Research opens the door to knowing the causes of non-genetic autism

Now, a scientific team from Invest InstituteBiomedical igation (IRB for its acronym in Catalan) of Barcelona, ​​led by doctors Raúl Méndez and Xavier Salvatellahas identified a molecular mechanism that explains why certain alterations in the neuronal protein CPEB4 are associated with idiopathic autism.

A previous work, published in 2018, found a clear correlation between the presence of a very short fragment of the protein and the development 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 emphasize.

“This work offers new perspectives on how small modifications in proteins regulating 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 Cell Cycle and Differentiation laboratory at IRB Barcelona.

The region of the CPEB4 protein where the segment is located lacks a three-dimensional structure well defined. «They are intrinsically disordered proteins and many copies of them can join together and form protein droplets called condensate – even visible from a microscope. In them, silenced molecules such as messenger RNAs (mRNAs) that code for other proteins involved in the functioning of neurons are stored. These condensates can assemble and disassemble in response to cellular signals, which allows the dynamic regulation of genetic 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 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. The genetic information is sequestered within these condensates and is not expressed, which alters neuronal development and is related to the appearance of autism,” explains Salvatella.

Irreversible dysfunction

“If CPEB4 condensates do not function properly due to the lack of the microexon, this can lead to alterations in neuronal development that manifest as symptoms of autism,” agree the authors of the research. “If this fragment is missing from the protein, the functioning of the condensates is disturbed and the dysfunction is irreversible,” says Xavier Salvatella.

“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,” the doctors comment. Carla Garcia-Cabau and TOnna Bartomeuresearchers at IRB Barcelona and first authors of the work.

Implications in aging

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, 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 point out.

One of the most promising findings of the study is that the function of the CPEB4 protein that has been affected by the lack of the microexon could be restored by placing an “artificial fragment”, that is, a sequence of amino acids in the cells to reverse the affectation and potentially also the symptoms. «We have seen that by placing the missing protein fragment designed in the laboratory, the alteration is reversible. However, if the fragment is missing and the genetic information is not replaced, it is trapped in the condensates and neuronal activity is altered,” explains the head of the Molecular Biophysics laboratory at IRB Barcelona.

«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 the IRB scientist. The researchers highlight that this finding still needs to undergo extensive experimental testing, such as studies in animal models and overcoming multiple technical barriers.

“We want to check if what happens in test tubes also happens when applied to cells or neurons, and then transfer it to preclinical models and, finally, test it in humans,” says Salvatella. “We will continue to explore this mechanism and its implications, with the hope that we can eventually translate these findings into benefits for affected people for autism,” concludes the IRB researcher.

The study represents an important step in the understanding of underlying molecular mechanisms to idiopathic autism and highlights the importance of short genetic sequences in the regulation of critical cellular functions. This work has been possible thanks to the collaboration of several prestigious institutions and scientists. Among them, doctors stand out Jose Lucasfrom the Severo Ochoa Molecular Biology Center (CBM Severo Ochoa) of the CSIC/UAM in Madrid, and Ruben Hervas from the Li Ka Shing Faculty of Medicine at the University of Hong Kong. In addition, the research has the participation of groups from the Linderstrøm-Lang Center for Protein Science of the University of Copenhagen and of Institute of Bioengineering of Catalonia (IBEC). They also collaborate Network Biomedical Research Center of the Neurodegenerative Diseases Area (Ciberned) Carlos III Health Institute in Madrid, University College (London), and the University of Barcelona (UB). This project has been mainly financed by the State Investigation Agency (AEI) and the European Research Council (ERC).