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

Carla Garcia-Cabau, Anna Bartomeu, Giulio Tesei, Kai Chit Cheung, Julia Pose-Utrilla, Sara Picó, Andreea Balaceanu, Berta Duran-Arqué, Marcos Fernández-Alfara, Judit Martín, Cesare Pace, Lorena Ruiz-Pérez, Jesús García, Giuseppe Battaglia, José J. Lucas, Rubén Hervás, Kresten Lindorff-Larsen, Raúl Méndez () and Xavier Salvatella ()
Additional contact information
Carla Garcia-Cabau: The Barcelona Institute of Science and Technology
Anna Bartomeu: The Barcelona Institute of Science and Technology
Giulio Tesei: University of Copenhagen
Kai Chit Cheung: The University of Hong Kong
Julia Pose-Utrilla: CSIC/UAM
Sara Picó: CSIC/UAM
Andreea Balaceanu: The Barcelona Institute of Science and Technology
Berta Duran-Arqué: The Barcelona Institute of Science and Technology
Marcos Fernández-Alfara: The Barcelona Institute of Science and Technology
Judit Martín: The Barcelona Institute of Science and Technology
Cesare Pace: University College London
Lorena Ruiz-Pérez: University College London
Jesús García: The Barcelona Institute of Science and Technology
Giuseppe Battaglia: University College London
José J. Lucas: CSIC/UAM
Rubén Hervás: The University of Hong Kong
Kresten Lindorff-Larsen: University of Copenhagen
Raúl Méndez: The Barcelona Institute of Science and Technology
Xavier Salvatella: The Barcelona Institute of Science and Technology

Nature, 2025, vol. 637, issue 8045, 496-503

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-024-08289-w

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