Project Portugal 2030

Summary

Understanding the relevance of telomeres and telomerases in post-mitotic (i.e., non-dividing) cells is an underexplored, yet hot topic of research. Indeed, although available data suggest that these cellular structures may critically contribute to the protection of post-mitotic neurons, the impact of telomere attrition or dysfunctional telomerases in the cellular response to neurotoxicants remains unknown. As such, we HYPOTHESIZE that telomere shortening and impaired telomerase activity in these cells may increase an individual’s, namely older adults, vulnerability to the neurotoxicity induced by alcohol abuse or other neurotoxicants. To address this hypothesis, ALCOHOLAGEING sets three main objectives: 1) Elucidate the potential role of telomeres and telomerase on post-mitotic neurons as protective agents against the neurotoxic effects of alcohol and its main active metabolite acetaldehyde (AcH). Specifically, we will ascertain whether human-induced pluripotent stem cell (hiPSC)-derived neurons with short telomeres (induced with a telomerase inhibitor) exposed to ethanol and AcH show altered levels of distinct neurotoxicity endpoints (e.g. oxidative stress, DNA damage), compared to hiPSC-derived neurons with functional telomeres exposed to the same substances. These assays will allow us to ascertain whether impaired telomere and/or telomerase function increase the cells’ susceptibility to alcohol. 2) Explore the mechanisms underlying telomeres- and telomerase-elicited neuroprotection. In particular, by using top-notch methodologies (e.g. nanopore sequencing) alongside classic Cell and Molecular Biology techniques (e.g. qPCR, Western-blot), we will ascertain the impact of telomere-related molecular targets on increased neurotoxicity, paving the way to the identification of new therapeutic targets for neurodegenerative conditions. 3) Ascertain the impact of alcohol on telomere shortening in post-mitotic neuronal cells and whether the alcohol use makes neurons more vulnerable to the effects of highly prevalent neurotoxicants. Such findings will represent an important contribution to strengthen risk assessment regarding alcohol abuse. ALCOHOLAGEING will go well beyond the state-of-the-art by 1) Determining whether shortened telomeres and/or impaired telomerase activity in neuronal cells underlie a higher susceptibility of these cells (and subsequently the brain) to alcohol exposure; 2) Advance knowledge on the pathways underlying the neuroprotective action of telomeres and telomerases; 3) Establishing a more suitable risk assessment model to predict the human risk, namely at the brain level, of exposure to alcohol.