Co-opting templated aggregation to degrade pathogenic tau assemblies and improve motor function by Lauren V.C. Miller, Guido Papa, instant download

Co-opting templated aggregation to degrade pathogenic tau assemblies and improve motor function by Lauren V.C. Miller, Guido Papa, instant download

SUMMARYProtein 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 strategycalled ‘‘RING-Bait,’’ which employs an aggregating protein sequence combined with an E3 ubiquitin ligase.RING-Bait is recruited into aggregates, whereupon clustering dimerizes the RING domain and activates itsE3 function, resulting in the degradation of the aggregate complex.We exemplify this concept by demonstratingthe specific degradation of tau aggregates while sparing soluble tau. Unlike immunotherapy, RING-Bait is effective against both seeded and cell-autonomous aggregation. RING-Bait removed tau aggregates seeded fromAlzheimer’s disease (AD) and progressive supranuclear palsy (PSP) brain extracts and was also effective in primary neurons. We used a brain-penetrant adeno-associated virus (AAV) to treat P301S tau transgenic 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.