Article Dans Une Revue Science Année : 2024

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

Luc Buée
David Klenerman

Résumé

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.

One-Sentence Summary: Redirecting a cytosolic immune pathway enables potent and aggregate-selective removal of pathological tau protein in cell and animal models.

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hal-04745023 , version 1 (19-10-2024)

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Jonathan Benn, Shi Cheng, Sophie Keeling, Annabel Smith, Marina Vaysburd, et al.. Aggregate-selective removal of pathological tau via clustering-activated degraders. Science, 2024, 385 (6712), pp.1009-1016. ⟨10.1126/science.adp5186⟩. ⟨hal-04745023⟩
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