Promoting Secretion of Pathological Tau Species Using an Induced Proximity Platform That Engages the Autophagy Pathway

Intracellular accumulation of aberrantly phosphorylated aggregated tau protein can contribute to neuronal dysfunction associated with many neurodegenerative diseases. Thus, removing such tau species is an attractive therapeutic hypothesis for these diseases. Targeted protein degradation (TPD) strategies leveraging the autophagy-lysosome pathway (ALP) are promising approaches to decrease protein aggregates by designating them for degradation. Here, we developed a novel heterobifunctional molecule, MRL828, combining a tau pathology-binding ligand and modified guanine moiety based on the autophagy-targeting chimaera technology to selectively designate aggregated tau proteins for clearance via the ALP. Surprisingly, the MRL828-dependent decrease in intracellular tau aggregates was dependent on the autophagosome, but not the lysosome. MRL828 treatment led to autophagosome-dependent secretion of oligomeric and phosphorylated tau species, suggesting a reduction of intracellular tau aggregates via secretory autophagy rather than degradation via the ALP. This work highlights a novel mechanism of action (MOA) of an ALP-based heterobifunctional molecule and a potential new strategy for the cellular removal of proteins of interest.