Eighty percent of people with an autism spectrum disorder have no known cause to explain their condition. In these cases, in which we speak of idiopathic autism, no key mutation is found that could be responsible.
In 2018, a team of researchers with participation from IRB Barcelona found a link to alterations in a protein called CPEB4, but the mechanism remained unknown. Now they have deciphered it and published it in the journal Nature.
According to the center, this is a “key advance in autism” that “could explain why some people develop autism without a genetic mutation” and “provides a glimpse of a possible therapeutic approach with new therapies”. To explain the study, its context and implications, and to resolve any questions that may arise, the Science Media Centre Spain organized an informative session with Raúl Méndez and Xavier Salvatella, the IRB Barcelona researchers who have led the study.
A subtle but crucial mechanism
The CPEB4 protein forms in neurons a kind of “droplet” that allows them to store instructions to make many others. However, in people with autism, a small part of it is lost.“ It is what we call a microexon,” explained Méndez.
In this case it is just “eight amino acids in a protein that has hundreds of them, that is, a very very small part.” In 2018 they verified the following: “If we generated a mouse without those eight amino acids, it developed all the manifestations of the autism spectrum,” recalled the researcher. Now they have discovered why.
The “droplets” are condensates that prevent instructions from being released and, therefore, different genes from being expressed. In people without autism, “when the neuron is stimulated, the condensates are reversibly diluted, allowing expression,” said Salvatella. However, when the eight amino acids are missing, the droplets remain undiluted, forming irreversible aggregates, and thus “hundreds of genes, many of which are involved in autism, are not activated. This causes the neuron to not function properly and neurodevelopmental alterations occur that ultimately lead to an autism spectrum disorder. In other words, there is not a specific mutation in a gene, but an incorrect regulation of hundreds of them. That is what we have discovered,” added Méndez.
A general key?
If 80% of autism cases have no known concrete explanation, how many of them could be explained by this mechanism? According to Méndez, “almost all the people with idiopathic autism studied had some degree of microexon loss.
The association was statistically significant and very striking, but we have no information on the relationship between the degree of loss and the manifestations. These are data we don't have at this time.”
Factors that might increase the risk are also unclear. “What seems to happen is that it occurs during embryonic development in response to different types of stress,” the researcher commented. However, “at the moment we only have hypotheses, we have not yet proven them 100%,” he acknowledged.
Possible treatments and projects needed
“Having understood the molecular mechanism by which autism can develop in the absence of mutations puts on the table the possibility of preventing the [irreversible] formation of these aggregates,” said Salvatella. “In this study we show that, at the very least, it is possible. And, obviously, we are going to work on it,” he announced.
“What we have achieved,” Méndez added, ”is to add those eight amino acids and get the droplets to 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 will go to humans. It is a very, very long road, but conceptually it is an approach that is likely to work”.
Autism is a neurodevelopmental disorder, closely linked to embryonic development. Given the difficulty or unfeasibility of a prenatal diagnosis, could a treatment that is not preventive, 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 the results are still very indirect”.
It is the typical project that arises from the coffee machine, from the multidisciplinary proximity while the experiments are being discussed
Raúl Méndez
The study has been carried out by several groups at IRB and with the participation of several national and international researchers.For Raúl Méndez, “it is the typical project that arises from the coffee machine, from the multidisciplinary proximity while the experiments are being discussed. It is a work that comes from the IRB coffee machine”.
The continuation of the project and the search for a better understanding and possible treatments will involve large consortia and funding, both researchers acknowledged. According to Salvatella, “right now we are at the beginning of the beginning. We have a proof of concept, which is important, but it is no more than that. That said, it is at least worth a try,” he concluded.
