Pathogenic Mis-splicing of CPEB4 in Schizophrenia

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Schizophrenia (SCZ) arises from genetic and environmental factors impacting gene expression.
• The CPEB family of RNA-binding proteins regulates gene translation.
• Previous research linked CPEB4 dysregulation to autism spectrum disorder (ASD) due to microexon mis-splicing.

Purpose of the Study:

• To investigate if CPEB4 mis-splicing is a mechanism in schizophrenia (SCZ).
• To explore the link between CPEB4 dysregulation and SCZ-related gene misexpression.
• To determine if shared genetic and pathogenic mechanisms exist between SCZ and ASD.

Main Methods:

• Genome-wide association study (GWAS) and RNA sequencing data analysis (PsychENCODE Consortium).
• Postmortem brain tissue analysis using RT-PCR and Western blot.
• Biochemical and behavioral analysis of mice with altered CPEB4 expression.

Main Results:

• SCZ-associated genes were enriched for CPEB4-binding transcripts.
• Decreased CPEB4 microexon usage was observed in SCZ patients.
• Mice overexpressing a CPEB4 variant exhibited SCZ-associated gene underexpression and behaviors.

Conclusions:

• Aberrant CPEB4 splicing is a novel etiological mechanism in SCZ.
• Downstream misexpression of SCZ risk genes is linked to CPEB4 splicing defects.
• This finding offers new insights into the molecular basis of schizophrenia.