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 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.
Authors
- Shi Cheng (ORCID: https://orcid.org/0000-0002-0092-564X)
- Catarina Franco (ORCID: https://orcid.org/0000-0003-2288-1518)
- Lauren V. C. Miller (ORCID: https://orcid.org/0000-0002-0612-494X)
- Clément Danis (ORCID: https://orcid.org/0000-0002-5895-4742)
- Isabelle Landrieu (ORCID: https://orcid.org/0000-0002-4883-2637)
- David A. Klenerman (ORCID: https://orcid.org/0000-0001-7116-6954)
- Annabel E. Smith (ORCID: https://orcid.org/0000-0001-5837-6121)
- Elian Dupré (ORCID: https://orcid.org/0000-0001-5281-0337)
- Sophie Keeling (ORCID: https://orcid.org/0000-0002-6413-2550)
- Luc Buée (ORCID: https://orcid.org/0000-0002-6261-4230)
- Marina Vaysburd (ORCID: https://orcid.org/0000-0001-7236-678X)
- Leo C. James (ORCID: https://orcid.org/0000-0003-2131-0334)
- William A. McEwan (ORCID: https://orcid.org/0000-0002-4408-0407)
- Dorothea Böken (ORCID: https://orcid.org/0009-0008-8443-4469)
- Jonathan Benn (ORCID: https://orcid.org/0000-0002-1225-6682)
- Panagiotis Katsinelos (ORCID: https://orcid.org/0000-0001-6951-3216)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- MRC Laboratory of Molecular Biology (GB)
- Université de Lille (FR)
- Institut Pasteur de Lille (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- UK Dementia Research Institute (GB)
- Computer Science Laboratory of Lille (FR)
Publication Details
- Journal
- Science
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1126/science.adp5186
- Citations
- 54
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 12.63
Funders
- Wellcome Trust
- European Federation of Pharmaceutical Industries and Associations
- Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
- European Commission
- Lister Institute of Preventive Medicine
- Agence Nationale de la Recherche
- UK Dementia Research Institute
- Medical Research Council
- Cambridge Institute for Medical Research, University of Cambridge
- Staatssekretariat für Bildung, Forschung und Innovation