Hsp70 Inhibits the Nucleation and Elongation of Tau and Sequesters Tau Aggregates with High Affinity

Franziska Kundel, Suman Mukhopadhyay, Patrick Flagmeier, Mathew Horrocks, Magnus Kjaergaard, Sarah L. Shammas, Sophie E. Jackson, Christopher M. Dobson, David Klenerman

Research output: Contribution to journalArticlepeer-review

Abstract

As a key player of the protein quality control network of the cell, the molecular chaperone Hsp70 inhibits the aggregation of the amyloid protein tau. To date, the mechanism of this inhibition and the tau species targeted by Hsp70 remain
unknown. This is partly due to the inherent difficulty of studying amyloid aggregates because of their heterogeneous and transient nature. Here, we used ensemble and single-molecule fluorescence measurements to dissect how Hsp70 counteracts the selfassembly process of K18 tau with the pathological deletion ΔK280. We found that Hsp70 blocks the early stages of tau aggregation
by suppressing the formation of tau nuclei. Additionally, Hsp70 sequesters oligomers and mature tau fibrils with nanomolar affinity into a protective complex, efficiently neutralizing their ability to damage membranes and seed further tau aggregation. Our results provide novel insights into the molecular mechanisms by which the chaperone Hsp70 counteracts the formation, propagation and toxicity of tau aggregates.
Original languageEnglish
JournalAcs chemical biology
Early online date4 Jan 2018
DOIs
Publication statusE-pub ahead of print - 4 Jan 2018

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