Key advance in autism: they discover the crucial role of CPEB4 condensates

Autism is a neurodevelopmental problem that causes challenges for the person in acquiring communication and social interaction skills. About 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 scientific team from the Barcelona Biomedical Research Institute (IRB Barcelona) led by Dr. Raúl Méndez and Dr. Xavier Salvatella has identified a molecular mechanism that explains why certain alterations in the neuronal protein CPEB4 are associated with idiopathic autism.

The study builds on previous work, published in 2018, in which the key role of the CPEB4 protein in the regulation of neuronal proteins related to autism was identified. Already in 2018, researchers observed that a neuron-specific microexon in the CPEB4 protein was lost in people with autism. The new study reveals why this small segment is essential for CPEB4 activity in the brain.

“This work provides new perspectives on how small modifications in the proteins that regulate gene expression can have a decisive impact on neuronal development, and opens new avenues to explore for future therapies,” explains Dr. Méndez, ICREA researcher and head of the Laboratory of Translational Control of Cell Cycle and Differentiation at IRB Barcelona.

Molecular condensates and genetic regulation

The region of the CPEB4 protein where the segment is located lacks a well-defined three-dimensional structure. Proteins with disordered regions can form condensates, which are like small droplets inside the cell where molecules such as messenger RNAs (mRNAs) are stored, silenced, which code for other proteins involved in the functioning of neurons. These condensates can assemble and disassemble in response to cellular signals, allowing dynamic regulation of gene expression.

“In this work we discovered that this neuronal microexon is essential to maintain the stability and dynamics of the condensates formed by CPEB4 in neurons. Without the microexon, the condensates become less dynamic and can form solid aggregates that do not function properly,” he explains. Dr. Salvatella, ICREA researcher and head of the Molecular Biophysics laboratory at IRB Barcelona.

This lack of dynamism means that the mRNAs stored in these condensates are not released when neurons are stimulated, and this results in a decrease in the production of proteins crucial for their development and function. Among these mRNAs are many of the genes that have previously been associated with autism.

Implications for neural development

The correct regulation of these genes is essential during brain development. If CPEB4 condensates do not function properly due to the lack of the neuronal microexon, this can lead to alterations in neuronal development that manifest as symptoms of autism. The described mechanism explains the complexity of idiopathic autism and its heterogeneous nature as well, since this spectrum includes multiple manifestations and degrees of severity.

“Our results suggest that even small decreases in microexon inclusion can have significant effects. This could explain why some people develop idiopathic autism without a genetic mutation,” explain researchers Dr. Carla Garcia-Cabau and Dr. Anna Bartomeu. from IRB Barcelona and first authors of the work.

The concept raised by this work of gene regulation in neurons through the formation of condensates may also have implications for aging. These condensates, with use, lose their plasticity, that is, their ability to assemble and disassemble, and this could prevent the correct functioning of neurons and favor the development of neurodegenerative diseases.

From left to right: Dr. Raúl Méndez, Dr. Anna Bartomeu, Dr. Xavier Salvatella and Dr. Carla Garcia-Cabau. (Photo: IRB Barcelona. CC BY-NC-ND)

Possible avenues for future therapies

One of the promising findings of the study is that microexon 4 appears to function “in trans,” meaning it might be possible to introduce this small amino acid sequence into cells to partially restore CPEB4 function and potentially reverse symptoms.

“Although we are still in the exploratory stages, this discovery is encouraging and allows us to glimpse a possible therapeutic approach that restores the function of CPEB4,” says Dr. Méndez. The researchers highlight that this finding still needs to undergo extensive experimental testing, such as studies in animal models and overcoming multiple technical barriers.

Interdisciplinary collaboration and future of research

This study is a leading example of how interdisciplinary collaboration can lead to significant advances in the understanding of complex conditions and diseases. Combining approaches from biochemistry, cell biology, biophysics and neuroscience, the IRB Barcelona team has managed to unravel a mechanism that could have profound implications for idiopathic autism.

“It is an achievement that reflects the strength of working in an environment that encourages interaction between different disciplines,” concludes Dr. Salvatella. “We will continue to explore this mechanism and its implications, with the hope that we can eventually translate these findings into benefits for people with autism.”

The study represents an important step in understanding the molecular mechanisms underlying idiopathic autism and highlights the importance of short genetic sequences in the regulation of critical cellular functions. While much remains to be researched, the findings offer a new direction for the development of therapies that could improve the quality of life for many individuals and families affected by autism.

This work has been possible thanks to the collaboration of several prestigious institutions and scientists. Among them, stand out Dr. José Lucas, from the Severo Ochoa Molecular Biology Center (CBM Severo Ochoa, from the Higher Council for Scientific Research (CSIC) and the Autonomous University of Madrid), in Spain, and Dr. Ruben Hervás from the University of Hong Kong in China. In addition, the research has the participation of groups from the Institute of Bioengineering of Catalonia (IBEC), and the Linderstrøm-Lang Center for Protein Science at the University of Copenhagen in Denmark. The Network Biomedical Research Center for Neurodegenerative Diseases (CIBERNED, of the Carlos III Health Institute, in Madrid), the University of Barcelona and the University College of London in the United Kingdom also collaborate.

The study is titled “Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD.” And it has been published in the academic journal Nature. (Source: IRB Barcelona)