Synergetic inhibition of deubiquitinases and acetyltransferases to regulate tau acetylation and aggregation in SH-SY5Y cell line model of Alzheimer's disease.

Tau protein homeostasis depends on a balance between ubiquitination and acetylation, two key post-translational modifications (PTMs) which simultaneously compete for lysine residues that govern tau stability. Importantly, ubiquitination signals of proteins for degradation through the 26S proteasome, whereas acetylation prevents ubiquitin attachment, leading to tau stabilization and an increased risk of aggregation. In Alzheimer's disease (AD), this balance is disrupted by upregulation of acetyltransferase activity, such as p300/CBP, and increased deubiquitinase (DUBs) activity, which together hinder proteasomal clearance and accumulation of pathological tau. Since these pathways are interconnected, targeting only one may be insufficient to address tau-mediated neurotoxicity. In this book chapter, we highlight the importance of a dual approach aimed at inhibiting both aberrant acetylation and deubiquitinases activity, thereby restoring ubiquitination and promoting tau degradation. In addition, the development of standardized cell culture models in the SH-SY5Y neuronal system will be crucial to evaluating the therapeutic potential of this synergetic inhibition strategy.