The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends

Matthias M. Schneider, Saurabh Gautam, Therese W. Herling, Ewa Andrzejewska, Georg Krainer, Alyssa M. Miller, Victoria A. Trinkaus, Quentin A. E. Peter, Francesco Simone Ruggeri, Michele Vendruscolo, Andreas Bracher, Christopher M. Dobson, F. Ulrich Hartl () and Tuomas P. J. Knowles ()
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Matthias M. Schneider: University of Cambridge
Saurabh Gautam: Max-Planck Institute of Biochemistry
Therese W. Herling: University of Cambridge
Ewa Andrzejewska: University of Cambridge
Georg Krainer: University of Cambridge
Alyssa M. Miller: University of Cambridge
Victoria A. Trinkaus: Max-Planck Institute of Biochemistry
Quentin A. E. Peter: University of Cambridge
Francesco Simone Ruggeri: University of Cambridge
Michele Vendruscolo: University of Cambridge
Andreas Bracher: Max-Planck Institute of Biochemistry
Christopher M. Dobson: University of Cambridge
F. Ulrich Hartl: Max-Planck Institute of Biochemistry
Tuomas P. J. Knowles: University of Cambridge

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Molecular chaperones contribute to the maintenance of cellular protein homoeostasis through assisting de novo protein folding and preventing amyloid formation. Chaperones of the Hsp70 family can further disaggregate otherwise irreversible aggregate species such as α-synuclein fibrils, which accumulate in Parkinson’s disease. However, the mechanisms and kinetics of this key functionality are only partially understood. Here, we combine microfluidic measurements with chemical kinetics to study α-synuclein disaggregation. We show that Hsc70 together with its co-chaperones DnaJB1 and Apg2 can completely reverse α-synuclein aggregation back to its soluble monomeric state. This reaction proceeds through first-order kinetics where monomer units are removed directly from the fibril ends with little contribution from intermediate fibril fragmentation steps. These findings extend our mechanistic understanding of the role of chaperones in the suppression of amyloid proliferation and in aggregate clearance, and inform on possibilities and limitations of this strategy in the development of therapeutics against synucleinopathies.

Date: 2021
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DOI: 10.1038/s41467-021-25966-w

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