Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

The Protein-Protein Interaction Network of First Episode Psychosis and Schizophrenia Reveals Possible Trigger Factors and New Drug Targets among Intracellular Signal Transduction Pathways and Neurotoxicity Processes

Version 1 : Received: 25 July 2021 / Approved: 27 July 2021 / Online: 27 July 2021 (09:16:54 CEST)

How to cite: Maes, M.; Plaimas, K.; Suratanee, A.; Noto, C.; Kanchanatawan, B. The Protein-Protein Interaction Network of First Episode Psychosis and Schizophrenia Reveals Possible Trigger Factors and New Drug Targets among Intracellular Signal Transduction Pathways and Neurotoxicity Processes. Preprints 2021, 2021070596 (doi: 10.20944/preprints202107.0596.v1). Maes, M.; Plaimas, K.; Suratanee, A.; Noto, C.; Kanchanatawan, B. The Protein-Protein Interaction Network of First Episode Psychosis and Schizophrenia Reveals Possible Trigger Factors and New Drug Targets among Intracellular Signal Transduction Pathways and Neurotoxicity Processes. Preprints 2021, 2021070596 (doi: 10.20944/preprints202107.0596.v1).

Abstract

There is evidence that schizophrenia is characterized by activation of the immune-inflammatory response (IRS) and compensatory immune-regulatory (CIRS) systems and lowered neuroprotection. Studies performed on antipsychotic-naïve first episode psychosis (AF-FEP) and schizophrenia (FES) patients are important as they may disclose the pathogenesis of the disease. However, the interactome of FEP/FES is not well delineated. The aim of the current study was to delineate the characteristics of the protein-protein interaction (PPI) network of AN-FEP and its transition to FES and the biological functions, pathways, and molecular patterns, which are over-represented in FEP/FES. PPI network analysis shows that FEP and FEP/FES are strongly associated with a response to a bacterium, TNF, NFκB, RELA, SP1, JAK-STAT, death receptor and TLR4 signaling, and tyrosine phosphorylation of STAT proteins. Specific molecular complexes of the peripheral immune response are associated with microglial activation, neuroinflammation and gliogenesis. FEP/FES is accompanied by lowered protection against inflammation in part attributable to dysfunctional miRNA maturation, deficits in neurotrophin/Trk, RTK and Wnt/catenin signaling and adherens junction organization. Lowered neuroprotection due to reduced neurotrophin/Trk and Wnt/catenin signaling, and DISC1 expression and multiple interactions between lowered BDNF, CDH1, CTNNB, and DISC1 expression, increase the vulnerability to the neurotoxic effects of immune products including cytokines and complement factors. All pathways or molecular patterns enriched in the interactome of FEP/FES are directly or indirectly affected by LPS. In summary: FEP appears to be triggered by a biotic stimulus (e.g. Gram-negative bacteria) which may induce neuro-immune toxicity cascades especially when anti-inflammatory and neurotrophic protections are deficient.

Keywords

schizophrenia; neuro-immune; inflammation; physiological stress; bacterial translocation; psychiatry; LPS

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