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

Cassandra Terry1,2, Robert L Harniman3, Jessica Sells1,4

  • 1MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK.

Scientific Reports
|January 25, 2019
PubMed

Insights

The structural difference between infectious prion protein (PrP) rods and non-infectious PrP fibrils was revealed. Infectious PrP rods are wider and contain a unique central gap, explaining their distinct properties in neurodegenerative diseases.

Area of Science:

  • Structural Biology
  • Neuroscience
  • Biochemistry

Background:

  • Protein misfolding and aggregation into amyloid fibrils are implicated in neurodegenerative diseases.
  • Prion-like mechanisms, involving the spread of misfolded proteins, are key in diseases like Creutzfeldt-Jakob disease.
  • While in vitro recombinant prion protein (PrP) fibrils are generally non-infectious, authentic mammalian prions are lethal agents, but their high-resolution structures remain elusive.

Purpose of the Study:

  • To elucidate the high-resolution structure of infectious prion protein (PrP) rods from mouse brain.
  • To compare the structure of infectious PrP rods with non-infectious recombinant PrP fibrils generated in vitro.
  • To understand the structural basis for the infectivity and pathogenicity of prions.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to examine the structure of PrP assemblies.
  • Atomic force microscopy (AFM) was used to probe the physical properties and adhesive forces of the fibrils.
  • Comparative structural analysis was performed on infectious PrP rods and in vitro recombinant PrP fibrils.

Main Results:

  • Non-infectious recombinant PrP fibrils are 10 nm wide single fibers with a double helical substructure.
  • Infectious PrP rods are 20 nm wide, composed of two parallel fibers separated by an 8-10 nm gap.
  • The central gap in infectious PrP rods contains irregularly structured material with distinct adhesive properties, differentiating them from non-infectious fibrils.

Conclusions:

  • The distinct 3D structure of infectious PrP rods, particularly the central gap region, differentiates them from non-infectious PrP fibrils.
  • These structural differences are likely responsible for the distinct biological activities and pathogenicity of authentic prions.
  • The findings provide a structural basis for understanding prion strain diversity and the mechanisms of prion-induced neurodegeneration.

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