Summary: Fenofibrate, a drug developed to control cholesterol, alleviated brain and behavioral abnormalities in mouse models of schizophrenia.
New therapies that improve connectivity and circuitry in the brain of people with schizophrenia could result from the discovery by a RIKEN-led team of a potential new target for drugs to treat the psychiatric disorder.
Treatment for schizophrenia has not changed much in 60 years. Doctors still generally prescribe medicines designed to tame psychosis by blocking neurotransmitter signaling in the brain. While the drugs ease symptoms such as delusions and hallucinations, they leave many other aspects of the illness untreated and their side effects can be off-putting to many patients. Researchers are thus keen to find new targets for drugs.
In search of new molecular targets, a team led by Takeo Yoshikawa and Motoko Maekawa from the RIKEN Center for Brain Science focused on a metabolic pathway previously implicated in the development of schizophrenia. They used targeted sequencing techniques to probe six genes, each encoding a protein from the peroxisome-proliferator-activated receptor (PPAR) family or one of its signaling partners.
By conducting a genetic analysis of 1,200 people with schizophrenia, the researchers identified several harmful mutations in the gene encoding PPARα that were absent in a large sequence database of DNA from Japanese individuals in the general population. Experiments involving cells showed that these mutations reduced the expression levels of PPARα. And mice engineered to lack PPARα displayed behavioral and molecular deficits consistent with symptoms of schizophrenia.
A gene-expression analysis of brain tissue taken from the mutant and normal mice revealed that PPARα is a key regulator of synapse formation in the brain. This adds to the protein’s known metabolic role throughout the body.
To boost synaptic function—a well-documented problem in people with schizophrenia—the team gave mice a drug called fenofibrate, which activates PPARα. Fenofibrate is already taken by millions of people every day to help control cholesterol and fat levels in the blood. The researchers showed that the drug helped alleviate brain and behavioral abnormalities in various mouse models of schizophrenia.
However, because fenofibrate does not readily cross the blood–brain barrier, the scientists had to administer very high doses of the drug. That approach would be risky in people, says Maekawa, since fenofibrate can sometimes seriously damage muscle tissue. To avoid that potential side effect, drug developers may have to refine the chemistry of fenofibrate or discover new agents that activate PPARα. “To test the therapeutic strategy in people, we need more drugs that penetrate the brain for clinical trials,” Maekawa says.
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Original Research: Open access.
“Peroxisome proliferator-activated receptor α as a novel therapeutic target for schizophrenia” by Yuina Wada et al. EBioMedicine
Peroxisome proliferator-activated receptor α as a novel therapeutic target for schizophrenia
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.
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.
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.
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.