Pathogenic mis-splicing of CPEB4 in schizophrenia

Ollà, Ivana, Pardinas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590, Parras, Alberto, Hernández, Ivó H., Santos-Galindo, María, Picó, Sara, Callado, Luis F., Elorza, Ainara, Rodríguez-López, Claudia, Fernández-Miranda, Gonzalo, Belloc, Eulàlia, Walters, James T. R. ORCID: https://orcid.org/0000-0002-6980-4053, O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379, Méndez, Raúl, Toma, Claudio, Meana, J.Javier, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862 and Lucas, José J. 2023. Pathogenic mis-splicing of CPEB4 in schizophrenia. Biological Psychiatry 94 (4) , pp. 341-351. 10.1016/j.biopsych.2023.03.010

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Abstract

BACKGROUND Schizophrenia (SCZ) is caused by an interplay of polygenic risk and environmental factors, which might alter regulators of gene expression leading to pathogenic mis-expression of SCZ-risk genes. The CPEB family of RNA-binding proteins (CPEB1-4) regulates translation of target RNAs (approximately 40% of overall genes). We previously identified CPEB4 as a key dysregulated translational regulator in autism spectrum disorder (ASD), as its neuronal-specific microexon (exon4) is mis-spliced in ASD brains, causing underexpression of numerous ASD-risk genes. The genetic and pathogenic mechanisms shared between SCZ and ASD led us to hypothesize CPEB4 mis-splicing in SCZ, leading to underexpression of multiple SCZ-related genes. METHODS We performed MAGMA-enrichment analysis in Psychiatric Genomics Consortium GWAS data and analyzed RNA-seq data from the PsychENCODE Consortium. RT-PCR and Western blot were performed on post-mortem brain tissue in which presence/absence of antipsychotics was assessed through toxicological analysis. Finally, mice with mild overexpression of exon4–lacking CPEB4 (CPEB4Δ4) were generated and biochemically and behaviorally analyzed. RESULTS We first found enrichment of SCZ-associated genes for CPEB4-binder transcripts. We also found decreased usage of CPEB4 microexon in SCZ probands, correlating with decreased protein levels of CPEB4-target SCZ-associated genes, selectively in antipsychotics-free individuals. Interestingly, differentially expressed genes fit those reported for SCZ, specifically in the SCZ probands with decreased CPEB4-microexon inclusion. Finally, we demonstrate that mice with mild overexpression of CPEB4Δ4 show decreased protein levels of CPEB4-target SCZ genes and SCZ-linked behaviors. CONCLUSION We identify aberrant CPEB4 splicing and downstream mis-expression of SCZ-risk genes as a novel etiological mechanism in SCZ.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Publisher:	Elsevier
ISSN:	0006-3223
Date of First Compliant Deposit:	31 March 2023
Date of Acceptance:	1 February 2023
Last Modified:	21 Mar 2024 17:16
URI:	https://orca.cardiff.ac.uk/id/eprint/158253

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