Peroxisome Proliferator-Activated Receptor Alpha As A Novel Therapeutic Target For Schizophrenia

Background: The pathophysiology of schizophrenia, a major psychiatric disorder, remains elusive. In this study, the role of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor (RXR) families, belonging to the ligand-activated nuclear receptor superfamily, in schizophrenia, was analyzed.Methods: The PPARIRXR family genes were screened by exploiting molecular inversion probe (MIP)-based targeted next-generation sequencing (NGS) using the samples of 1,200 Japanese patients with schizophrenia. The results were compared with the whole-genome sequencing databases of the Japanese cohort (ToMMo) and the gnomAD. To reveal the relationship between PPAR/RXR dysfunction and schizophrenia, Ppara KO mice and fenofibrate (a clinically used PPAR alpha agonist)-administered mice were assessed by performing behavioral, histological, and RNA-seq analyses.Findings: Our findings indicate that c.209-2delA, His117Gln, Arg141Cys, and Arg226Trp of the PPARA gene are risk variants for schizophrenia. The c.209-2delA variant generated a premature termination codon. The three missense variants significantly decreased the activity of PPAR alpha as a transcription factor in vitro. The Ppara KO mice exhibited schizophrenia-relevant phenotypes, including behavioral deficits and impaired synaptogenesis in the cerebral cortex. Oral administration of fenofibrate alleviated spine pathology induced by phencyclidine, an N-methyl-D-aspartate (NMDA) receptor antagonist. Furthermore, pre-treatment with fenofibrate suppressed the sensitivity of mice to another NMDA receptor antagonist, MK-801. RNA-seq analysis revealed that PPAR alpha regulates the expression of synaptogenesis signaling pathway-related genes.Interpretation: The findings of this study indicate that the mechanisms underlying schizophrenia pathogenesis involve PPAR alpha-regulated transcriptional machinery and modulation of synapse physiology. Hence, PPAR alpha can serve as a novel therapeutic target for schizophrenia. (C) 2020 The Authors. Published by Elsevier B.V.