They find a protein involved in the development of schizophrenia

Different genetic and epidemiological evidence indicates that schizophrenia is the result of genetic and environmental risk factors that alter the correct development of the brain, as well as the interaction between factors. Within the studies on its genetic origin, in recent years, new genomic techniques have identified hundreds of susceptibility genes for schizophrenia. However, each of the risk variants in these genes slightly increases the risk of developing the disease. This indicates the importance of investigating proteins that can simultaneously regulate the expression of multiple schizophrenia susceptibility genes, regardless of whether these genes are altered in affected individuals.

In 2018, a team led by researchers from the Severo Ochoa Molecular Biology Center (CBMSO), an entity dependent on the Higher Council for Scientific Research (CSIC) and the Autonomous University of Madrid (UAM), in Spain all these institutions, observed that the CPEB4 protein was key in the regulation of risk genes responsible for autism spectrum disorders. Now, a study by the same team shows that the same protein has a similar regulatory function in susceptibility genes for schizophrenia, a serious psychiatric disorder that affects almost 1% of the adult population and causes abnormalities in thought and cognition. . These results suggest that therapies capable of regulating CPEB4 could enhance the beneficial effect of current antipsychotic treatments.

The CPEB4 protein regulates the expression of a multitude of genes necessary for neuronal activity. Already in 2018, the team led by José Javier Lucas, a researcher at the CBMSO and the Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED) in Spain, showed that CPEB4 plays an important pathogenic role in autism spectrum disorders. This work, published in the academic journal Nature, was made possible by analyzing post-mortem brain samples from patients with autism spectrum disorders, which made it possible to verify that this protein was altered in a high percentage of individuals with autism. In addition, the study authors demonstrated that said alteration is capable of decreasing the expression of many of the autism risk genes.

The fact that schizophrenia and autism spectrum disorders share many susceptibility genes and, by inference, pathogenic mechanisms, led Lucas’s team to hypothesize that an alteration in CPEB4 might also be seen in people with schizophrenia. Now, the new study corroborates it.

The first signatory of the new study is the CBMSO researcher Ivana Ollà. The study was carried out in collaboration with the Barcelona Institute for Research in Biomedicine (IRB), the University of the Basque Country, the Mental Health Network Biomedical Research Center (CIBERSAM) and Cardiff University.

The symptoms of schizophrenia usually begin between the ages of 16 and 30. (Image: Ivana Olla)

The alteration of the CPEB4 protein observed in the brain samples with schizophrenia refers to a deficient inclusion of a neuronal microexon, that is, of a small fragment of genetic material involved in the encoding of a few amino acids (the basic components of proteins ). This same alteration is the one that was previously observed in samples from patients with autism spectrum disorders, so these findings would further support the parallelism in the pathogenic molecular mechanisms of both diseases. “We were surprised to see the degree of enrichment of the genes that are regulated by CPEB4 among the schizophrenia risk genes,” says Claudio Toma, a CBMSO researcher who, in collaboration with researchers from Cardiff University, has carried out the genetic analysis with data from 67,390 patients with schizophrenia and 94,015 individuals without this disease (control group) from the PGC (Psychiatric Genomics Consortium).

Schizophrenia is treated with drugs called antipsychotics, which substantially improve the quality of life of patients. “Interestingly, the CPEB4 alteration is only observed in individuals who were not taking antipsychotics at the time of death,” explains Ollà. This suggests that the beneficial effect of antipsychotics could be partly due to the fact that they help to correct the alteration of the CPEB4 protein. On the other hand, not all patients with schizophrenia respond equally to antipsychotic treatment. “For this reason, in collaboration with other groups, we are exploring molecular strategies capable of correcting the alteration of CPEB4 in cultured neurons with the hope that, in the future, they can be used in combination with antipsychotic drugs to enhance the beneficial effect of them”, points out José Lucas.

The study is titled “Pathogenic Mis-splicing of CPEB4 in Schizophrenia”. And it has been published in the academic journal Biological Psychiatry. (Source: Alejandro Parrilla García / CSIC)