作者：
Izumi, Ryuta;Hino, Mizuki;Yabe, Hirooki
雷帕霉素（mTOR）信号传导和二氢嘧啶酶样2（DPYSL 2）的机制靶点作为精神分裂症的潜在治疗靶点越来越受到关注，它们通过5&PRIME; TOP基序的Cap依赖性翻译连接。我们定量分析了24例精神分裂症患者和32例对照者的死后脑组织样本的前额叶皮层（PFC）和上级颞回（STG）中构成mTOR信号传导和DPYSL 2的分子的表达，并进行了关联分析，以检查精神分裂症中mTOR信号传导对DPYSL 2表达的异常调节。精神分裂症患者PFC和STG中核糖体蛋白S6（S6）的平均水平较低（P <0.01）。DPYSL 2表达与磷酸化S6表达水平呈显著正相关，磷酸化S6是mTOR翻译调控的效应物，磷酸化S6与DPYSL 2表达之间的相关性斜率在病例组和对照组之间存在差异。对这些mTOR信号传导和DPYSL 2改变与遗传多态性和临床特征的关联分析表明，DPYSL 2的某些遗传变体需要高mTOR信号传导活性。因此，这些发现证实了精神分裂症中S6表达水平的降低，并支持mTOR信号传导和DPYSL 2之间通过5-PRIME; TOP Cap依赖性翻译的关系，从而提供了将与mTOR信号传导和DPYSL 2相关的两种主要精神分裂症治疗策略联系起来的见解。
The mechanistic target of rapamycin (mTOR)-signaling and dihydropyrimidinase-like 2 (DPYSL2), which are increasingly gaining attention as potential therapeutic targets for schizophrenia, are connected via Cap dependent translation of the 5 & PRIME;TOP motif. We quantified the expression of molecules constituting the mTORsignaling and DPYSL2 in the prefrontal cortex (PFC) and superior temporal gyrus (STG) of postmortem brain tissue samples from 24 patients with schizophrenia and 32 control individuals and conducted association analysis to examine abnormal regulation of DPYSL2 expression by the mTOR-signaling in schizophrenia. The average ribosomal protein S6 (S6) levels in the PFC and STG were lower in patients with schizophrenia (p < 0.01). DPYSL2 expression showed a significant positive correlation with phospho-S6 expression levels, which were effectors of mTOR translational regulation, and the correlation slope between phospho-S6 and DPYSL2 expressions differed between cases and controls. Association analyses of these mTOR-signaling and DPYSL2 alterations with genetic polymorphisms and the clinical profile suggested that certain genetic variants of DPYSL2 require high mTOR-signaling activity. Thus, the findings confirmed decreased S6 expression levels in schizophrenia and supported the relationship between the mTOR-signaling and DPYSL2 via 5 & PRIME;TOP Cap-dependent translation, thus providing insights connecting the two major schizophrenia treatment strategies associated with the mTORsignaling and DPYSL2.