Him Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by difficulties in communication and social behavior. Two out of ten cases of autism are linked to a specific genetic mutation, but the origin of the remaining 80% of cases, known as idiopathic autism, remains a mystery.
Now, a scientific team of investment InstituteBiomedical sanitization (IRB for its acronym in Catalan) of Barcelona, led by doctors Raúl Méndez and Xavier Salvatellahas identified a molecular mechanism that explains the reason for some alterations in the neuronal protein CPEB4 are associated with idiopathic autism.
Previous work, published in 2018, found a clear correlation between the presence of a very short fragment of the protein and the progress of autism. The researchers observed that in people with autism, a neuronal microexon – very short fragments of the genome – was lost in the CPEB4 protein. The work published today in the journal Nature reveals why this small segment is essential for the activity of CPEB4 in the brain, the researchers point out.
“This work offers new perspectives on how small changes in proteins that regulate gene expression can have a decisive impact on neuronal development and opens new avenues to explore for future therapies,” he explains. MendezICREA researcher and head of the Translational Control of the Cell Cycle and Differentiation laboratory at the IRB Barcelona.
The region of the CPEB4 protein in which the segment is located a three-dimensional structure is missing well defined. «They are intrinsically disordered proteins and many copies of them can come together and form protein droplets called condensate, which are also visible under a microscope. Stored in them are silenced molecules such as messenger RNAs (mRNAs) that code for other proteins involved in the functioning of neurons. These condensates can assemble and disassemble in response to cellular signals, which allows dynamic regulation of gene expression,” Xavier Salvatella, ICREA researcher and head of the Molecular Biophysics laboratory at IRB Barcelona, told ABC.
«In this work we discovered that this neuronal microhexon is essential for maintaining 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. Genetic facts is sequestered in these condensates and is not expressed, which alters neuronal development and is linked to the onset of autism,” explains Salvatella.
Irreversible dysfunction
“If CPEB4 condensates do not function properly due to a lack of microexons, this can lead to alterations in neuronal development which manifest themselves as symptoms of autism”, agree the authors of the research.”If this fragment is missing in the protein, the functioning of the condensates is disturbed and the dysfunction is irreversible”, explains Xavier Salvatella.
“Our findings 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,” the doctors comment.Carla Garcia-Cabau Yes AI Bartomeuresearchers from IRB Barcelona and first authors of the work.
Implications in aging
The concept raised by this work of genetic regulation in neurons, through the formation of condensates, could also have implications for aging. These condensations, with use, they lose their plasticitythat is, the ability to assemble and disassemble, and this could prevent the correct functioning of neurons and thus favor the development of neurodegenerative diseases, the researchers underline.
one of the most promising results of the study is that the function of the CPEB4 protein, compromised by the lack of the microhexon, could be restored by inserting an “artificial fragment”, i.e. a sequence of amino acids into cells to reverse the slicing and perhaps also the symptoms. «We have seen that by inserting the designed missing protein fragment into the laboratory,the alteration is reversible. However,if the fragment is missing and the genetic information is not replaced,it remains trapped in the condensates and neuronal activity is altered”,explains the head of the Molecular Biophysics laboratory of the IRB Barcelona.
«Although we are still in the exploratory phase, this discovery is encouraging and allows us to glimpse a possible therapeutic approach which restores the function of CPEB4,” says the IRB scientist. The researchers point out that this discovery still needs to be subjected to extensive experimental testing, such as animal model studies and overcoming multiple technical barriers.
“we want to verify if what happens in the test tube also happens when it is applied to cells or neurons,to then transfer it to preclinical models and,test it on humans”,explains Salvatella. “We will continue to explore this mechanism and its implications, with the hope of eventually translating these findings into benefits for those affected for autism,” concludes the IRB researcher.
The study represents an critically important step in understanding the underlying molecular mechanisms to idiopathic autism and highlights the importance of short genetic sequences in the regulation of critical cellular functions. This work was possible thanks to the collaboration of several prestigious institutions and scientists. Among these, doctors stand out Jose Lucasfrom the Severo Ochoa Molecular Biology Center (CBM Severo Ochoa) of the CSIC/UAM of Madrid, and Ruben Hervas from the Li ka Shing Faculty of Medicine, University of Hong Kong. Furthermore, the research involves the participation of groups from the Linderstrøm-Lang Center for Protein Science University of Copenhagen and of Institute of Bioengineering of Catalonia (IBEC). They also collaborate Biomedical Research Center Network of the Neurodegenerative Diseases Area (Cyberned) del Carlos III Health Institute in Madrid, University college (London) and the university of Barcelona (UB). This project was mainly funded by State investigative agency (AEI) and the European Research council (CER).
How do microexons impact neuronal function and progress in individuals with autism?
Time.news Editor (TNE): Welcome, everyone, to another insightful edition of our interview series. Today, we have the pleasure of speaking with Dr.Raúl Méndez and dr. Xavier salvatella from the Biomedical research Institute in Barcelona, who have made significant strides in understanding Autism Spectrum Disorder. Thank you both for joining us!
Dr. Raúl Méndez (RM): Thank you for having us. It’s a pleasure to be here.
Dr. Xavier Salvatella (XS): Yes, thank you! we’re excited to share our findings with your audience.
TNE: Let’s dive right in! Autism Spectrum Disorder,or ASD,affects many individuals worldwide,and as you know,a significant portion of cases—about 80%—remain idiopathic,meaning the causes are unknown. Can you explain how your recent research contributes to solving this puzzle?
RM: Absolutely! Our study focuses on the neuronal protein CPEB4, notably a very short segment known as a microexon that is often lost in individuals with idiopathic autism. Previously,we established a correlation between the presence of this microexon and the progression of autism.This current work delves deeper to elucidate the molecular mechanisms involved.
TNE: that’s captivating. You mentioned the concept of protein condensates formed by CPEB4. Can you elaborate on why these structures are essential for neuronal function?
XS: Certainly! CPEB4 is part of a group of intrinsically disordered proteins that can form dynamic droplets known as condensates. These condensates hold silenced mRNAs that are crucial for the synthesis of other proteins essential for neuronal function. Their ability to assemble and disassemble in response to cellular signals is vital for regulating gene expression efficiently.
TNE: So, what happens when the microexon is missing? Can you explain the implications?
RM: When that microexon is absent, the dynamics of these condensates are severely affected. They tend to aggregate and lose their functionality, which means that crucial genetic information is sequestered and not expressed. This disruption can lead to alterations in neuronal development, which we believe is linked to the manifestations of autism symptoms.
TNE: It sounds like the absence of just a small piece of protein can lead to significant challenges. How dose this finding change the way we view the neurodevelopmental origins of autism?
XS: This finding suggests that small changes in protein structure—even as minute as one microexon—can have colossal impacts on neuronal function and development. It challenges the customary view that only major genetic mutations are responsible for idiopathic autism. Instead, our research points to the possibility that even slight variations can lead to developmental issues.
TNE: That’s a powerful insight. Given these findings, what do you envision for the future in terms of research or potential therapies?
RM: We hope that this research can pave the way for new therapeutic approaches targeting the stabilization and function of CPEB4 and its condensates. Understanding the underlying mechanisms offers promising avenues for intervention that could ultimately improve outcomes for individuals with autism.
TNE: It’s an exciting prospect! Before we wrap up,is there a message you would like to convey to families affected by autism?
XS: Yes,we want families to know that research is advancing. While the path to understanding autism is complex and varies widely among individuals, our work underscores the importance of continued exploration. There is hope for new therapies that could lead to improved support and treatment options.
TNE: Thank you,Dr. Méndez and Dr. Salvatella, for your valuable insights and the critically important work you’re doing in this field. We look forward to seeing how your research progresses and impacts those affected by autism.
RM & XS: Thank you for having us!
TNE: And thank you to our readers for tuning in. Stay informed and engaged with us as we continue to cover groundbreaking research in health and medicine.