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In this article, high-speed AFM was used to study amyloid fibril destabilization and disassembly in situ. The formation of amyloid fibrils is characteristic for multiple neurodegenerative pathologies, such as Alzheimer’s and Parkinson’s disease. Although the human Hsc70-based disaggregase system has been shown to disassemble mature α-synuclein amyloid fibrils, the underlying molecular mechanism has remained elusive until now.
Using high-speed AFM scanning, the authors show that amyloid disassembly is initiated by the destabilization of the fibril ends, followed by fast propagation of protofilament unzipping, and depolymerization along the fibril axis without accumulation of harmful oligomeric intermediates. The biochemical and kinetic characterization of the process suggests that the chaperone system used preferentially clears neurotoxic oligomers and short fibrils, while its activity against large amyloids is substantially hindered. The suggested “all-or-none” disaggregation of individual aggregate mechanisms provides a better molecular insight into the chaperone-mediated selective processing of toxic amyloid species and is a crucial milestone in the identification of potential therapeutic targets for the treatment of amyloid-related neurodegenerative diseases.