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Updated: Aug 30, 2025
Protein Misfolding Cyclic Amplification of Prions
Published on: November 7, 2012
Prion strains viewed through the lens of cryo-EM
Szymon W Manka1, Adam Wenborn1, John Collinge2
1MRC Prion Unit at UCL, Institute of Prion Diseases, University College London, 33 Cleveland Street, London, W1W 7FF, UK.
Abstract:
Mammalian prions are lethal transmissible pathogens that cause fatal neurodegenerative diseases in humans and animals. They consist of fibrils of misfolded, host-encoded prion protein (PrP) which propagate through templated protein polymerisation. Prion strains produce distinct clinicopathological phenotypes in the same host and appear to be encoded by distinct misfolded PrP conformations and assembly states. Despite fundamental advances in our understanding of prion biology, key knowledge gaps remain. These include precise delineation of prion replication mechanisms, detailed explanation of the molecular basis of prion strains and inter-species transmission barriers, and the structural definition of neurotoxic PrP species. Central to addressing these questions is the determination of prion structure. While high-resolution definition of ex vivo prion fibrils once seemed unlikely, recent advances in cryo-electron microscopy (cryo-EM) and computational methods for 3D reconstruction of amyloids have now made this possible. Recently, near-atomic resolution structures of highly infectious, ex vivo prion fibrils from hamster 263K and mouse RML prion strains were reported. The fibrils have a comparable parallel in-register intermolecular β-sheet (PIRIBS) architecture that now provides a structural foundation for understanding prion strain diversity in mammals. Here, we review these new findings and discuss directions for future research.
Insights
Mammalian prions, misfolded prion protein (PrP) fibrils, cause fatal neurodegenerative diseases. New cryo-electron microscopy structures reveal a shared architecture, explaining prion strain diversity and disease.
Area of Science:
- Neuroscience
- Structural Biology
- Infectious Diseases
Background:
- Mammalian prions are lethal pathogens causing fatal neurodegenerative diseases.
- Prions are composed of misfolded prion protein (PrP) fibrils that propagate via templated polymerization.
- Distinct prion strains lead to varied disease phenotypes, suggesting encoded structural differences.
Purpose of the Study:
- To review recent advances in determining the high-resolution structure of ex vivo prion fibrils.
- To discuss how these structures provide a foundation for understanding prion strain diversity and disease mechanisms.
- To highlight future research directions in prion structural biology.
Main Methods:
- Cryo-electron microscopy (cryo-EM) for high-resolution imaging of amyloid structures.
- Computational methods for 3D reconstruction of ex vivo prion fibrils.
- Structural analysis of hamster 263K and mouse RML prion strains.
Main Results:
- Near-atomic resolution structures of infectious ex vivo prion fibrils were determined.
- A conserved parallel in-register intermolecular β-sheet (PIRIBS) architecture was identified in different prion strains.
- This shared architecture offers a molecular basis for prion strain diversity.
Conclusions:
- Recent cryo-EM advances enable high-resolution prion structure determination.
- The PIRIBS architecture provides a structural framework for understanding prion diversity and transmission.
- Further structural studies are crucial for elucidating prion replication and neurotoxicity.
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