Co-opting templated aggregation to degrade pathogenic tau assemblies and improve motor function
Protein aggregation causes a wide range of neurodegenerative diseases. Targeting and removing aggregates, but not the functional protein, is a considerable therapeutic challenge. Here, we describe a therapeutic strategy called "RING-Bait," which employs an aggregating protein sequence combined with an E3 ubiquitin ligase. RING-Bait is recruited into aggregates, whereupon clustering dimerizes the RING domain and activates its E3 function, resulting in the degradation of the aggregate complex. We exemplify this concept by demonstrating the specific degradation of tau aggregates while sparing soluble tau. Unlike immunotherapy, RING-Bait is effective against both seeded and cell-autonomous aggregation. RING-Bait removed tau aggregates seeded from Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) brain extracts and was also effective in primary neurons. We used a brain-penetrant adeno-associated virus (AAV) to treat P301S tau transgenic mice, reducing tau pathology and improving motor function. A RING-Bait strategy could be applied to other neurodegenerative proteinopathies by replacing the Bait sequence to match the target aggregate.
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)
- Paul W. Sweeney (ORCID: https://orcid.org/0000-0003-3385-0696)
- Melissa Huang (ORCID: https://orcid.org/0000-0002-0698-6996)
- Marina Vaysburd (ORCID: https://orcid.org/0000-0001-7236-678X)
- Guido Papa (ORCID: https://orcid.org/0000-0002-5215-0014)
- Sophie Sanford (ORCID: https://orcid.org/0000-0002-7712-0575)
- Leo C. James (ORCID: https://orcid.org/0000-0003-2131-0334)
- William A. McEwan (ORCID: https://orcid.org/0000-0002-4408-0407)
- Katie Higginson
- Jonathan Benn (ORCID: https://orcid.org/0000-0002-1225-6682)
- Panagiotis Katsinelos (ORCID: https://orcid.org/0000-0001-6951-3216)
- Jasmine Farnsworth
- Holly Joyner
- Annabel N. Smith
Institutions
- MRC Laboratory of Molecular Biology (GB)
- Cancer Research UK (GB)
- UK Dementia Research Institute (GB)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Cell
- Published
- 2024-09-13
- DOI
- https://doi.org/10.1016/j.cell.2024.08.024
- Citations
- 40
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 13.04
Funders
- Wellcome Trust
- European Federation of Pharmaceutical Industries and Associations
- Alzheimer's Society
- Innovative Health Initiative
- Cancer Research UK
- European Commission
- Lister Institute of Preventive Medicine
- UK Dementia Research Institute
- Medical Research Council