biostudies-literatureSchneider MMEuropean Research CouncilWellcome Trust5999https://www.ebi.ac.uk/biostudies/studies/S-EPMC8516981biostudies-literatureUnknown12(1)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 littleNature communicationsThe Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends.PMC8516981MBAG/301 RG84912337969Herling TWMiller AMKrainer GTrinkaus VARuggeri FSDobson CMHartl FUKnowles TPJAndrzejewska EPeter QAEVendruscolo MBracher ASchneider MMGautam SfalseThe Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends.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 little2021-01-01T00:00:00Z2021 Oct2025-04-19T06:07:48.389Z2025-04-19T06:07:48.389ZS-EPMC85169813465003710.1038/s41467-021-25966-w