Targeted tau protein degradation: a promising therapeutic approach for tauopathies

Tauopathies are a spectrum of diseases characterized by the pathological aggregation of tau proteins. Several therapeutic strategies have been developed to treat or stop the progression of these diseases, but all have failed in clinical trials. One potential reason for these failures is that disease-causing proteins are resilient to treatment with conventional drugs since they lack a predefined monomeric structure and an active binding site. Tau is an intrinsically disordered protein; paradoxically, its flexible conformation makes it an ideal candidate for targeted protein degradation (TPD) approaches, which bypass the need for structured binding pockets by inducing proximity-based recruitment to degradative machinery. TPD uses bifunctional molecules to recruit proteins to the ubiquitin-proteasome system (UPS) or autophagy-lysosomal pathways, overcoming limitations of traditional small-molecule inhibitors (SMIs). As these technologies have been effective in degrading several disease-related proteins, they hold significant promise for treating tauopathies caused by protein aggregation. Herein, we review the tau structure and functions, summarize the main post-translational modifications (PTMs) of tau including those causing pathological aggregation of tau, the major degradative cellular machinery and their defects in pathological state, and discuss the advantages and current progress of targeted protein degradation strategies compared to traditional approaches.