Key breakthrough in autism: pivotal role of CPEB4 condensates revealed

[Sly Saint]

A study by IRB Barcelona, based in the Barcelona Science Park, unveils how the lack of a fraction of the CPEB4 protein causes a decrease in the expression of genes that are crucial for neuronal development. The research is a notable example of how interdisciplinary collaboration can lead to significant advancements in the understanding of complex conditions and diseases, by combining approaches from biochemistry, cell biology, biophysics, and neuroscience. Published in the journal Nature, this work opens new avenues for the development of targeted treatments for autism.

Autism is a neurodevelopmental condition that presents challenges for individuals in acquiring communication and social interaction skills. Approximately 20% of cases are linked to a specific genetic mutation, but the origin of the remaining 80%, known as idiopathic autism, remains a mystery.

A team of scientists led by Dr. Raúl Méndez and Dr. Xavier Salvatella at IRB Barcelona has identified a molecular mechanism that explains why certain alternations of the neuronal protein CPEB4 are associated with idiopathic autism.

The study is based on previous work published in 2018 that identified CPEB4 as a key protein in the regulation of neuronal proteins related to autism. Back in 2018, the researchers observed that, in individuals with autism, the CPEB4 protein lacked a specific neuronal microexon — a tiny segment of genetic material crucial for protein function in the neurons. The work published today in the journal Nature reveals that this small fragment is key for neuronal activity because it preserves the flexibility of CPEB4 to assemble into condensates and disassemble them.

“This study provides new insights into how small modifications in proteins that regulate gene expression can have a significant impact on neuronal development, opening new avenues to explore future therapies,” explains Dr. Méndez, ICREA researcher and head of the Translational Control of Cell Cycle and Differentiation laboratory at IRB Barcelona.

Key breakthrough in autism: pivotal role of CPEB4 condensates revealed - Parc Científic de Barcelona

» Reference article: Garcia-Cabau, C., Bartomeu, A., Tesei, G. et al. Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD. Nature (2024). doi: 10.1038/s41586-024-08289-w

 

[SNT Gatchaman]

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.

Link | PDF (Nature) [Open Access]

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)