A Degron Decoy System Co-opts Pathological Seeding to Enable Clearance of Multimeric α-Synuclein

ABSTRACT Pathological seeding of protein misfolding is a hallmark of proteinopathies. However therapeutic strategies to clear these aggregates are lacking, impairing both study of their biological importance in disease etiology and progression as well as development of therapeutics. This is due in part to the need to selectively clear oligomerized proteins whilst leaving functional monomers intact, as well as the challenge of developing molecules that act on the full complement of ‘misfolds’ the protein can adopt throughout the course of disease. In this work, we describe a dopant system consisting of an engineered alpha-synuclein protein construct that rapidly co-aggregates into existing WT alpha-synuclein oligomers, enabling rapid degradation of the entire assembly in the presence of a small molecule trigger. This work provides proof-of-principle for an approach that transforms pathological seeding from a disease-driver into a therapeutic vulnerability, and is potentially applicable to any proteinopathy without requiring a small molecule binder of the pathologic species.