Structural features distinguishing infectious ex vivo mammalian prions from non-infectious fibrillar assemblies generated in vitro

• Published in: Scientific reports Vol. 9; no. 1; p. 376
• Main Authors: Terry, Cassandra, Harniman, Robert L., Sells, Jessica, Wenborn, Adam, Joiner, Susan, Saibil, Helen R., Miles, Mervyn J., Collinge, John, Wadsworth, Jonathan D. F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.01.2019; Nature Publishing Group
• Subjects: 101/28; 631/45/460; 631/535/1258/1259; 82/83; Amyloid; Amyloid - chemistry; Amyloid - ultrastructure; Animals; Atomic force microscopy; Double-stranded; Electron microscopy; Fibers; Fibrils; Humanities and Social Sciences; Mammals; Microscopy; Microscopy, Atomic Force; multidisciplinary; Neurodegeneration; Neurodegenerative diseases; Polymerization; Prion protein; Prion Proteins - chemistry; Prions; Prions - chemistry; Prions - ultrastructure; Protein Conformation; Protein Folding; Recombinant Proteins; Rods; Science; Science (multidisciplinary); Structure-Activity Relationship
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-36700-w

Seeded polymerisation of proteins forming amyloid fibres and their spread in tissues has been implicated in the pathogenesis of multiple neurodegenerative diseases: so called “prion-like” mechanisms. While ex vivo mammalian prions, composed of multichain assemblies of misfolded host-encoded prion protein (PrP), act as lethal infectious agents, PrP amyloid fibrils produced in vitro generally do not. The high-resolution structure of authentic infectious prions and the structural basis of prion strain diversity remain unknown. Here we use cryo-electron microscopy and atomic force microscopy to examine the structure of highly infectious PrP rods isolated from mouse brain in comparison to non-infectious recombinant PrP fibrils generated in vitro . Non-infectious recombinant PrP fibrils are 10 nm wide single fibres, with a double helical repeating substructure displaying small variations in adhesive force interactions across their width. In contrast, infectious PrP rods are 20 nm wide and contain two fibres, each with a double helical repeating substructure, separated by a central gap of 8–10 nm in width. This gap contains an irregularly structured material whose adhesive force properties are strikingly different to that of the fibres, suggestive of a distinct composition. The structure of the infectious PrP rods, which cause lethal neurodegeneration, readily differentiates them from all other protein assemblies so far characterised in other neurodegenerative diseases.