A tiny fragment of DNA inserted into a large gene on chromosome 5 is responsible for brain development failures that cause autism spectrum disorder (ASD), according to research by the Institute for Research in Biomedicine (IRB Barcelona) being presented today in the journal Nature.
The authors of the study have discovered in in vitro experiments that if this DNA fragment is lost, as is the case in autism, neurons do not function correctly. However, if its action is restored, the normal functioning of neurons is recovered. Building on this finding, they have initiated the search for therapies that can improve the lives of people with ASD.
Technically called microexon 4, the DNA fragment involved in the origin of autism is part of the CPEB4 gene. Scientists at IRB Barcelona discovered in a previous study, also published in Nature and a finalist for the Vanguardia de la Ciencia award, that this gene is key in autism. They even demonstrated that dysfunctions in the CPEB4 gene trigger a cascade of reactions in neurons that affect other genes related to autism.
Xavier Salvatella, Raúl Méndez, Carla Garcia-Cabau, and Anna Bartomeu (co-directors and co-first authors of the research, from left to right), at the IRB Barcelona institute.
Therefore, they identified CPEB4 as a central switch on which the initiation of changes in the brain leading to autism depends at a critical stage of neurodevelopment. However, they did not manage to uncover exactly what goes wrong in the CPEB4 gene in individuals with ASD.
Six years later they have the answer. The key lies in microexon 4 (me4), which consists of only 24 nucleotides (the basic units that make up DNA, of which there are 3.000 million in the human genome)
Their discovery explains cases of idiopathic autism, that is, of unknown cause until now, which represent 80% of all cases of the disorder, explains Raúl Méndez, Icrea researcher at IRB Barcelona, and co-director of the research along with Xavier Salvatella. The remaining 20% of cases have a known genetic cause. It has not yet been studied what percentage of cases of idiopathic autism are due to a deficiency of me4, but the fact that it affects a central neurodevelopmental switch like CPEB4 indicates that the percentage may be high.
The researchers are looking for therapies based on this discovery to improve the lives of people with ASD
According to the findings presented today in Nature, me4 causes the protein CPEB4 (produced by the CPEB4 gene) to remain active in neurons. This protein regulates genes that are crucial for the proper development of the hypothalamus, a key brain region in autism. However, if there is a deficiency of me4, then CPEB4 loses the ability to regulate these other genes, leading to the development of ASD.
At a chemical level, what happens is that ME4 produces eight amino acids, which are added to the ones that the CPEB4 protein has in cells different from neurons (which have the same gene but without the microexon).
Restoring these eight amino acids in neurons allows the CPEB4 protein to regain its function. “We still do not know to what extent the altered neuronal architecture during neurodevelopment is recoverable at later ages. But we do know that the brain has neuronal plasticity, and in fragile X syndrome, which is related to CPEB1 [a protein similar to CPEB4], there is a capacity for recovery; this allows us to be optimistic,” states Raúl Méndez.
“We have started exploring the possibility of developing therapies for people with ASD,” adds Xavier Salvatella, also a researcher at IRB Barcelona, who acknowledges that the road to a treatment will be long. “The in vitro results are spectacular. For the treatment to reach the brain, it could be injected into the spinal cord. We do not see insurmountable technical obstacles.”
“We are not saying that Autism Spectrum Disorder is a disease,” clarifies Raúl Méndez. “We say it's a phenotype. There are people for whom it is very disabling and we would like to create a therapy that can help them.”
