Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
The Fourth People's Hospital of Wuhu, Wuhu, China.
EBioMedicine. 2021 Feb;64:103239. doi: 10.1016/j.ebiom.2021.103239. Epub 2021 Feb 10.
Schizophrenia (SZ) is a severe mental disease with highly heterogeneous clinical manifestations and pathological mechanisms. Schizophrenia is linked to abnormalities in cell membrane phospholipids and blunting of the niacin skin flush response, but the associations between these phenotypes and its molecular pathogenesis remain unclear. This study aimed to describe the PLA2/COX pathway, the key link between phospholipids and niacin flush, and to illustrate the pathogenic mechanisms in schizophrenia that mediate the above phenotypes.
A total of 166 patients with schizophrenia and 54 healthy controls were recruited in this study and assigned to a discovery set and a validation set. We assessed the mRNA levels of 19 genes related to the PLA2/COX cascade in leukocytes by real-time PCR. Plasma IL-6 levels were measured with an ELISA kit. Genetic association analysis was performed on PLA2G4A and PTGS2 to investigate their potential relationship with blunted niacin-skin response in an independent sample set.
Six of the 19 genes in the PLA2/COX pathway exhibited significant differences between schizophrenia and healthy controls. The disturbance of the pathway indicates the activation of arachidonic acid (AA) hydrolysis and metabolization, resulting in the abnormalities of membrane lipid homeostasis and immune function, further increasing the risk of schizophrenia. On the other hand, the active process of AA hydrolysis from cell membrane phospholipids and decreased transcription of CREB1, COX-2 and PTGER4 may explain the reported findings of a blunted niacin response in schizophrenia. The significant genetic associations between PLA2G4A and PTGS2 with the niacin-skin responses further support the inference.
These results suggested that the activation of AA hydrolysis and the imbalance in COX-1 and COX-2 expression are involved in the pathogenesis of schizophrenia and blunting of the niacin flush response.
This work was supported by the National Key R&D Program of China (2016YFC1306900, 2016YFC1306802); the National Natural Science Foundation of China (81971254, 81771440, 81901354); Interdisciplinary Program of Shanghai Jiao Tong University (ZH2018ZDA40, YG2019GD04, YG2016MS48); Grants of Shanghai Brain-Intelligence Project from STCSM (16JC1420500); Shanghai Key Laboratory of Psychotic Disorders (13DZ2260500); and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01); China Postdoctoral Science Foundation (2018M642029, 2018M630442, 2019M661526, 2020T130407); Natural Science Foundation of Shanghai (20ZR1426700); and Startup Fund for Youngman Research at SJTU (19 × 100040033).
精神分裂症（SZ）是一种临床表现和病理机制高度异质的严重精神疾病。精神分裂症与细胞膜磷脂异常和烟酸皮肤潮红反应迟钝有关，但这些表型与分子发病机制之间的关系尚不清楚。本研究旨在描述 PLA2/COX 途径，即磷脂和烟酸潮红反应之间的关键联系，并阐明介导上述表型的精神分裂症发病机制中的致病机制。
本研究共招募了 166 名精神分裂症患者和 54 名健康对照者，分为发现集和验证集。我们通过实时 PCR 评估白细胞中与 PLA2/COX 级联相关的 19 个基因的 mRNA 水平。使用 ELISA 试剂盒测量血浆 IL-6 水平。对 PLA2G4A 和 PTGS2 进行遗传关联分析，以研究它们在独立样本集中与烟酸皮肤反应迟钝的潜在关系。
PLA2/COX 通路的 19 个基因中有 6 个在精神分裂症和健康对照组之间存在显著差异。该通路的紊乱表明花生四烯酸（AA）水解和代谢的激活，导致膜脂质稳态和免疫功能异常，进一步增加精神分裂症的风险。另一方面，从细胞膜磷脂中水解 AA 和 CREB1、COX-2 和 PTGER4 转录减少可能解释了报道的精神分裂症中烟酸反应迟钝的发现。 PLA2G4A 和 PTGS2 与烟酸皮肤反应之间的显著遗传关联进一步支持了这一推断。
这些结果表明 AA 水解的激活和 COX-1 和 COX-2 表达的失衡参与了精神分裂症的发病机制和烟酸潮红反应的迟钝。
本工作得到了中国国家重点研发计划（2016YFC1306900，2016YFC1306802）；中国国家自然科学基金（81971254，81771440，81901354）；上海交通大学跨学科项目（ZH2018ZDA40，YG2019GD04，YG2016MS48）；上海市科委脑-智工程（16JC1420500）；上海精神障碍重点实验室（13DZ2260500）；上海市重大科技项目（2017SHZDZX01）；中国博士后科学基金会（2018M642029、2018M630442、2019M661526、2020T130407）；上海市自然科学基金（20ZR1426700）；上海交通大学青年教师启航基金（19×100040033）。
Zotero 插件
