PROTAC-Based Strategies in Neurodegenerative Diseases: Challenges and Perspectives

Abstract

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional molecules that induce the selective degradation of a protein of interest by recruiting an E3 ubiquitin ligase, thereby triggering ubiquitination and proteasomal clearance. As part of the broader targeted protein degradation (TPD) paradigm, PROTACs offer a powerful strategy to eliminate pathogenic proteins that are difficult to modulate with traditional occupancy-based inhibitors. However, their clinical translation is often limited by poor aqueous solubility, suboptimal cellular permeability, and off-target effects. Notably, some PROTACs retain potent biological activity despite limited membrane permeability, owing to their catalytic mechanism of action, which allows even a small number of molecules reaching the target site to drive substantial protein degradation and produce important pharmacological effects. Growing evidence supports the application of PROTAC-based approaches in neurodegenerative diseases, where the selective removal of toxic or misfolded proteins is particularly attractive. This review summarizes recent advances in chemical protein degradation strategies for neurodegenerative disorders and highlights potential future perspectives of multifunctional PROTACs for therapeutic development.