Scientists have discovered that when a person has a protein that lacks a small protein sequence with eight specific amino acids, it may lead to autism. A lead researcher says that this finding offers a fresh perspective on the origins of autism and opens potential avenues for treatment.
The absence of a small protein sequence (microexon) of eight amino acids can cause a protein in the brain to malfunction, potentially resulting in autism. A new study has linked the role of these microexons to the protein’s function and to autism symptoms for the first time.
The research also elucidates why up to 80% of autism cases cannot be attributed to genetic changes and instead may have entirely different causes.
The pressing question now is whether the missing amino acids are only important during fetal development or whether giving them to individuals with autism could be a transformative treatment.
“Now we know what the problem is, and we have some ideas about how to repair the damage. We have also seen signs that restoring the lost cellular function resulting from the absence of the microexon may not be overly complex. We hope that we can develop an effective treatment for adults with autism,” explains a researcher behind the study, Xavier Salvatella, Professor and Group Leader, Laboratory of Molecular Biophysics, IRB Barcelona: Institute for Research in Biomedicine, Spain.
The research has been published in Nature and was jointly led by ICREA Research Professors at IRB Barcelona, Raúl Méndez and Xavier Salvatella, who are both main authors of the paper.
Autism results from mis-splicing of a microexon
The research builds on a 2018 study in which Xavier Salvatella’s colleagues linked the CPEB4 protein and autism. Individuals with autism frequently lacked a microexon of eight amino acids in CPEB4.
When researchers removed this microexon in experimental mice, they began exhibiting traits associated with autism.
This study, also published in Nature, explained why genetics is not the cause for most people’s autism.
“The ultimate form and function of a protein are not solely determined by gene sequences; they can also result from many other factors. CPEB4 has a highly specialised role in neurons and requires this microexon,” says Xavier Salvatella.
Many investigations
In this new study, the researchers aimed to delve deeper into the role of the microexon and to understand why its absence in CPEB4 is so critical that it may lead to the development of autism.
The research spanned numerous disciplines, involving computer simulations, experiments with proteins and neurons in test tubes and animal studies.
Overall, this research highlights the importance of CPEB4 and the absence of a microexon in developing autism.
CPEB4 is part of exceptionally large protein complexes containing hundreds of proteins. When CPEB4 functions correctly, part of it ensures that the entire complex acts like a dynamic fluid – a condensate – that serves as a reservoir for messenger RNA (mRNA).
This means that the CPEB4 condensate absorbs and releases protein-coding mRNA as required, making it essential for correctly expressing genes as proteins within neurons.
Strongly affects the expression of autism-related proteins
The new research reveals that the missing microexon is located in the region of CPEB4 that enables the protein complex to create a dynamic condensate.
In the absence of the microexon, the proteins aggregate differently, and the condensate becomes more rigid in structure, which disrupts the dynamic exchange of mRNA with the surrounding environment.
The mRNA pieces exchanged by the condensate include many that are vital for normal neuronal function, and disrupting them is closely linked to the development of autism.
“The microexon is critically important for keeping the condensate as fluid. This enables us to link the absence of the microexon in CPEB4 with the development of autism. However, we still do not know exactly when the problem originates. It could occur during fetal development or may remain relevant in the brain later,” notes Xavier Salvatella.
Treatment for autism?
Based on this new understanding of how autism may develop, the researchers are optimistic that forthcoming studies will deepen knowledge of when the problem arises and whether it can be addressed.
The immediate focus is to pinpoint where and when the absence of the microexon contributes to developing autism. This could prove crucial in determining the optimal timing for potential treatments.
These findings also lead to discussions about treatment options. Notably, the researchers demonstrated that restoring the condensate’s function does not require reintroducing the microexon into CPEB4.
If the microexon is present in the condensate, it functions as intended, so existing proteins and genes do not need to be altered if restoring the function of the condensate treats autism.
“Now we understand the problem and know that the function of the condensate can be restored. The next steps are to learn more about how restoring the condensate’s function affects cells and experimental animals and whether this can eliminate autistic traits. We hope to identify a potential treatment mechanism. Remember that, even when the brain has been damaged, it is highly plastic and capable of recovering from adverse events such as strokes and surgical interventions. Perhaps it can also recover from lacking a functional condensate of CPEB4,” concludes Xavier Salvatella.
