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

Schneider, Matthias M.; Gautam, Saurabh; Herling, Therese W.; Andrzejewska, Ewa; Krainer, Georg; Miller, Alyssa M.; Trinkaus, Victoria A.; Peter, Quentin A. E.; Ruggeri, Francesco Simone; Vendruscolo, Michele; Bracher, Andreas; Dobson, Christopher M.; Hartl, F. Ulrich und Knowles, Tuomas P. J. (2021): The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends. In: Nature Communications, Bd. 12, Nr. 1, 5999

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 alpha-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 alpha-synuclein disaggregation. We show that Hsc70 together with its co-chaperones DnaJB1 and Apg2 can completely reverse alpha-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. Molecular chaperones from the Hsp70 family can break up protein aggregates, including amyloids. Here, the authors utilize microfluidic diffusional sizing to assess the mechanism of alpha-synuclein (alpha S) disaggregation by the Hsc70-DnaJB1-Apg2 system, and show that single alpha S molecules are removed directly from the fibril ends.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198