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A structural basis for prion strain diversity

Szymon W Manka1, Adam Wenborn1, Jemma Betts1

  • 1MRC Prion Unit at UCL, Institute of Prion Diseases, University College London, London, UK.

Nature Chemical Biology
|January 16, 2023
PubMed

Insights

This study reveals distinct prion protein (PrP) structures in mouse prion strains ME7 and RML using cryo-electron microscopy. These structures explain how different prion strains emerge from the same PrP substrate.

Area of Science:

  • Structural biology
  • Neuroscience
  • Biochemistry

Background:

  • Prion diseases are linked to misfolded prion protein (PrP) forming amyloid fibrils.
  • Previous studies identified a parallel in-register intermolecular β-sheet (PIRIBS) architecture in hamster and mouse prion strains.
  • Understanding strain-specific conformations is crucial for deciphering prion disease mechanisms.

Purpose of the Study:

  • To determine the near-atomic resolution cryo-electron microscopy (cryo-EM) structure of infectious mouse prion fibrils from the ME7 prion strain.
  • To compare the ME7 fibril structure with the previously determined RML fibril structure.
  • To elucidate the structural basis of intra-species prion strain diversity.

Main Methods:

  • Cryogenic electron microscopy (cryo-EM) was employed to resolve the structure of ex vivo mouse prion fibrils.
  • Comparative structural analysis was performed between ME7 and RML prion strains.

Main Results:

  • The cryo-EM structure of ME7 mouse prion fibrils was determined at near-atomic resolution.
  • Comparison with the RML fibril structure revealed distinct folding subdomains within the prion protein (PrP) rungs.
  • Specific interrelationships between these folding subdomains were identified, defining strain-specific conformations.

Conclusions:

  • The study provides a structural definition of intra-species prion strain-specific conformations.
  • Divergent prion strain conformations arise from distinct folding patterns of PrP monomers within the fibril structure.
  • This work advances the understanding of prion protein misfolding and strain emergence.

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