Aggregate selective removal of pathological tau via clustering-activated degraders

Selective degradation of pathological protein aggregates while sparing
monomeric forms is of major therapeutic interest. The E3 ligase TRIM21
degrades antibody-bound proteins in an assembly state-specific manner,
owing to the requirement of TRIM21 RING domain clustering for activation,
yet effective targeting of intracellular assemblies remains challenging.
Here, we fused the RING domain of TRIM21 to a target-specific nanobody to
create intracellularly expressed constructs capable of selectively
degrading assembled proteins. We evaluated this approach against histone
2B-GFP and tau, a protein that undergoes pathological aggregation in
Alzheimer’s and other neurodegenerative diseases. RING-nanobody degraders
prevented or reversed tau aggregation in culture and in vivo, with minimal
impact on monomeric tau. This approach may have therapeutic potential for
the many disorders driven by intracellular protein aggregation.