Peroxisome proliferator-activated receptor α as a novel therapeutic target for schizophrenia.
EBioMedicine
; 62: 103130, 2020 Dec.
Article
de En
| MEDLINE
| ID: mdl-33279456
ABSTRACT
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.Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Schizophrénie
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Marqueurs biologiques
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Récepteur PPAR alpha
Type d'étude:
Etiology_studies
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Prognostic_studies
Limites:
Adult
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Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Langue:
En
Journal:
EBioMedicine
Année:
2020
Type de document:
Article