Key breakthrough in autism: pivotal role of CPEB4 condensates revealed

Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD
Garcia-Cabau, Carla; Bartomeu, Anna; Tesei, Giulio; Cheung, Kai Chit; Pose-Utrilla, Julia; Picó, Sara; Balaceanu, Andreea; Duran-Arqué, Berta; Fernández-Alfara, Marcos; Martín, Judit; De Pace, Cesare; Ruiz-Pérez, Lorena; García, Jesús; Battaglia, Giuseppe; Lucas, José J.; Hervás, Rubén; Lindorff-Larsen, Kresten; Méndez, Raúl; Salvatella, Xavier

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 disorders. 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). 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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Following prior work

Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing (2018)
Parras, Alberto; Anta, Héctor; Santos-Galindo, María; Swarup, Vivek; Elorza, Ainara; Nieto-González, José L.; Picó, Sara; Hernández, Ivó H.; Díaz-Hernández, Juan I.; Belloc, Eulàlia; Rodolosse, Annie; Parikshak, Neelroop N.; Peñagarikano, Olga; Fernández-Chacón, Rafael; Irimia, Manuel; Navarro, Pilar; Geschwind, Daniel H.; Méndez, Raúl; Lucas, José J.

Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1–4 (CPEB1–4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity.

Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes.

Together, these data identify CPEB4 as a regulator of ASD risk genes.

Link | PDF (Nature)