CPEB4, a telltale protein in the development of autism

In 2018, a regulator of protein synthesis, CPEB4, was found to be affected in most cases of autism. The researchers found that defects in CPEB4 cause the expression of most of a set of 200 risk genes to be dysregulated.

The study was carried out by an international team co-led by Raúl Méndez, from the Barcelona Biomedical Research Institute (IRB Barcelona), and by José Javier Lucas, a researcher at the Severo Ochoa Molecular Biology Center (CBMSO), dependent on the Higher Council for Scientific Research (CSIC) and the Autonomous University of Madrid (UAM), and the Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), all of these entities in Spain.

The study, which was published in the academic journal Nature and recognized Lucas with the XV Caja Rural Granada Foundation Health Sciences Award in 2019, contributed to the knowledge of an aspect of the genetic basis of autism, unknown until then. Discovering that a protein exerted a regulatory function on risk genes, responsible for the development of autism spectrum disorders (ASD), opened a hopeful path towards the development of therapies.

Autism is a disease of neurobiological origin that affects the configuration of the nervous system and brain function. By some estimates, autism spectrum disorders affect one in 100 people. There are about 200 genes that, when they have mutations, increase the risk of developing them, but the molecular mechanism that connects these risk factors with each other, and with other environmental aspects that could play an important role in the origin of these disorders, was unknown.

The aforementioned researchers saw that a protein called CPEB4 could be that link capable of regulating the expression of most risk genes for autism spectrum disorders.

Samples in the laboratory of José Javier Lucas at the CBMSO. (Photo: Álvaro Muñoz Guzmán)

Since 2018 and throughout these years, works have appeared that have delved into what Lucas, Méndez and Alberto Parras, first author and researcher at the CBMSO, discovered. Some studies identify new genes that regulate gene expression that in autism have the same type of alteration that they saw in CPEB4. In addition, in his group they have verified that the alteration of CPEB4 also appears in the disease of schizophrenia. Regarding the potential as a therapeutic target that their work already warned about in 2018, they have proven that a technique other than gene editing can be used to correct the imbalance of the forms of CPEB4.

At the moment, they have only been able to test it on cells in culture, but they are studying ways to explore its potential in vivo and have patented the new tool that has been developed in collaboration with a group from CBMSO, led by Lourdes Ruiz Desviat, and another from the Danish University of Syddansk, led by Brage Andresen. “It is also possible that at some point gene editing could be used to intervene in the CPEB4 gene in order to correct its alteration in autism. But it is not trivial, because this technique, above all, makes it possible to correct a gene when there is a fault in its sequence, but in the case of autism it is about correcting the imbalance between two forms of the CPEB4 protein without the gene harboring no mutation”, comments José Lucas.

Important advances have been made in recent years thanks to genetic analysis in thousands of patients, but a paradigm shift is still needed. “We are probably in a similar situation with regard to autism that we were in with regard to cancer a few decades ago. At first, cancer was considered a single disease characterized by uncontrolled cell division. Significant advances in the understanding and treatment of cancer have come in a second stage in which it was seen that there is not one cancer but many types. Categorizing the patients according to their type of cancer made it possible to discover the specific causes of each subtype and to develop specific therapies for many of them”, Lucas points out.

Therefore, for the scientific community, a current challenge in autism research is to identify biomarkers; neuroimaging diagnostic tests, analysis of cerebrospinal fluid, blood, urine, or feces, or genetic tests, which allow cases to be classified into subcategories that may have common molecular causes and in which specific therapies can be tested.

Most cases of autism spectrum disorder manifest in the first months or years of life. It reveals a limited interest of the patient to carry out certain activities and difficulties when it comes to relating, communicating or behaving. These symptoms are common to many individuals who, on the other hand, are very different from each other. “It is very likely that this common symptomatic presentation is reached from various molecular alterations,” Lucas points out.

Méndez qualifies that “this work is an example of how the expression of hundreds of genes has to be perfectly coordinated for the correct functioning of the organs and cells that compose it. In this case, the neurons and the brain”. To which Parras adds that “since CPEB4 is known to regulate numerous genes during embryonic development, it is presented as a possible link between environmental factors that alter brain development and genes predisposing to autism.”

Human beings have some 22,000 genes that contain the information necessary to generate as many proteins, which are the nanomachines that carry out the specialized functions that take place inside cells. The functions performed by a neuron are different from those performed by other cell types, such as hepatocytes, and the functional needs of cells also change depending on their state of activity at all times. Thus, neurons specifically generate the proteins that make them neurons and function as such at each physiological stage. They are the genes that neurons express, while the rest remain silent. “There are proteins specialized in controlling which genes are more or less expressed in each cell type and according to the physiological moment. One of these regulators is CPEB4, the protein that we saw altered in autism, which leads to a lower expression of many of the genes that it controls and that have to do with the altered state of the functioning of neurons in autism”, Lucas concludes. .

This chronic neurological dysfunction has a strong genetic basis. Knowing its biological bases will favor the design of experimental therapies and tools that improve its diagnosis. The work of Lucas and his team contributes to the molecular understanding of these disorders and to the understanding of the complexity of gene regulation of genes associated with the risk of developing them. Their research is crucial to understand how it originates and to be able to design corrective therapies that have not existed until now. (Source: CSIC)