Pathogenic Mis-splicing of CPEB4 in Schizophrenia.

Autor: Ollà I; Center for Molecular Biology 'Severo Ochoa,' Spanish National Research Council/Autonomous University of Madrid, Madrid, Spain; Networking Research Center on Neurodegenerative Diseases (Centro de Investigación Biomédica en Red|Enfermedades Neurodegenerativas), Instituto de Salud Carlos III, Madrid, Spain., Pardiñas AF; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK., Parras A; Center for Molecular Biology 'Severo Ochoa,' Spanish National Research Council/Autonomous University of Madrid, Madrid, Spain; Networking Research Center on Neurodegenerative Diseases (Centro de Investigación Biomédica en Red|Enfermedades Neurodegenerativas), Instituto de Salud Carlos III, Madrid, Spain., Hernández IH; Center for Molecular Biology 'Severo Ochoa,' Spanish National Research Council/Autonomous University of Madrid, Madrid, Spain; Networking Research Center on Neurodegenerative Diseases (Centro de Investigación Biomédica en Red|Enfermedades Neurodegenerativas), Instituto de Salud Carlos III, Madrid, Spain., Santos-Galindo M; Center for Molecular Biology 'Severo Ochoa,' Spanish National Research Council/Autonomous University of Madrid, Madrid, Spain; Networking Research Center on Neurodegenerative Diseases (Centro de Investigación Biomédica en Red|Enfermedades Neurodegenerativas), Instituto de Salud Carlos III, Madrid, Spain., Picó S; Center for Molecular Biology 'Severo Ochoa,' Spanish National Research Council/Autonomous University of Madrid, Madrid, Spain; Networking Research Center on Neurodegenerative Diseases (Centro de Investigación Biomédica en Red|Enfermedades Neurodegenerativas), Instituto de Salud Carlos III, Madrid, Spain., Callado LF; Department of Pharmacology, University of the Basque Country, UPV/EHU, Biocruces Bizkaia Health Research Institute and Networking Research Center on Mental Health (Centro de investigación Biomédica en Red | Salud Mental), Leioa, Bizkaia, Spain., Elorza A; Center for Molecular Biology 'Severo Ochoa,' Spanish National Research Council/Autonomous University of Madrid, Madrid, Spain; Networking Research Center on Neurodegenerative Diseases (Centro de Investigación Biomédica en Red|Enfermedades Neurodegenerativas), Instituto de Salud Carlos III, Madrid, Spain., Rodríguez-López C; Center for Molecular Biology 'Severo Ochoa,' Spanish National Research Council/Autonomous University of Madrid, Madrid, Spain; Networking Research Center on Neurodegenerative Diseases (Centro de Investigación Biomédica en Red|Enfermedades Neurodegenerativas), Instituto de Salud Carlos III, Madrid, Spain., Fernández-Miranda G; Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain., Belloc E; Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain., Walters JTR; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK., O'Donovan MC; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK., Méndez R; Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain; Institució Catalana de RIcerca i Estudis Avançats, Barcelona, Spain., Toma C; Center for Molecular Biology 'Severo Ochoa,' Spanish National Research Council/Autonomous University of Madrid, Madrid, Spain; Neuroscience Research Australia, Sydney, New South Wales, Australia; School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia., Meana JJ; Department of Pharmacology, University of the Basque Country, UPV/EHU, Biocruces Bizkaia Health Research Institute and Networking Research Center on Mental Health (Centro de investigación Biomédica en Red | Salud Mental), Leioa, Bizkaia, Spain., Owen MJ; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK., Lucas JJ; Center for Molecular Biology 'Severo Ochoa,' Spanish National Research Council/Autonomous University of Madrid, Madrid, Spain; Networking Research Center on Neurodegenerative Diseases (Centro de Investigación Biomédica en Red|Enfermedades Neurodegenerativas), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: jjlucas@cbm.csic.es.
Jazyk: angličtina
Zdroj: Biological psychiatry [Biol Psychiatry] 2023 Aug 15; Vol. 94 (4), pp. 341-351. Date of Electronic Publication: 2023 Mar 22.
DOI: 10.1016/j.biopsych.2023.03.010
Abstrakt: Background: Schizophrenia (SCZ) is caused by an interplay of polygenic risk and environmental factors, which may alter regulators of gene expression leading to pathogenic misexpression 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) because its neuronal-specific microexon (exon 4) is mis-spliced in ASD brains, causing underexpression of numerous ASD risk genes. The genetic factors 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 on Psychiatric Genomics Consortium genome-wide association study data and analyzed RNA sequencing data from the PsychENCODE Consortium. Reverse transcriptase polymerase chain reaction and Western blot were performed on postmortem brain tissue, and the presence/absence of antipsychotics was assessed through toxicological analysis. Finally, mice with mild overexpression of exon 4-lacking CPEB4 (CPEB4Δ4) were generated and analyzed biochemically and behaviorally.
Results: First, we found enrichment of SCZ-associated genes for CPEB4-binder transcripts. We also found decreased usage of CPEB4 microexon in SCZ probands, which was correlated with decreased protein levels of CPEB4-target SCZ-associated genes only in antipsychotic-free individuals. Interestingly, differentially expressed genes fit those reported for SCZ, specifically in the SCZ probands with decreased CPEB4-microexon inclusion. Finally, we demonstrated that mice with mild overexpression of CPEB4Δ4 showed decreased protein levels of CPEB4-target SCZ genes and SCZ-linked behaviors.
Conclusions: We identified aberrant CPEB4 splicing and downstream misexpression of SCZ risk genes as a novel etiological mechanism in SCZ.
(Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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