Dysregulation of phospholipase and cyclooxygenase expression is involved in Schizophrenia

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.

Funding: 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).

Keywords: COX-1; COX-2; Niacin skin flush responses; PLA2; Schizophrenia.

Fig. 1

All detected PLA2/COX pathway genes and regulatory factors and alterations in their transcription levels between patients with schizophrenia and healthy controls

Fig. 2

Plot of niacin-skin response levels in different genotypes. P-values of rs10798064 and rs4648250 were obtained by T-test.

Fig. 3

Schematic illustrating the role of the PLA2/COX cascade in the pathogenesis of schizophrenia and blunting of the niacin flush response. The PLA2/COX pathway is significantly disrupted in patients with schizophrenia: the level of cPLA2, which primarily mediates the dissociation of AA, is significantly increased, and catabolism of free AA is enhanced by COX-1. The metabolites affect nervous system function by interfering with the release of neurotransmitters and inducing overexpression of cytokines such as IL-6. However, downregulation of CREB1 and COX-2, as well as the decrease in the level of the PGE2 receptor EP4, may be related to the blunting of the niacin skin flush response.