Although medical approaches exist to improve the quality of life of people suffering from neurodegenerative pathologies, more research is needed to develop effective therapies.
In this context and by conducting studies in vitro CONICET specialists have discovered a possible therapeutic target against Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, Huntington’s disease and other neurodegenerative pathologies. The work is described in the journal Biochemical and Biophysical Acta – Molecular basis of disease.
“In our work, we have verified that different molecular mechanisms that have been studied in parallel do indeed interact and that this interaction could play an important role in various neurodegenerative pathologies. Likewise, we have identified a potential therapeutic target for these conditions,” says Carina Weissmann, CONICET researcher at the Institute of Physiology, Molecular Biology and Neurosciences (IFIBYNE, CONICET-UBA) based in Buenos Aires.
Studies in vitro
Various researches have noted a decrease in pH (an increase in acidity) and an increase in a cytokine called interleukin 6 (a major modulator of the immune system in the brain) in the pathological processes of neuroinflammation that occur in neurodegenerative diseases.
At the same time, other work began to reveal the mechanisms by which a certain type of protein called ASIC1a, highly distributed in neurons of the central nervous system, could play an important role in various neurodegenerative pathologies.
“In this recent work, we verified that these molecular mechanisms studied in parallel (activation of ASIC1 proteins, low pH conditions and interleukin 6) interact and that this interaction could play a significant role in many neurodegenerative diseases,” emphasizes Weissmann.
In experiments performed on cell models (human cells and mouse brain neurons) that simulate neuroinflammatory processes, the research team was able to demonstrate that an increase in interleukin 6 leads to the redistribution of ASIC1a proteins from intracellular areas to the membrane of neurons.
“When the presence of ASIC1a proteins increases in the membrane of neurons, more sodium and calcium enter the intracellular medium and this activates other molecules. We were able to evaluate that in the cells it caused changes in morphology that lead to cell death. We were able to avoid these changes by blocking the activation of ASIC1a proteins,” explains Catalina Salinas, CONICET PhD student at IFIBYNE and first author of the study. And he continues: “By blocking ASIC1a proteins, we prevent cell death.”
“Our results show that the interaction between interleukin 6 and ASIC1a proteins triggers cellular cascades that could lead to cell death. However, blocking ASIC1a proteins in the presence of interleukin 6 and low pH prevents these deleterious effects, suggesting that ASIC1a proteins could be therapeutic targets. Future studies will have to confirm this,” says Weissmann.
“Interestingly, the study in vitro They allowed us to thoroughly unravel the various molecules and mechanisms involved in the processes that maintain life or, conversely, cause the death of neurons. This approach gives us an assessment based on solid foundations. In any case, future research on animal models for the study of neurodegenerative diseases is an interesting alternative to gather more data on the therapeutic target we are analyzing and to lay the foundations for the search for new therapies,” concludes Weissmann, a biochemist who graduated in 2002. from UBA with doctoral work at the University of Osnabrück, Germany, and postdoctoral work at the VIB-KU Brain and Disease Research Center in Leuven, Belgium..
Bibliographic reference:
Castellanos, LCS, Gatto, RG, Malnati, GOM, Montes, MM, Uchitel, OD, & Weissmann, C. (2024). IL-6-triggered redistribution of ASIC1a channels: Potential role of ASIC1a in neuroinflammation. Biochemistry and Biophysics Acta (BBA)-Molecular Basis of Disease, 1870(2), 166927.
https://doi.org/10.1016/j.bbadis.2023.166927
