Aggregate-selective removal of pathological tau via clustering-activated degraders

Homotypic protein assembly is a critical mediator of biological function and disease state. Selective degradation of protein assemblies, while sparing monomeric forms, is required for interrogation of biological mechanisms and assembly-specific therapeutic intervention. We have exploited the requirement of intermolecular clustering for activation of the E3 ligase TRIM21 to produce TRIM21-nanobody fusions capable of rapidly and selectively degrading assembled proteins. We demonstrate this approach against histone 2B-GFP and tau, a protein that undergoes pathological aggregation in Alzheimer’s and other neurodegenerative diseases. Intracellular expression of TRIM21-nanobody degraders prevented or reversed tau aggregation in culture systems and in vivo, with minimal impact on soluble tau. Our results demonstrate that homotypic quaternary structure is a property of proteins that may be exploited for their selective degradation.