Co-opting templated aggregation to selectively degrade pathogenic tau assemblies

Protein aggregation causes a wide range of neurodegenerative diseases. Targeting and removing aggregates, but not the functional protein, is a considerable therapeutic challenge. Here we describe a therapeutic strategy called ‘RING-Bait’ which employs an aggregating protein sequence combined with an E3 ubiquitin ligase. RING-Bait is recruited into aggregates, whereupon clustering dimerises the RING domain and activates its E3 function, resulting in degradation of the aggregate complex. We exemplify this concept by demonstrating specific degradation of tau aggregates whilst sparing soluble tau. Unlike immunotherapy, RING-Bait is effective against both seeded and cell autonomous aggregation. RING-Bait removed tau aggregates seeded from AD and PSP brain extract and was also effective in primary neurons. We used brain penetrant AAV to treat P301S tau mice, reducing tau pathology and improving motor function. A RING-Bait strategy could be applied to other neurodegenerative proteinopathies by replacing the Bait sequence to match the target aggregate.