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Issue 27, 2018
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Origin of metastable oligomers and their effects on amyloid fibril self-assembly

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Abstract

Assembly of rigid amyloid fibrils with their characteristic cross-β sheet structure is a molecular signature of numerous neurodegenerative and non-neuropathic disorders. Frequently large populations of small globular amyloid oligomers (gOs) and curvilinear fibrils (CFs) precede the formation of late-stage rigid fibrils (RFs), and have been implicated in amyloid toxicity. Yet our understanding of the origin of these metastable oligomers, their role as on-pathway precursors or off-pathway competitors, and their effects on the self-assembly of amyloid fibrils remains incomplete. Using two unrelated amyloid proteins, amyloid-β and lysozyme, we find that gO/CF formation, analogous to micelle formation by surfactants, is delineated by a “critical oligomer concentration” (COC). Below this COC, fibril assembly replicates the sigmoidal kinetics of nucleated polymerization. Upon crossing the COC, assembly kinetics becomes biphasic with gO/CF formation responsible for the lag-free initial phase, followed by a second upswing dominated by RF nucleation and growth. RF lag periods below the COC, as expected, decrease as a power law in monomer concentration. Surprisingly, the build-up of gO/CFs above the COC causes a progressive increase in RF lag periods. Our results suggest that metastable gO/CFs are off-pathway from RF formation, confined by a condition-dependent COC that is distinct from RF solubility, underlie a transition from sigmoidal to biphasic assembly kinetics and, most importantly, not only compete with RFs for the shared monomeric growth substrate but actively inhibit their nucleation and growth.

Graphical abstract: Origin of metastable oligomers and their effects on amyloid fibril self-assembly

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Publication details

The article was received on 01 Apr 2018, accepted on 12 Jun 2018 and first published on 13 Jun 2018


Article type: Edge Article
DOI: 10.1039/C8SC01479E
Citation: Chem. Sci., 2018,9, 5937-5948
  • Open access: Creative Commons BY-NC license
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    Origin of metastable oligomers and their effects on amyloid fibril self-assembly

    F. Hasecke, T. Miti, C. Perez, J. Barton, D. Schölzel, L. Gremer, C. S. R. Grüning, G. Matthews, G. Meisl, T. P. J. Knowles, D. Willbold, P. Neudecker, H. Heise, G. Ullah, W. Hoyer and M. Muschol, Chem. Sci., 2018, 9, 5937
    DOI: 10.1039/C8SC01479E

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