Evaluating the effect of a new inhibitor of USP14 in a Drosophila model of ALS

Protein and organelle homeostasis (proteostasis) comprises the cellular mechanisms responsible for maintaining protein and organelle stability, which is essential for cell physiology and proper function. Two primary quality control systems oversee protein and organelle turnover and are in charge of degrading damaged proteins and organelles: the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system. Both processes share a common molecular tag, ubiquitination, which targets the substrate for degradation. Ubiquitination is a post-translational modification that is attached to substrates by specific E3-ubiquitin ligases. This process is reversible thanks to the action of deubiquitinating enzymes (DUBs), which can hydrolyse the ubiquitin bonds, and trim ubiquitination moieties from substrates. Proteostasis can be compromised during ageing and in many neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS). Thus, approaches that enhance cellular proteostasis may benefit human diseases like ALS. We can enhance proteostasis by acting on DUBs: inhibiting specific DUBs stabilizes ubiquitination, and enhance the activity of the UPS and autophagy, thus promoting cellular proteostasis. In this project, we explore the potential beneficial effect of inhibiting USP14, a proteasome-associated DUB that negatively regulates both autophagy and the UPS. Using a Drosophila melanogaster model of ALS, we aim to determine whether enhancing proteostasis by USP14 inhibition can ameliorate the disease phenotype of these flies.