Pathogenic mis-splicing of CPEB4 in schizophrenia

Olla, I.; Pardinas, A. F.; Parras, A.; Hernandez, I. H.; Santos-Galindo, M.; Pico, S.; Callado, L. F.; Elorza, A.; Fernandez-Miranda, G.; Belloc, E.; Walters, J. T. R.; O'Donovan, M.; Toma, C.; Mendez, R.; Meana, J. J.; Owen, M. J.; Lucas, J. J.

doi:10.1101/2022.09.22.508890

bioRxiv · 10.1101/2022.09.22.508890

Pathogenic mis-splicing of CPEB4 in schizophrenia

Olla, I.·Pardinas, A. F.·Parras, A.·Hernandez, I. H.·Santos-Galindo, M.·Pico, S.·Callado, L. F.·Elorza, A.·Fernandez-Miranda, G.·Belloc, E.·Walters, J. T. R.·O'Donovan, M.·Toma, C.·Mendez, R.·Meana, J. J.·Owen, M. J.·Lucas, J. J.

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Abstract

Schizophrenia (SCZ) is caused by a complex interplay of polygenic risk and environmental factors, which might alter regulators of gene expression leading to pathogenic mis-expression of SCZ risk genes. The RNA binding protein family CPEB (CPEB1, CPEB2, CPEB3, CPEB4) regulates the translation of target RNAs bearing CPE sequences in their 3UTR (approximately 40% of overall genes). We previously identified CPEB4 as a key dysregulated translational regulator in autism spectrum disorder (ASD), proving that its neuronal-specific microexon (exon 4) is mis-spliced in brains of ASD probands, leading to concerted underexpression of a plethora of high confidence ASD-risk genes. The genetic and pathogenic mechanisms shared between SCZ and ASD make it plausible that mis-splicing of CPEB4 might occur also in SCZ patients, leading to downstream altered brain expression of multiple SCZ-related genes. In this study, we first analyzed Psychiatric Genomics Consortium GWAS data and found significant enrichment of SCZ-associated genes for CPEB4-binder transcripts. We also found decreased inclusion of CPEB4 microexon in postmortem prefrontal cortex of SCZ probands. This mis-splicing is associated with decreased protein levels of SCZ-associated genes that are targets of CPEB4. Interestingly, this happens specifically in individuals with low exposure to antipsychotic medication. Finally, we show that mild overexpression of a CPEB4 transcript lacking exon 4 (CPEB4{Delta}4) in mice suffices to induce decreased protein levels of SCZ genes targeted by CPEB4; these mice are also characterized by SCZ-linked behaviors. In summary, this study identifies aberrant CPEB4 splicing and downstream mis-expression of SCZ-risk genes as a novel etiological mechanism in SCZ.

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Olla, I., Pardinas, A. F., Parras, A., Hernandez, I. H., Santos-Galindo, M., Pico, S., Callado, L. F., Elorza, A., Fernandez-Miranda, G., Belloc, E., Walters, J. T. R., O'Donovan, M., Toma, C., Mendez, R., Meana, J. J., Owen, M. J., Lucas, J. J.. 2022-09-23. Pathogenic mis-splicing of CPEB4 in schizophrenia. https://doi.org/10.1101/2022.09.22.508890

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