Visualizing and trapping transient oligomers in amyloid assembly pathways

Emma E. Cawood, Theodoros K. Karamanos, Andrew J. Wilson*, Sheena E. Radford

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

82 Citations (Scopus)
28 Downloads (Pure)

Abstract

Oligomers which form during amyloid fibril assembly are considered to be key contributors towards amyloid disease. However, understanding how such intermediates form, their structure, and mechanisms of toxicity presents significant challenges due to their transient and heterogeneous nature. Here, we discuss two different strategies for addressing these challenges: use of (1) methods capable of detecting lowly-populated species within complex mixtures, such as NMR, single particle methods (including fluorescence and force spectroscopy), and mass spectrometry; and (2) chemical and biological tools to bias the amyloid energy landscape towards specific oligomeric states. While the former methods are well suited to following the kinetics of amyloid assembly and obtaining low-resolution structural information, the latter are capable of producing oligomer samples for high-resolution structural studies and inferring structure-toxicity relationships. Together, these different approaches should enable a clearer picture to be gained of the nature and role of oligomeric intermediates in amyloid formation and disease.

Original languageEnglish
Article number106505
Number of pages14
JournalBiophysical Chemistry
Volume268
Early online date10 Nov 2020
DOIs
Publication statusPublished - Jan 2021

Bibliographical note

Funding Information:
We thank members of our laboratories for helpful discussions. This work was supported by The Wellcome Trust (109154/Z/15/Z and 204963), the EPSRC (EP/N035267/1, EP/N013573/1) and the ERC (322408). A.J.W. holds a Royal Society Leverhulme Trust Senior Fellowship (SRF/R1/191087). EEC and TKK wrote the first draft. All authors curated information, reviewed, and edited the manuscript.

Publisher Copyright:
© 2020

Keywords

  • Amyloid disease
  • Chemical tool
  • NMR
  • Oligomer stabilization
  • Single particle
  • Transient intermediate

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Organic Chemistry

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