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Secondary nucleation of monomers on fibril surface dominates α-synuclein aggregation and provides autocatalytic amyloid amplification

  • Ricardo Gaspar (a1) (a2), Georg Meisl (a3), Alexander K. Buell (a3) (a4), Laurence Young (a5), Clemens F. Kaminski (a5), Tuomas P. J. Knowles (a3), Emma Sparr (a1) and Sara Linse (a2)...
Abstract
Abstract

Parkinson's disease (PD) is characterized by proteinaceous aggregates named Lewy Bodies and Lewy Neurites containing α-synuclein fibrils. The underlying aggregation mechanism of this protein is dominated by a secondary process at mildly acidic pH, as in endosomes and other organelles. This effect manifests as a strong acceleration of the aggregation in the presence of seeds and a weak dependence of the aggregation rate on monomer concentration. The molecular mechanism underlying this process could be nucleation of monomers on fibril surfaces or fibril fragmentation. Here, we aim to distinguish between these mechanisms. The nature of the secondary processes was investigated using differential sedimentation analysis, trap and seed experiments, quartz crystal microbalance experiments and super-resolution microscopy. The results identify secondary nucleation of monomers on the fibril surface as the dominant secondary process leading to rapid generation of new aggregates, while no significant contribution from fragmentation was found. The newly generated oligomeric species quickly elongate to further serve as templates for secondary nucleation and this may have important implications in the spreading of PD.

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This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author
*Authors for correspondence: Emma Sparr, Department of Physical-Chemistry, Lund University, Lund, Sweden and Sara Linse, Department of Biochemistry and Structural Biology, Lund University, Lund, Sweden. Email: emma.sparr@fkem1.lu.se and sara.linse@biochemistry.lu.se
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