Abstract
Background As the protein quality control centre of the cell molecular chaperones tightly regulate amyloid proteins and seem to alleviate their cytotoxicity. However, the precise mechanism of this interplay and how its modification leads to disease remain elusive. Particularly oligomeric species of amyloid proteins have emerged as the most important mediators of neurotoxicity in neurodegenerative diseases. However, these oligomers are exceedingly hard to characterize as they are transient, heterogeneous and rare relative to the monomeric and fibrillar states. We have developed single molecule FRET techniques for the time-resolved detection and characterisation of oligomeric species [1-3]. Here, we characterise the oligomers evolving during the aggregation of a tau variant carrying the Δ280K mutation associated with some forms of frontotemporal dementia. Further, we study the interaction of these oligomers with the intracellular chaperone Hsp70 which has previously been identified as a key regulator of tau turnover.
Highlights
As the protein quality control centre of the cell molecular chaperones tightly regulate amyloid proteins and seem to alleviate their cytotoxicity
We have developed single molecule FRET techniques for the time-resolved detection and characterisation of oligomeric species [1-3]
The heparin induced tau oligomers at picomolar concentrations are flowed through the confocal volume using a microfluidic device and coincident fluorescent bursts of donor and receptor fluorophores are readily detected
Summary
As the protein quality control centre of the cell molecular chaperones tightly regulate amyloid proteins and seem to alleviate their cytotoxicity. Oligomeric species of amyloid proteins have emerged as the most important mediators of neurotoxicity in neurodegenerative diseases. These oligomers are exceedingly hard to characterize as they are transient, heterogeneous and rare relative to the monomeric and fibrillar states.
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