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dc.contributor.authorSchneider, Matthias M
dc.contributor.authorGautam, Saurabh
dc.contributor.authorHerling, Therese W
dc.contributor.authorAndrzejewska, Ewa
dc.contributor.authorKrainer, Georg
dc.contributor.authorMiller, Alyssa M
dc.contributor.authorTrinkaus, Victoria A
dc.contributor.authorPeter, Quentin A E
dc.contributor.authorRuggeri, Francesco Simone
dc.contributor.authorVendruscolo, Michele
dc.contributor.authorBracher, Andreas
dc.contributor.authorDobson, Christopher M
dc.contributor.authorHartl, F Ulrich
dc.contributor.authorKnowles, Tuomas P J
dc.description.abstractMolecular 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.
dc.rightsAttribution 4.0 International
dc.sourceessn: 2041-1723
dc.sourcenlmid: 101528555
dc.titleThe Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends.
prism.publicationNameNature communications
dc.contributor.orcidSchneider, Matthias M [0000-0002-1894-1859]
dc.contributor.orcidGautam, Saurabh [0000-0003-0366-6169]
dc.contributor.orcidKrainer, Georg [0000-0002-9626-7636]
dc.contributor.orcidPeter, Quentin A E [0000-0002-8018-3059]
dc.contributor.orcidRuggeri, Francesco Simone [0000-0002-1232-1907]
dc.contributor.orcidVendruscolo, Michele [0000-0002-3616-1610]
dc.contributor.orcidBracher, Andreas [0000-0001-8530-7594]
dc.contributor.orcidHartl, F Ulrich [0000-0002-7941-135X]
dc.contributor.orcidKnowles, Tuomas P J [0000-0002-7879-0140]
pubs.funder-project-idEuropean Research Council (337969)

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International