Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD

The inclusion of microexons by alternative splicing occurs frequently in neuronal proteins. The roles of these sequences are largely unknown, and changes in their degree of inclusion are associated with neurodevelopmental disorders1. We have previously shown that decreased inclusion of a 24-nucleoti...

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Autores: Garcia Cabau, Carla, Bartomeu, Anna, Tesei, Giulio, Chit Cheung, Kai, Pose Utrilla, Julia, Picó, Sara, Balaceanu, Andreea, Duran-Arqué, Berta, Fernández-Alfara, Marcos, Martín, Judit, De Pace, Cesare, Ruiz-Perez, Lorena, García Arroyo, Jesús, Battaglia, Giuseppe, Lucas, J. José, Hervás, Rubén, Lindorff-Larsen, Kresten, Méndez, Raúl, Salvatella i Giralt, Xavier
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/220250
Acceso en línea:https://hdl.handle.net/2445/220250
Access Level:acceso abierto
Palabra clave:Trastorns de l'espectre autista
Nucleòtids
Neurones
Autism spectrum disorders
Nucleotides
Neurons
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spelling Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASDGarcia Cabau, CarlaBartomeu, AnnaTesei, GiulioChit Cheung, KaiPose Utrilla, JuliaPicó, SaraBalaceanu, AndreeaDuran-Arqué, BertaFernández-Alfara, MarcosMartín, JuditDe Pace, CesareRuiz-Perez, LorenaGarcía Arroyo, JesúsBattaglia, GiuseppeLucas, J. JoséHervás, RubénLindorff-Larsen, KrestenMéndez, RaúlSalvatella i Giralt, XavierTrastorns de l'espectre autistaNucleòtidsNeuronesAutism spectrum disordersNucleotidesNeuronsThe inclusion of microexons by alternative splicing occurs frequently in neuronal proteins. The roles of these sequences are largely unknown, and changes in their degree of inclusion are associated with neurodevelopmental disorders1. We have previously shown that decreased inclusion of a 24-nucleotide neuron-specific microexon in CPEB4, a RNA-binding protein that regulates translation through cytoplasmic changes in poly(A) tail length, is linked to idiopathic autism spectrum disorder (ASD)2. Why this microexon is required and how small changes in its degree of inclusion have a dominant-negative effect on the expression of ASD-linked genes is unclear. Here we show that neuronal CPEB4 forms condensates that dissolve after depolarization, a transition associated with a switch from translational repression to activation. Heterotypic interactions between the microexon and a cluster of histidine residues prevent the irreversible aggregation of CPEB4 by competing with homotypic interactions between histidine clusters. We conclude that the microexon is required in neuronal CPEB4 to preserve the reversible regulation of CPEB4-mediated gene expression in response to neuronal stimulation.Nature Publishing Group2025202520252025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion8 p.application/pdfhttps://hdl.handle.net/2445/220250Articles publicats en revistes (Física Aplicada)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1038/s41586-024-08289-wNature, 2025, vol. 637, p. 496-503https://doi.org/10.1038/s41586-024-08289-wcc-by-nc-nd (c) Garcia Cabau, Carla et al., 2025info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2202502026-05-29T05:05:01Z
dc.title.none.fl_str_mv Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD
title Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD
spellingShingle Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD
Garcia Cabau, Carla
Trastorns de l'espectre autista
Nucleòtids
Neurones
Autism spectrum disorders
Nucleotides
Neurons
title_short Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD
title_full Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD
title_fullStr Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD
title_full_unstemmed Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD
title_sort Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD
dc.creator.none.fl_str_mv Garcia Cabau, Carla
Bartomeu, Anna
Tesei, Giulio
Chit Cheung, Kai
Pose Utrilla, Julia
Picó, Sara
Balaceanu, Andreea
Duran-Arqué, Berta
Fernández-Alfara, Marcos
Martín, Judit
De Pace, Cesare
Ruiz-Perez, Lorena
García Arroyo, Jesús
Battaglia, Giuseppe
Lucas, J. José
Hervás, Rubén
Lindorff-Larsen, Kresten
Méndez, Raúl
Salvatella i Giralt, Xavier
author Garcia Cabau, Carla
author_facet Garcia Cabau, Carla
Bartomeu, Anna
Tesei, Giulio
Chit Cheung, Kai
Pose Utrilla, Julia
Picó, Sara
Balaceanu, Andreea
Duran-Arqué, Berta
Fernández-Alfara, Marcos
Martín, Judit
De Pace, Cesare
Ruiz-Perez, Lorena
García Arroyo, Jesús
Battaglia, Giuseppe
Lucas, J. José
Hervás, Rubén
Lindorff-Larsen, Kresten
Méndez, Raúl
Salvatella i Giralt, Xavier
author_role author
author2 Bartomeu, Anna
Tesei, Giulio
Chit Cheung, Kai
Pose Utrilla, Julia
Picó, Sara
Balaceanu, Andreea
Duran-Arqué, Berta
Fernández-Alfara, Marcos
Martín, Judit
De Pace, Cesare
Ruiz-Perez, Lorena
García Arroyo, Jesús
Battaglia, Giuseppe
Lucas, J. José
Hervás, Rubén
Lindorff-Larsen, Kresten
Méndez, Raúl
Salvatella i Giralt, Xavier
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Trastorns de l'espectre autista
Nucleòtids
Neurones
Autism spectrum disorders
Nucleotides
Neurons
topic Trastorns de l'espectre autista
Nucleòtids
Neurones
Autism spectrum disorders
Nucleotides
Neurons
description The inclusion of microexons by alternative splicing occurs frequently in neuronal proteins. The roles of these sequences are largely unknown, and changes in their degree of inclusion are associated with neurodevelopmental disorders1. We have previously shown that decreased inclusion of a 24-nucleotide neuron-specific microexon in CPEB4, a RNA-binding protein that regulates translation through cytoplasmic changes in poly(A) tail length, is linked to idiopathic autism spectrum disorder (ASD)2. Why this microexon is required and how small changes in its degree of inclusion have a dominant-negative effect on the expression of ASD-linked genes is unclear. Here we show that neuronal CPEB4 forms condensates that dissolve after depolarization, a transition associated with a switch from translational repression to activation. Heterotypic interactions between the microexon and a cluster of histidine residues prevent the irreversible aggregation of CPEB4 by competing with homotypic interactions between histidine clusters. We conclude that the microexon is required in neuronal CPEB4 to preserve the reversible regulation of CPEB4-mediated gene expression in response to neuronal stimulation.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/220250
url https://hdl.handle.net/2445/220250
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41586-024-08289-w
Nature, 2025, vol. 637, p. 496-503
https://doi.org/10.1038/s41586-024-08289-w
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Garcia Cabau, Carla et al., 2025
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Garcia Cabau, Carla et al., 2025
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 8 p.
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Física Aplicada)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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