| First Author | Wada Y | Year | 2020 |
| Journal | EBioMedicine | Volume | 62 |
| Pages | 103130 | PubMed ID | 33279456 |
| Mgi Jnum | J:313946 | Mgi Id | MGI:6801367 |
| Doi | 10.1016/j.ebiom.2020.103130 | Citation | Wada Y, et al. (2020) Peroxisome proliferator-activated receptor alpha as a novel therapeutic target for schizophrenia. EBioMedicine 62:103130 |
| abstractText | 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 PPAR/RXR 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 PPARalpha 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 PPARalpha 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 PPARalpha regulates the expression of synaptogenesis signaling pathway-related genes. INTERPRETATION: The findings of this study indicate that the mechanisms underlying schizophrenia pathogenesis involve PPARalpha-regulated transcriptional machinery and modulation of synapse physiology. Hence, PPARalpha can serve as a novel therapeutic target for schizophrenia. |
