Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by problems in communication and social interaction. Although it is known that about 20% of cases are related to specific genetic mutations, the origin of the remaining 80%, which is known as idiopathic autism, is still unknown.
A team of researchers from the Biomedical Research Institute (IRB Barcelona), led by Raúl Méndez and Xavier Salvatella, has discovered a molecular mechanism that links alterations in the neuronal protein CPEB4 with idiopathic autism and that could help to better understand its causes.
The finding is based on a previous study from 2018, where the key role of the CPEB4 protein in the regulation of neuronal proteins associated with autism was identified. The researchers then observed that in people with ASD, a specific microexon was missing from the CPEB4 protein. The study, recently published in Nature, reveals why this segment is essential for CPEB4 function in the brain.
“This discovery opens new doors to understanding how small modifications in key proteins can influence neuronal development, and could pave the way to future therapies,” explained Méndez, researcher of the ICREA program at IRB Barcelona in a note published by the center. .
Implications on brain development
The region of the CPEB4 protein where the microexon is located does not have a defined three-dimensional structure, which allows it to form molecular condensates. These condensates act as compartments within cells, where molecules such as messenger RNAs (mRNAs) are temporarily stored. This process facilitates the dynamic regulation of gene expression in neurons.
According to Salvatella, also a researcher in the ICREA program, “we discovered that the neuronal microexon is essential to maintain the stability and dynamics of the condensates formed by CPEB4. Without this segment, the condensates lose dynamism and can form solid aggregates, which affects their functionality.” When the condensates do not function properly, stored mRNAs are not released upon neuronal stimulation, reducing the production of proteins essential for the development and function of neurons. Many of these mRNAs are associated with genes previously linked to autism.
The proper regulation of these genes is essential during brain development. If CPEB4 condensates do not operate correctly due to the lack of the microexon, this can cause neuronal alterations that lead to symptoms associated with autism. Furthermore, this mechanism could help understand why idiopathic autism is so heterogeneous in nature and variable in severity.
“We are in the early stages, but this advance gives us hope and points to a possible therapeutic approach to address idiopathic autism”
“Our results suggest that even minimal reductions in microexon inclusion can have significant effects. This could explain why some people develop idiopathic autism without presenting specific genetic mutations,” commented Carla Garcia-Cabau and Anna Bartomeu, researchers at IRB Barcelona and main authors of the study.
The concept of gene regulation through molecular condensates could also be relevant in the context of aging. Over time, these condensates lose their plasticity, which affects their ability to assemble and disassemble, potentially contributing to the development of neurodegenerative diseases.
Potential therapeutic uses to reduce autism symptoms
One of the most promising discoveries of the study is that the missing microexon could be functionally restored. According to the researchers, it would be possible to introduce this small sequence of amino acids into cells, which would partially recover the function of the CPEB4 protein and potentially mitigate the symptoms of autism.
“We are in the early stages, but this advance gives us hope and points to a possible therapeutic approach to address idiopathic autism,” Méndez concluded. However, he emphasized that additional testing in animal models and several technical challenges need to be overcome before this approach can be applied in clinical therapies.
“Having understood the molecular mechanism by which autism can develop in the absence of mutations gives us the possibility of avoiding the formation of [irreversible] of these aggregates,” stated Xavier Salvatella in statements to SMC Spain. “In this study we show that, at a minimum, it is possible. And, obviously, we are going to work on it,” he announced.
“What we have achieved,” Méndez added in statements to the same medium, “is to add those eight amino acids and make the droplets become liquid again. We have done it in the test tube, but then we will have to demonstrate that it works in neurons, then in the mouse and from there we would go to humans. “It is a very, very long road, but conceptually it is an approach that has the potential to work.”
Autism is a neurodevelopmental disorder, closely linked to embryonic development. Given the difficulty or infeasibility of a prenatal diagnosis, could a non-preventive treatment, but rather after its manifestation, be effective? Méndez does not rule it out: “There are very preliminary data in mice that suggest that this could be the case, but they are still very indirect results,” he concludes.
