PT - JOURNAL ARTICLE AU - Sun, Yuanzi AU - Jack, Kezia AU - Ercolani, Tiziana AU - Sangar, Daljit AU - Hosszu, Laszlo AU - Collinge, John AU - Bieschke, Jan TI - Direct Observation of Competing Prion Protein Fibril Populations with Distinct Structures and Kinetics AID - 10.1101/2022.08.10.503301 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.08.10.503301 4099 - http://biorxiv.org/content/early/2022/08/13/2022.08.10.503301.short 4100 - http://biorxiv.org/content/early/2022/08/13/2022.08.10.503301.full AB - In prion diseases, fibrillar assemblies of misfolded prion protein (PrP) self-propagate by incorporating PrP monomers. Using total internal reflection and transient amyloid binding super-resolution microscopy, our study analyses elongation of single PrP fibrils to reveal polymorphic populations, featuring structural and dynamic heterogeneity similar to prion strains, which were previously hidden in ensemble measurements. PrP fibrils elongated along a preferred direction by an intermittent ‘stop- and-go’ mechanism. Fibrils fell into three main populations, which each displayed distinct elongation mechanisms incorporating different monomer structures and which maintained their properties even under elongation conditions favouring a different fibril type. Elongation of RML and ME7 prion rods likewise exhibited unique kinetic features. The discovery of polymorphic fibril populations of amyloid and prions growing in competition suggests that prions may present as quasispecies of structural isomorphs and that the replication environment may tilt the balance between prion isomorphs and amyloid species.HighlightsSynthetic prion fibril populations contain structurally distinct fibril typesFibril types faithfully elongate by different mechanismsFibril types compete for substrate depending on environmentFibril populations model quasi-species behavior of prion strainseTOC Replication of different prion strains causes distinct disease phenotypes. Sun et al. analyzed the growth of individual synthetic prion protein fibrils by super-resolution microscopy and found populations of structurally distinct fibril types, which grew in competition to each other as a quasi-species, recapitulating basic prion strain characteristics in vitro.Competing Interest StatementThe authors have declared no competing interest.