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ARUK UCL Drug Discovery Institute Seminar
January 18 @ 4:00 pm - 5:00 pm
In this ARUK UCL Drug Discovery Institute Seminar Dr Lauren Miller, University of Cambridge explore how TRIM21 RING-Bait technology selectively degrades pathological tau assemblies.
Protein aggregation causes a wide range of neurodegenerative diseases. Targeting and removing aggregates, but not the functional protein, is a considerable therapeutic challenge. To address this, we have developed a technology called ‘RING-Bait’, which combines an aggregating protein sequence with an E3 ubiquitin ligase. We utilised the RING domain of cytosolic Fc receptor TRIM21, which activates via clustering, to specifically target assembled species of protein. RING-Bait is recruited into aggregates, whereupon clustering dimerises the RING and activates its E3 function, resulting in degradation of the aggregate complex.
We exemplify this concept by demonstrating specific degradation of tau aggregates while leaving soluble tau protein untouched. Unlike immunotherapy, RING-Bait is effective against both seeded and cell autonomous aggregation. RING-Bait removed tau aggregates seeded from AD and PSP brain extract and was also effective in primary neurons. We also used CNS penetrant AAV to treat P301S tau mice, concomitantly reducing brain aggregate levels and improving motor function. RING-Bait technology can be applied to other aggregate diseases by replacing the Bait sequence to match the target aggregate.
