1. The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends
- Author
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Tuomas P. J. Knowles, Christopher M. Dobson, Quentin Peter, Ewa Andrzejewska, Michele Vendruscolo, Matthias Schneider, Georg Krainer, F. Ulrich Hartl, Therese W. Herling, Francesco Simone Ruggeri, Andreas Bracher, Alyssa M. Miller, Victoria A. Trinkaus, Saurabh Gautam, Schneider, Matthias M [0000-0002-1894-1859], Gautam, Saurabh [0000-0003-0366-6169], Krainer, Georg [0000-0002-9626-7636], Peter, Quentin AE [0000-0002-8018-3059], Ruggeri, Francesco Simone [0000-0002-1232-1907], Vendruscolo, Michele [0000-0002-3616-1610], Bracher, Andreas [0000-0001-8530-7594], Hartl, F Ulrich [0000-0002-7941-135X], Knowles, Tuomas PJ [0000-0002-7879-0140], Apollo - University of Cambridge Repository, Schneider, Matthias M. [0000-0002-1894-1859], Peter, Quentin A. E. [0000-0002-8018-3059], Hartl, F. Ulrich [0000-0002-7941-135X], Knowles, Tuomas P. J. [0000-0002-7879-0140], Peter, Quentin A E [0000-0002-8018-3059], and Knowles, Tuomas P J [0000-0002-7879-0140]
- Subjects
Amyloid ,631/45/470/2284 ,147/3 ,123 ,Science ,Kinetics ,General Physics and Astronomy ,macromolecular substances ,Fibril ,General Biochemistry, Genetics and Molecular Biology ,101/62 ,639/638/440/56 ,chemistry.chemical_compound ,Single-molecule biophysics ,Biophysical chemistry ,Chaperones ,Escherichia coli ,Life Science ,Humans ,HSP70 Heat-Shock Proteins ,Fragmentation (cell biology) ,82/62 ,Synucleinopathies ,Multidisciplinary ,'de novo' protein folding ,HSC70 Heat-Shock Proteins ,article ,Parkinson Disease ,General Chemistry ,HSP40 Heat-Shock Proteins ,humanities ,Monomer ,631/57/2272/1590 ,chemistry ,alpha-Synuclein ,Biophysics ,631/57/2265 ,α synuclein ,631/45/470/1981 ,Protein aggregation ,Molecular Chaperones - Abstract
Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199, Funder: EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council); doi: https://doi.org/10.13039/100010663, 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.
- Published
- 2021