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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Detalles Bibliográficos
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
Descripción
Sumario: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.

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