Sun, Yuanzi;
Jack, Kezia;
Ercolani, Tiziana;
Sangar, Daljit;
Hosszu, Laszlo;
Collinge, John;
Bieschke, Jan;
(2023)
Direct Observation of Competing Prion Protein Fibril Populations with Distinct Structures and Kinetics.
ACS Nano
10.1021/acsnano.2c12009.
(In press).
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Abstract
In prion diseases, fibrillar assemblies of misfolded prion protein (PrP) self-propagate by incorporating PrP monomers. These assemblies can evolve to adapt to changing environments and hosts, but the mechanism of prion evolution is poorly understood. We show that PrP fibrils exist as a population of competing conformers, which are selectively amplified under different conditions and can "mutate" during elongation. Prion replication therefore possesses the steps necessary for molecular evolution analogous to the quasispecies concept of genetic organisms. We monitored structure and growth of single PrP fibrils by total internal reflection and transient amyloid binding super-resolution microscopy and detected at least two main fibril populations, which emerged from seemingly homogeneous PrP seeds. All PrP fibrils elongated in a preferred direction by an intermittent "stop-and-go" mechanism, but each population possessed distinct elongation mechanisms that incorporated either unfolded or partially folded monomers. Elongation of RML and ME7 prion rods likewise exhibited distinct kinetic features. The discovery of polymorphic fibril populations growing in competition, which were previously hidden in ensemble measurements, suggests that prions and other amyloid replicating by prion-like mechanisms may represent quasispecies of structural isomorphs that can evolve to adapt to new hosts and conceivably could evade therapeutic intervention.
| Type: | Article |
|---|---|
| Title: | Direct Observation of Competing Prion Protein Fibril Populations with Distinct Structures and Kinetics |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acsnano.2c12009 |
| Publisher version: | https://doi.org/10.1021/acsnano.2c12009 |
| Language: | English |
| Additional information: | © 2023 The Authors. Published by American Chemical Society. This is an open access article under the CC BY 4.0 license Attribution 4.0 International (https://creativecommons.org/licenses/by/4.0/) |
| Keywords: | polymorphic amyloid structures, prion protein, protein misfolding, real-time kinetic measurements, super-resolution microscopy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10165645 |
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