Peroxisome proliferator-activated receptor α as a novel therapeutic target for schizophrenia
Yuina Wada,
Motoko Maekawa,
Tetsuo Ohnishi,
Shabeesh Balan,
Shigeru Matsuoka,
Kazuya Iwamoto,
Yoshimi Iwayama,
Hisako Ohba,
Akiko Watanabe,
Yasuko Hisano,
Yayoi Nozaki,
Tomoko Toyota,
Tomomi Shimogori,
Masanari Itokawa,
Tetsuyuki Kobayashi,
Takeo Yoshikawa
Affiliations
Yuina Wada
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan; Department of Biological Science, Graduate School of Humanities and Science, Ochanomizu University, Tokyo 112-8610, Japan; Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan
Motoko Maekawa
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan; Department of Biological Science, Graduate School of Humanities and Science, Ochanomizu University, Tokyo 112-8610, Japan; Corresponding authors.
Tetsuo Ohnishi
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan; Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan
Shabeesh Balan
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan; Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan
Shigeru Matsuoka
Faculty of Medicine, Oita University, Oita 879-5593, Japan
Kazuya Iwamoto
Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
Yoshimi Iwayama
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan
Hisako Ohba
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan
Akiko Watanabe
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan
Yasuko Hisano
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan
Yayoi Nozaki
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan
Tomoko Toyota
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan
Tomomi Shimogori
Laboratory for Molecular Mechanisms of Brain Development, RIKEN Center for Brain Science, Saitama 351-0198, Japan
Masanari Itokawa
Center for Medical Cooperation, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
Tetsuyuki Kobayashi
Department of Biological Science, Graduate School of Humanities and Science, Ochanomizu University, Tokyo 112-8610, Japan
Takeo Yoshikawa
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan; Department of Biological Science, Graduate School of Humanities and Science, Ochanomizu University, Tokyo 112-8610, Japan; Corresponding authors.
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 PPARα 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 PPARα 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 PPARα regulates the expression of synaptogenesis signaling pathway-related genes. Interpretation: The findings of this study indicate that the mechanisms underlying schizophrenia pathogenesis involve PPARα-regulated transcriptional machinery and modulation of synapse physiology. Hence, PPARα can serve as a novel therapeutic target for schizophrenia.
