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  • Review Article
  • Published:

The state of the prion

Nature Reviews Microbiology volume 2, pages 861–871 (2004)Cite this article

Key Points

  • Since the early 1950s researchers have been studying slow and invariably fatal diseases such as scrapie (sheep), Creutzfeldt–Jakob disease and kuru (humans), bovine spongiform encephalopathy (cattle and sheep) and chronic wasting disease (deer) that are now known to be caused by transmissible agents dubbed 'prions'. After decades of investigation the precise structure of the prion is still debated.

  • The 'protein-only' hypothesis posits that prions are congruent with PrPSc, a misfolded form of the naturally occurring 'cellular prion protein' (PrPC). PrPC is encoded by the Prnp locus and is normally attached to the cell surface by a glycosylphosphatidyl inositol (GPI) anchor. Replication of the prion is attributed to PrPSc-catalysed conversion of PrPC to PrPSc. The 'virus' and 'virino' hypotheses propose that the infectious agent contains an informational nucleic acid; however, despite the best efforts of many laboratories, no such molecule has been identified so far.

  • Infectivity purified from infected brain material contains aggregates of PrPSc as the major protein component, bundled together with other substances including glycosaminoglycans and polysaccharides. Solubilization of the aggregates by denaturants causes loss of infectivity, which so far is irreversible.

  • The replication of prions is discussed, together with experimental evidence obtained from whole organisms, cell lines and cell-free in vitro systems. Research into so-called 'yeast prions', self-propagating conformational isoforms of certain yeast proteins, has added experimental support to the protein-only hypothesis.

  • Differences in strains and factors that affect prion transmission are considered in light of the protein-only prion hypothesis. Expression of cellular PrP is essential for susceptibility to prion disease and for prion replication, but other genes also have a modulating role. The spread of prions within organisms also requires expression of the cellular form PrPC, both within and outside the central nervous system. Certain cells of the immune system serve as amplification sites in prion spread.

  • The origin and evolution of prions are considered. Misfolded PrP may have evolved to serve a useful purpose and at the same time acquired a pathogenic potential that, in early evolutionary times, when the human life span was short, did not confer a selective disadvantage. Alternatively, prions could be derived from ancient exogenous pathogens that are now fully integrated into host chromosomes. More trivially, prions are misfolded proteins that by coincidence have the ability to invade a host through the digestive tract, make their way into the lymphoreticular system where they are amplified and transfer themselves into the central nervous system, which they then destroy.

Abstract

There is little doubt that the main component of the transmissible agent of spongiform encephalopathies — the prion — is a conformational variant of the ubiquitous host protein PrPC, and that the differing properties of various prion strains are associated with different abnormal conformations of this protein. The precise structure of the prion is not yet known, nor are the mechanisms of infection, conformational conversion and pathogenesis understood.

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Figure 1: Models for the propagation of the TSE agent (prion).
Figure 2: Models for the conversion of PrPC to PrPSc.
Figure 3: The dynamic susceptibility model for prion propagation.

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Authors and Affiliations

  1. Department of Neurodegenerative Disease, MRC Prion Unit, Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Charles Weissmann

  2. Department of Infectology, Scripps Research Institute Florida, Boca Raton, 33431, Florida, USA

    Charles Weissmann

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DATABASES

Infectious Disease Information

Bovine spongiform encephalopathy

OMIM

Creutzfeldt–Jacob disease

kuru

Glossary

STRAINS

Types of prions differing in regard to the clinical course of the disease and the neuropathology they elicit, their transmissibility and the physico-chemical properties of the PrP isoforms that they are associated with.

PRION

Protein-containing infectious agent causing transmissible spongiform encephalopathy (TSE), unusually resistant to agents known to inactivate nucleic acids. As used in this article the term does not imply any specific components or structure.

VIRINO

An infectious particle that is conjectured to consist of a TSE-specific nucleic acid enveloped by PrPSc.

UNIFIED THEORY

This theory proposes that a PrP isoform, PrP*, is indeed the essential infectious component, but that its properties can be modified by a physically associated small RNA, the co-prion, such as a siRNA. The co-prion would have to be amplified in the host cell and remain bound to the newly formed PrP* to explain the stability of strains, and different siRNAs would be responsible for the phenotypic differences between prion strains.

SYMPATHECTOMY

A chemical or surgical procedure that destroys innervation by the sympathetic nervous system.

AMYLOID

Fibrillary, mostly β-sheet-rich deposits of protein. PrP in amyloid form is found in some but not all forms of prion disease in humans and animals.

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Weissmann, C. The state of the prion. Nat Rev Microbiol 2, 861–871 (2004). https://doi.org/10.1038/nrmicro1025

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  • DOI: https://doi.org/10.1038/nrmicro1025

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