Scientists from the State University of Campinas (Unicamp) 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 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 mentoring 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 already occupying leadership positions”, he says to FAPESP Agency the neuroscientist and corresponding author of the article Iscia Lopes-Cendes. 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) from FAPESP.
Data from the United Nations (UN) 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 individual sacrifices to be recognized”, adds Lopes-Cendes.
The first three authors of the article, who at some point were supervised by Lopes-Cendes, have been occupying leadership positions. It is the case of the teacher Claudia Maurer-Morelli, who is coordinator of the Graduate General Commission of the Faculty of Medical Sciences at Unicamp and of the Graduate Program in Medical Sciences; of the researcher and teacher Jaíra Ferreira de Vasconcellos, research group leader at James Madison University, in Virginia (United States); and the researcher Estela Maria Bruxel postdoctoral fellow at Unicamp, who is on a period 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, as well as pathways of chemokine receptors (a type of cytokine that controls the movement of defense cells).
“We used large-scale gene expression signatures to characterize the disease mechanism. 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 hypothesis that in sporadic ELTM the most activated pathway was inflammation and we have now confirmed it. The difference in our study was working with tissue from patients with the familiar 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 coordinator of BRAINN, 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 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; 03/18254-7; It is 19/25948-3).
The article Gene expression profile suggests different mechanisms underlying sporadic and familial mesial temporal lobe epilepsy can be read at: https://journals.sagepub.com/doi/10.1177/15353702221126666?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed.