Graphical abstract. Source: Miller et al., 2024. “Co-opting templated aggregation to degrade pathogenic tau assemblies and improve motor function”, Cell 2024.08.024. Licensed under an Attribution 4.0 international license.

RING-Bait technology, a novel approach for targeting intracellular protein aggregates in neurodegenerative diseases, has been introduced in a new study by Miller et al. The researchers focused on tau aggregates, which are implicated in conditions like Alzheimer’s disease and progressive supranuclear palsy. RING-Bait combines a “Bait” element matching part of the target protein aggregate with the RING domain from the E3 ligase TRIM21. When incorporated into growing aggregates, RING-Bait activates, leading to ubiquitination and degradation of the aggregate while leaving soluble protein copies intact.

The team demonstrated RING-Bait’s efficacy in HEK293 cells, primary neurons, and in vivo using a mouse model of tauopathy. The study employed gene therapy for delivery, using an AAV vector to cross the blood-brain barrier. They observed significant reductions in tau aggregates and improvements in motor function in treated mice. The technology’s specificity was confirmed through mass spectrometry analysis, showing no off-target protein degradation.

RING-Bait offers several advantages over current approaches, including intracellular targeting, aggregate specificity, and the potential for broader application to other neurodegenerative diseases.

This research is important as it presents a promising therapeutic strategy for neurodegenerative diseases characterized by intracellular protein aggregates.

The study utilized an IonOpticks Aurora Ultimate TS 25×75 C18 UHPLC column for high-resolution peptide separation, enabling comprehensive proteomic analysis to validate the technology’s specificity and efficacy.

Publication
Cell

Authors

Lauren V.C. Miller, Guido Papa, Marina Vaysburd, Shi Cheng, Paul W. Sweeney, Annabel Smith, Catarina Franco, Taxiarchis Katsinelos, Melissa Huang, Sophie A.I. Sanford, Jonathan Benn, Jasmine Farnsworth, Katie Higginson, Holly Joyner, William A. McEwan, Leo C. James

Title

Co-opting templated aggregation to degrade pathogenic tau assemblies and improve motor function