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.
Highlights
Molecular chaperones contribute to the maintenance of cellular protein homoeostasis through assisting de novo protein folding and preventing amyloid formation
The diffusion profiles are analysed by considering advection–diffusion processes to extract the distribution of diffusion coefficients and the corresponding hydrodynamic radii (Rh) of the individual species present in solution[40,42]
By bringing together microfluidic measurements with chemical kinetics and thermodynamic analysis, we have investigated this process here in a quantitative manner
Summary
Molecular chaperones contribute to the maintenance of cellular protein homoeostasis through assisting de novo protein folding and preventing amyloid formation. We show that Hsc[70] together with its co-chaperones DnaJB1 and Apg[2] 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. Misfolding and aggregation of proteins and peptides into amyloidogenic fibrils are hallmarks of a wide range of neurodegenerative disorders[1,2,3], including α-synuclein (αS) in Parkinson’s disease, the Aβ-peptide in Alzheimer’s disease, and Huntingtin (HTT) in Huntington’s disease[4] The accumulation of such fibrillar deposits in the central nervous system occurs in an age-dependent manner; earlier in life, this process is counteracted by efficient cellular protein quality control machinery that inhibits the amyloid formation and disease[5,6,7]. The constitutively expressed chaperone heat shock cognate Hsc[70] (HSPA8) together with the Hsp[40] class B
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