Title :

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

Author(s) :

Benn, Jonathan [Auteur]
University of Cambridge [UK] [CAM]
Cheng, Shi [Auteur]
University of Cambridge [UK] [CAM]
Keeling, Sophie [Auteur]
University of Cambridge [UK] [CAM]
Smith, Annabel [Auteur]
University of Cambridge [UK] [CAM]
Vaysburd, Marina [Auteur]
MRC Laboratory of Molecular Biology [Cambridge, UK] [LMB]
Böken, Dorothea [Auteur]
University of Cambridge [UK] [CAM]
Miller, Lauren [Auteur]
MRC Laboratory of Molecular Biology [Cambridge, UK] [LMB]
Katsinelos, Taxiarchis [Auteur]
University of Cambridge [UK] [CAM]
MRC Laboratory of Molecular Biology [Cambridge, UK] [LMB]
Franco, Catarina [Auteur]
MRC Laboratory of Molecular Biology [Cambridge, UK] [LMB]
Dupré, Elian [Auteur]
Biologie Structurale Intégrative [ERL 9002 - INSERM U1167 - BSI]
Danis, Clément [Auteur]
Biologie Structurale Intégrative [ERL 9002 - INSERM U1167 - BSI]
Equipe Alzheimer and Tauopathies - LilNCog [U1172 Inserm]
Landrieu, Isabelle [Auteur]
Biologie Structurale Intégrative [ERL 9002 - INSERM U1167 - BSI]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Buee, Luc [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Klenerman, David [Auteur]
James, Leo [Auteur]
MRC Laboratory of Molecular Biology [Cambridge, UK] [LMB]
Mcewan, William [Auteur]
University of Cambridge [UK] [CAM]

Journal title :

Science

Pages :

1009-1016

Publisher :

American Association for the Advancement of Science (AAAS)

Publication date :

2024-08-30

ISSN :

0036-8075

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

<div><p>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 ...
Show more ><div><p>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.</p><p>One-Sentence Summary: Redirecting a cytosolic immune pathway enables potent and aggregate-selective removal of pathological tau protein in cell and animal models.</p></div>Show less >

Language :

Anglais

Popular science :

Non

ANR Project :

Caractérisation moléculaire et cellulaire de nanobodies dirigés contre Tau

Collections :

• Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167

Source :

Harvested from HAL

Submission date :

2024-10-22T04:41:40Z