Study shows genetic profile of the severe form of epilepsy – 09/03/2023 – Science

Scientists from Unicamp (State University of Campinas) took an important step towards deepening the understanding of one of the types of epilepsy, mesial temporal lobe epilepsy (MTLE), considered the most common and refractory to pharmacological treatment.

In a recently published study, the group showed that, despite the phenotypic similarities (observable characteristics of the disease), there are differences in the process of decoding genetic information (gene expression profile) between patients with the familial and sporadic variant.

The work evaluated, for the first time, the profile of messenger RNA (mRNA, a molecule that contains the information for the production of proteins) of surgical tissue obtained from patients with familial ELTM and compared it with sporadic ELTM. Since the discovery, the group has been looking for compounds and substances that could be candidates for new treatment alternatives. Another step already in progress is the search for possible genetic mutations that can lead to the disease.

Developed by members of the Brazilian Institute of Neuroscience and Neurotechnology (Brainn), the research is featured in a special edition of the scientific journal Society for Experimental Biology and Medicine (SEBM). The thematic edition is dedicated to the contributions of women leaders in biomedical sciences from several countries, including Brazil, with the aim of recognizing their fundamental role in academic spheres and so that they can inspire the next generation of scientists.

“This special edition is a tribute to women scientists considered leaders, who include and encourage their advisees in mentorships and among the authors of the works. I find it extremely rewarding to be able to train students and see them putting themselves forward, but I am particularly happy to train women researchers, who are also occupying leadership positions”, says neuroscientist and corresponding author of the article Iscia Lopes-Cendes to Agência Fapesp. She is a professor at the Faculty of Medical Sciences at Unicamp and a member of Brainn, a Center for Research, Innovation and Dissemination (Cepid) at FAPESP.

Data from the UN (United Nations) show that in the world, although women represent a third of researchers, they are less than 12% of members of national science academies. According to UN estimates, female researchers tend to have shorter and less paid careers, with work under-represented in high-profile publications. In the case of engineering, for example, they account for 28% of graduates.

“We still face many difficulties and obstacles. Women manage to get far, in prominent positions that they aspire to, but their performance and dedication have to be above what a man would need for the same position. We still suffer this invisibility, even making sacrifices individuals to be recognized”, completes Lopes-Cendes.

The first three authors of the article, who at some point were supervised by Lopes-Cendes, have been occupying leadership positions. This is the case of Professor Claudia Maurer-Morelli, who is the coordinator of the General Postgraduate Commission of the Faculty of Medical Sciences at Unicamp and of the Postgraduate Program in Medical Sciences; researcher and professor Jaíra Ferreira de Vasconcellos, leader of the research group at the James Madison University, in Virginia (United States); and researcher Estela Maria Bruxel, a postdoctoral student at Unicamp, who is currently abroad.

The discoveries

The research results indicate that, despite the phenotypic similarities, the two forms of mesial temporal lobe epilepsy present distinct molecular signatures, suggesting different molecular mechanisms.

In tissue from patients with familial ELTM, the scientists found an overrepresentation of biological pathways related to protein response, mRNA processing, plasticity (the brain’s ability to adapt to changes in the environment), and synaptic function.

In sporadic ELTM, the gene expression profile of the hippocampus —an important area of ​​the brain linked to learning and memory—suggests that the inflammatory response is highly activated. In this case, synthesis and regulation of prostaglandins (lipid compounds with hormone-like effects) and phagocytosis pathways of microglial pathogens (a type of cell in the central nervous system that performs several functions) were recorded.

In both groups, enrichment of sets of genes involved in cytokines (molecules that make “communication” between cells of the immune system) and inflammatory mediators, in addition to chemokine receptor pathways (a type of cytokine that controls the movement of defense cells).

“We used large-scale gene expression signatures to characterize the mechanism of the disease. With these high-performance techniques, it is possible to obtain a map of the molecular pathways present, whether they are activated or inhibited. We identified that the most activated pathways are different. We already had the information. hypothesis that in sporadic ELTM the most activated pathway was inflammation and we are now finding out. The difference in our study was working with tissue from patients with the familial form who underwent surgery”, explains Lopes-Cendes.

The epilepsies form a set of chronic neurological syndromes characterized by spontaneous epileptic seizures caused by abnormal neuronal discharges. Of the epileptic syndromes in adults, mesial temporal lobe epilepsy affects between 30% and 40% of these patients, who do not have a satisfactory response to existing medications and often need to undergo surgery.

In most patients with MTLE, a characteristic lesion involving the hippocampus is found, the so-called mesial temporal sclerosis (TMS), characterized by extensive neuronal death leading to hippocampal atrophy.

In the 2000s, the Lopes-Cendes group, including Professor Fernando Cendes, Brainn coordinator, identified and described familial mesial temporal lobe epilepsy based on genetic studies developed at the time and questionnaires involving information about the patients’ families.

“I work with women who serve as an inspiration to continue developing quality research and which aims, who knows, one day, to find solutions that will bring well-being to patients suffering from epilepsy”, says Bruxel.

The study received support from FAPESP through five other projects (05/56578-4; 08/54789-6; 10/17440-5; 18/03254-7; and 19/25948-3).

The article “Gene expression profile suggests different mechanisms underlying sporadic and familial mesial temporal lobe epilepsy” can be read here.