Origin of metastable oligomers and their effects on amyloid fibril self-assembly. Issue 27 (25th June 2018)

• Record Type: Journal Article
• Authors: Hasecke, Filip; Miti, Tatiana; Perez, Carlos; Barton, Jeremy; Schölzel, Daniel; Gremer, Lothar; Grüning, Clara S. R.; Matthews, Garrett; Meisl, Georg; Knowles, Tuomas P. J.; Willbold, Dieter; Neudecker, Philipp; Heise, Henrike; Ullah, Ghanim; Hoyer, Wolfgang; Muschol, Martin
• Is Part Of: Chemical science. Volume 9:Issue 27(2018)
• Page Start: 5937
• Page End: 5948
• Publication Date: 2018-06-25
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c8sc01479e
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Simultaneous analysis of oligomer and fibril assembly kinetics reveals inhibitory effects of metastable oligomers on amyloid fibril formation. 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.