2. Academic Validation
  3. Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD

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

  • Nature. 2024 Dec 4. doi: 10.1038/s41586-024-08289-w.
Carla Garcia-Cabau # 1,  Anna Bartomeu # 1,  Giulio Tesei 2,  Kai Chit Cheung 3,  Julia Pose-Utrilla 4 5,  Sara Picó 4 5,  Andreea Balaceanu 1,  Berta Duran-Arqué 1,  Marcos Fernández-Alfara 1,  Judit Martín 1,  Cesare De Pace 6,  Lorena Ruiz-Pérez 6 7 8,  Jesús García 1,  Giuseppe Battaglia 6 7 9,  José J Lucas 4 5,  Rubén Hervás 3,  Kresten Lindorff-Larsen 2,  Raúl Méndez 10 11,  Xavier Salvatella 12 13
Affiliations

Affiliations

  • 1 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
  • 2 Structural Biology and NMR Laboratory, Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
  • 3 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR.
  • 4 Center for Molecular Biology Severo Ochoa (CBM Severo Ochoa), CSIC/UAM, Madrid, Spain.
  • 5 Networking Research Center on Neurodegenerative Diseases (CIBER-NED), Instituto de Salud Carlos III, Madrid, Spain.
  • 6 Department of Chemistry and Institute for Physics of Living Systems, University College London, London, UK.
  • 7 Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain.
  • 8 Department of Applied Physics, University of Barcelona, Barcelona, Spain.
  • 9 Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
  • 10 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain. raul.mendez@irbbarcelona.org.
  • 11 Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. raul.mendez@irbbarcelona.org.
  • 12 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain. xavier.salvatella@irbbarcelona.org.
  • 13 Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. xavier.salvatella@irbbarcelona.org.
  • # Contributed equally.
PMID: 39633052 DOI: 10.1038/s41586-024-08289-w
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.

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