Autism is a disorder that affects one in every 100 boys and girls in the world, according to the World Health Organization, but it remains a mystery to science. Only 20% of cases are linked to a genetic mutation; For the rest, the so-called idiopathic autism, there are still many questions to be answered. Research led by the Institute for Biomedical Research (IRB) of Barcelona, published this Wednesday in ‘Nature’, has taken another step in unraveling these questions.
In 2018, scientists already identified a protein (CPEB4) altered in the brains of people with autism spectrum disorder without a genetic cause. It was found that this protein lost a small specific segment of neurons (a microexon). Now, six years later, the work of Raúl Méndez and Xavier Salvaterra reveals why minimal modifications in this protein, specifically eight amino acids out of hundreds, can have a “determining impact on neuronal development.”
“We did not understand why these eight amino acids that were lost, which is apparently nothing, caused such a strong effect,” says Méndez, head of the Translational Control of Cell Cycle and Differentiation laboratory at IRB Barcelona, in statements to Science Media Center Spain. The scientists came across a region of the unstructured protein, Salvaterra continues, which was “a challenge” when it came to understanding what was happening.
They finally verified, through in vitro observations, that the loss of amino acids causes a type of small droplets to become more solid structures. By becoming less dynamic, they prevent the release of key instructions for the functioning of neurons. “This lack of dynamism means that the mRNAs stored in these condensates are not released when the neurons are stimulated and this translates into a decrease in the production of proteins crucial for their development and function,” points out IRB Barcelona in a note.
Moving towards a “therapeutic solution”
The mechanism shows the complexity to explain idiopathic autism, which is also very heterogeneous because it appears in different manifestations and degrees of severity. Researchers, however, have not yet been able to see different cellular behaviors under the microscope depending on the degree of affectation by the disorder. They do know that in the minority of cases that can be explained by a specific genetic mutation, the phenotypes, that is, the symptoms, “are much stronger.” “It is not only a problem of neuronal function but also of development in more organs,” says Méndez.
One of the most promising findings of the study is that microexon 4, the one that is lost, appears to function again if the amino acid sequence is introduced artificially to restore the protein’s function. “This offers a new direction in the development of therapies that could improve the quality of life of many individuals and families affected by autism,” the research institute assumes.
The idea, although there are still many steps to take in between, is to move towards a “therapeutic solution.” “If the failure is this, that solids are formed, adding new amino acids we see that we achieve liquidity again, that they dissolve,” illustrates Salvaterra, who directs the Molecular Biophysics laboratory at IRB Barcelona.
#Spanish #researchers #step #deciphering #mystery #autism
