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

Selective degradation of pathological protein aggregates while sparing monomeric forms is of major therapeutic interest. The E3 ligase tripartite motif–containing protein 21 (TRIM21) degrades antibody-bound proteins in an assembly state–specific manner due to the requirement of TRIM21 RING domain cl...

Full description

Saved in:
Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2024-08, Vol.385 (6712), p.1009-1016
Main Authors: Benn, Jonathan, Cheng, Shi, Keeling, Sophie, Smith, Annabel E., Vaysburd, Marina J., Böken, Dorothea, Miller, Lauren V. C., Katsinelos, Taxiarchis, Franco, Catarina, Dupré, Elian, Danis, Clément, Landrieu, Isabelle, Buée, Luc, Klenerman, David, James, Leo C., McEwan, William A.
Format: Article
Language:English
Subjects:
Aggregates
Clustering
Nanobodies
Neurodegenerative diseases
Proteins
Tau protein
Transgenic mice
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Selective degradation of pathological protein aggregates while sparing monomeric forms is of major therapeutic interest. The E3 ligase tripartite motif–containing protein 21 (TRIM21) degrades antibody-bound proteins in an assembly state–specific manner due 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 green fluorescent protein–tagged histone 2B (H2B-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. Editor’s summary Protein aggregates are the major cause of neuronal death in many neurodegenerative disorders. However, in the nonaggregate form, the same proteins play important physiological roles. Benn et al . developed a strategy to target intracellular protein aggregates while sparing the monomeric form. Exploiting the clustering-dependent activation of TRIM21, the authors generated degraders combining the RING domain of TRIM21 with a target-specific nanobody. As proof of principle, they targeted tau aggregates in vitro and in vivo. In a tau-transgenic mouse model, the degraders, which were delivered through AAV vectors, reduced tau pathology, suggesting that this approach might be effective for selectively and safely removing protein aggregates. —Mattia Maroso
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.adp5186