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  • Review Article
  • Published:

Prions: health scare and biological challenge

Nature Reviews Molecular Cell Biology volume 2, pages 118–126 (2001)Cite this article

Key Points

  • Prions are the infectious agents that cause both bovine spongiform encephalopathy in cows and Creutzfeldt?Jakob disease in humans. In both, clinically detectable degeneration is only seen in the central nervous system (CNS).

  • In yeast, prions are defined as proteins that can exist in two conformations, one of which can induce the conversion of further prion molecules from one conformation into the other, and so is self-perpetuating and heritable.

  • In vitro conversion of the mammalian endogenous prion protein ? PrPC ? results in a moiety that has the physiochemical properties of PrpSc, the disease-associated protein. No experiments have so far unambiguously shown that PrpSc is a transmissable agent.

  • Neuronal cytotoxicity of PrpSc depends on the expression of cellular PrPC by target cells. Evidence indicates that the conversion of PrPC into PrPSc is the deleterious event. PrpC can adopt two orientations in the membrane, one of which, CtmPrP, correlates well with neurodegenerative changes.

  • Like viruses, prions can enter the enter the CNS through the immune system, lymphocytes and follicular dendritic cells. The presence of PrPC and terminally differentiated B cells is essential for invasion by infectious prions. How prions move from the germinal centres to the CNS is less clear, but might involve peripheral nerves and lymphocytes.

  • New variant (nv) CJD can be distinguished from sporadic CJD in that it mainly affects young people, develops more slowly and is distinguished by widespread vacuolation of the cortical neurophil and an accumulation of protein plaques in the brain.

  • Studies of neural degeneration patterns in mice, the biochemical properties of prions and epidemiology support the idea that the agent causing nvCJD is identical to that causing BSE when transmitted to humans.

  • It is unclear whether there is a subclinical or carrier status of the diease. To rule out the possibility of iatrogenic transmission, attention is now focused on preparation of blood products. Understanding the molecular basis of invasion should help to identify possible targets for intervention.

Abstract

Although human prion diseases are rare, the incidence of 'new variant' Creutzfeldt?Jakob disease in the United Kingdom is increasing exponentially. Given that this disease is probably the result of infection with bovine prions, understanding how prions replicate ? and how to counteract their action ? has become a central issue for public health. What are the links between the bovine and human prion diseases, and how do prions reach and damage the central nervous system?

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Figure 1: Confirmed cases of BSE plotted by month and year of onset.
Figure 2: The 'protein-only' hypothesis and two popular models for the conformational conversion of PrPC into PrPSc.
Figure 3: Neuropathological features of transmissible spongiform encephalopathies.
Figure 4: Three-stage model of prion pathogenesis, and possible role of CtmPrP in cell death.
Figure 5: Model of prion neuroinvasion in mice.
Figure 6: Models of the signalling pathways required for the establishment and maintenance of functional follicular dendritic cells.

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Acknowledgements

We thank B. Chesebro, V. Lingappa, and B. Caughey for critical reading. The work of our laboratory is supported by the Kanton of Zürich, the Bundesämter für Gesundheit, Veterinärwesen, Bildung und Wissenschaft, by grants of the Swiss Nationalfonds, and by the companies Baxter, Abbott, Migros and Coop.

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Authors and Affiliations

  1. Institute of Neuropathology, University of Zurich, Schmelzbergstrasse 12, Zurich, CH-8091, Switzerland

    Adriano Aguzzi, Fabio Montrasio & Pascal S. Kaeser

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  1. Adriano Aguzzi
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Correspondence to Adriano Aguzzi.

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DATABASE LINKS

Creutzfeldt-Jakob disease

PrP

Gerstmann-Sträussler-Scheinker syndrome

HIV

TNFR1

TNF-α

lymphotoxin-β

lymphotoxin-β receptor

Sup35

Ure2p

PRNP

FURTHER INFORMATION

World Organization for Animal Health

The Official Mad Cow Disease Home Page

Department of Health CJD page

ENCYCLOPEDIA OF LIFE SCIENCES

Amyloidosis

Glossary

EPIZOOTIC

Refers to a disease that is temporally prevalent and widespread in a population of animals.

PRION-ONLY HYPOTHESIS

States that the prion is devoid of informational nucleic acid and consists of protein (or glycoprotein) as its essential pathogenic component.

PRPSC OR PRP-RES

An 'abnormal' form of the mature Prnp gene product found in tissue of transmissable spongiform encephalopathy sufferers, operationally defined as being partly resistant to proteinase K digestion under defined reaction conditions. It is believed to differ from PrPC only (or mainly) conformationally, and is rich in β-sheet structure. Within the framework of the protein-only hypothesis it is often considered to be the transmissible agent or prion.

AMYLOID PROTEINS

A term introduced by Rudolf Virchow a century ago to designate proteins that show birefringence under polarized light when stained with Congo red. A more modern concept defines amyloids as proteins that attain their energy minimum in a highly ordered, aggregated state.

PRPC OR PRP-SEN

The naturally occurring form of the mature Prnp gene product.

GERMINAL CENTRES

Specialized areas of lymphoid organs that are important for affinity maturation of B cells.

PRION STRAINS

Prion strains have different phenotypes ? for example, incubation times, distribution of lesions in the brain, relative abundance of mono-, di- and unglycosylated PrPSc, and electrophoretic mobility of the protease-resistant part of PrPSc. But they can all be propagated in the same inbred mouse strain, indicating that, within the framework of the protein-only hypothesis, the same polypeptide chain can mediate different strain phenotypes.

IATROGENIC

Caused by medical treatment.

THALAMUS

A conglomerate of neuronal groups in the diencephalon.

CORTICAL CEREBRAL RIBBON

The grey matter located underneath the surface of the brain.

FLORID PLAQUES

Deposits of prion protein surrounded by a rim of vacuolated brain tissue.

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Aguzzi, A., Montrasio, F. & Kaeser, P. Prions: health scare and biological challenge. Nat Rev Mol Cell Biol 2, 118–126 (2001). https://doi.org/10.1038/35052063

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