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  • Review Article
  • Published:

Prion diseases — close to effective therapy?

Nature Reviews Drug Discovery volume 3, pages 874–884 (2004)Cite this article

Key Points

  • Prions represent a new class of infectious agents which propagate on a protein-only level, not requiring agent-encoded nucleic acids.

  • Newly emergent prion diseases such as bovine spongiform encephalopathy, variant Creutzfeldt–Jakob disease (CJD), and chronic wasting disease are a source of critical concern to physicians, veterinarians, economists, politicians — and the general public.

  • Numerous strategies and targets have been proposed for the immunotherapy of prion diseases, based on the necessity of agent replication in lymphoid tissue prion to neuro-invasion, and the sensitivity of prion propagation to antibodies in vitro.

  • Prion replication in cell lines in vitro is sensitive to antibodies directed against the normal and abnormal isoforms of the prion protein.

  • Numerous strategies and potential targets for treating transmissible spongiform encephalopathies have been suggested, with the most studied target being the inhibition of PrPSc accumulation.

  • The development of higher-throughput screening assays based on scrapie-infected cell cultures have been developed and have greatly accelerated the pace of discovery of PrPSc inhibitors.

  • Several classes of inhibitors of PrPSc formation have been identified, some of which show prophylactic activity against scrapie in rodents. However, chemotherapeutic treatments of clinically affected scrapie-infected rodents and CJD-infected humans have been largely ineffectual.

  • Compounds that destabilize PrPSc and/or reduce scrapie infectivity have been identified that could be useful as decontaminants.

  • The most effective therapeutic strategies might require not only the inhibition of PrPSc formation but also the reversal of TSE-associated neuropathology.

Abstract

The transmissible spongiform encephalopathies could represent a new mode of transmission for infectious diseases — a process more akin to crystallization than to microbial replication. The prion hypothesis proposes that the normal isoform of the prion protein is converted to a disease-specific species by template-directed misfolding. Therapeutic and prophylactic strategies to combat these diseases have emerged from immunological and chemotherapeutic approaches. The lessons learned in treating prion disease will almost certainly have an impact on other diseases that are characterized by the pathological accumulation of misfolded proteins.

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Figure 1: PrPSc formation in scrapie-infected cells.
Figure 2: Possible spread of scrapie infectivity from the gut lumen to the nervous system following oral infection (route indicated by dotted line).
Figure 3: Tyr-Tyr-Arg antibodies selectively recognize PrPSc.
Figure 4: High-throughput cell-based screen for inhibitors of PrP-res formation.
Figure 5: Solid-phase cell-free PrP conversion assay for inhibition of PrP-res formation.

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Acknowledgements

N.R.C.'s work is supported by Canadian Institutes of Health Research (Institute of Infection and Immunity), Caprion Pharmaceuticals and McDonald's Corp.

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Authors and Affiliations

  1. Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, M553H2, Ontario, Canada

    Neil R. Cashman

  2. Rocky Mountain Laboratories, National Institutes of Health, 903 South Fourth Street, Hamilton, 57840, Montana, USA

    Byron Caughey

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Competing interests

N.R.C is receives funding for research from Caprion Pharmaceuticals. B.C holds patents on the use of Congo red, cyclic tetrapyrroles and PrP peptides for TSE treatments.

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DATABASES

Entrez Gene

Amyloid precursor protein

TNF-α

OMIM

Amyotrophic lateral sclerosis

Alzheimer's disease

Parkinson's disease

FURTHER INFORMATION

Encyclopedia of Life Sciences

Prions

prion diseases

Glossary

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY

A class of infectious diseases characterized by neuronal degeneration, spongiform change, gliosis and accumulation of amyloid protein deposits.

SPONGIFORM CHANGE

Microvacuolization of brain tissue, which typically accompanies prion disease.

CREUTZFELDT–JAKOB DISEASE

(CJD). The most common human prion disease, classically comprising sporadic, familial and iatrogenic forms, and now including variant CJD (vCJD).

VARIANT CJD

(vCJD). A newly emergent form of human prion disease, initially linked to comsumption of cattle afflicted with bovine spongiform encephalopathy.

BOVINE SPONGIFORM ENCEPHALOPATHY

(BSE). A naturally acquired transmissible spongiform encephalopathies of cattle, epidemically amplified by feed supplementation with rendered products from afflicted bovines.

CHRONIC WASTING DISEASE

(CWD). A relatively contagious prion disease of captive and wild cervids (elk and deer).

SCRAPIE

A naturally acquired prion disease of sheep, clinically recognized for ∼300 years. Mouse-adapted scrapie agent strains are now used in many paradigms to identify therapies to prion disease.

PRION HYPOTHESIS

The proposal that transmissible spongiform encephalopathies infectivity comprises the conformational conversion of the host-encoded cellular prion protein PrPC into the disease-associated isoform PrPSc.

PrPC

The native, protease-sensitive, normally expressed form of PrP, named for its 'cellular' location.

PrP-SEN

A generic operational term referring to forms of PrP that are protease-sensitive. This includes native PrPC as well as various non-native or abnormal forms of PrP (for example, recombinant or mutant forms) that are protease-sensitive.

PrPSC

The native disease-associated isoform of PrP, originally named for its association with scrapie. Now often used generically to refer to the disease-associated form of PrP in prion diseases other than scrapie.

PrP-RES

A generic term referring to the disease-associated form of PrP that is recognizable by its partial resistance to proteolytic digestion, and therefore partially synonymous with PrPSc when the latter is applied generically. Also commonly used to denote the highly protease-resistant 27–30 kDa product of partial proteolysis of native disease-associated PrP.

PRNP

The human gene that encodes PrP. Also used to designate the prion protein gene in other species, although the mouse nomenclature is Prnp.

GERSTMANN–STRAUSSLER SYNDROME

A familial prion disease, linked with mutations in the PRNP open reading frame.

GLIOSIS

Activation and proliferation of astrocytes and microglial cells in the brain.

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Cashman, N., Caughey, B. Prion diseases — close to effective therapy?. Nat Rev Drug Discov 3, 874–884 (2004). https://doi.org/10.1038/nrd1525

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