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A Single-Molecule Technology for Resolving Chaperone Action in Neurodegenerative Diseases

Project description

The role of chaperones in neurodegenerative disorders

Molecular chaperones are proteins implicated in the folding and unfolding of molecules including proteins. However, the mechanism of resolving protein aggregates such as those implicated in Alzheimer’s and Parkinson’s diseases is poorly understood. The key objective of the EU-funded MicroSPARK project is to elucidate the mechanism by which chaperones target and disassemble amyloid protein species. Using a single-molecule fluorescence spectroscopy approach, researchers will analyse individual chaperone–aggregate complexes, unveiling the chaperones' mechanism of action. Results will pave the way for the design of novel small-molecule modulators of chaperone activity in neurodegenerative disorders.

Objective

A range of debilitating neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, arise from the formation of amyloidogenic protein aggregates. Molecular chaperones can counteract aggregate formation, but their molecular action mechanisms remain poorly understood. This is chiefly due to the fundamental challenge of resolving heterogeneous and dynamic aggregating protein species in the presence of chaperones. In order to address this challenge and to advance our knowledge of chaperone action, I propose establishing µSPARK, a novel technology that will allow, for the first time, the unravelling of the detailed microscopic mechanisms by which chaperones target and disassemble amyloidogenic protein species in heterogeneous mixtures at the single-molecule level. These new insights will become possible through the first-time combination and seamless integration of two advanced technologies: (i) Miniaturized fluidic sorting devices and (ii) single-molecule fluorescence spectroscopy combined with three-colour coincidence detection. This will enable high-throughput single-particle interrogation of individual chaperone–aggregate complexes providing fundamentally new means for understanding key aspects of chaperone function. To demonstrate the new possibilities, µSPARK will be exploited to unravel the action mechanisms of heat-shock proteins in curtailing amyloid-β peptide and α-synuclein aggregation. This will provide new insights into proteostatic regulatory mechanisms in Alzheimer’s and Parkinson’s disease. The µSPARK technology will then be exploited to dissect—with high throughput and single-particle resolution—the molecular action mechanisms of small-molecule modulators that promote the inhibitory function of chaperones on protein aggregation. This will allow identifying new strategies to ameliorate aggregate toxicity and will pave the way for µSPARK to become a novel screening tool for drug development.

Coordinator

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Net EU contribution
€ 212 933,76
Address
TRINITY LANE THE OLD SCHOOLS
CB2 1TN Cambridge
United Kingdom

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Region
East of England East Anglia Cambridgeshire CC
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 212 933,76