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  • Review Article
  • Published:

Rational targeting for prion therapeutics

Nature Reviews Neuroscience volume 6, pages 23–34 (2005)Cite this article

Key Points

  • Prion diseases, or transmissible spongiform encephalopathies, are fatal neurodegenerative conditions that affect humans and other animals, and are transmissible within or between mammalian species. The recognition in 1996 of a new human prion disease — variant CreutzfeldtJakob disease (vCJD) — and the experimental confirmation that it is caused by bovine spongiform encephalopathy (BSE)-like prions derived from infected beef products have led to fears of a human epidemic.

  • Prion diseases are all associated with the accumulation in the brain of an abnormal, partially protease-resistant, isoform of host-encoded prion protein (PrP). The disease-related isoform (PrPSc) is derived from the normal cellular isoform PrPC by a post-translational process that involves conformational change and aggregation. Many studies support the 'protein-only' hypothesis of prion propagation, according to which an abnormal PrP isoform is the principal, and possibly the sole, constituent of the transmissible agent or prion. Therefore, PrPSc is thought to act as a conformational template, recruiting PrPC to form further PrPSc.

  • However, the cause of neuronal death in prion disease remains unclear. The assumption that neurodegeneration follows from direct toxicity of PrPSc and/or prions has been increasingly challenged. Evidence against the direct toxicity of PrPSc is discussed, with particular reference to the occurrence of sub-clinical forms of prion infection, in which high levels of PrPSc accumulate in the absence of neurotoxicity or clinical symptoms, as well as the more recent demonstration that switching off PrPC expression in mice with neuroinvasive prion disease results in the reversal of early spongiform degeneration and long-term survival of animals despite ongoing non-neuronal PrPSc production.

  • Other potential mechanisms of neurotoxicity in prion diseases are presented, including possible roles for PrPC in cell survival and cell death signalling pathways and the potential toxicity of aberrant PrPC processing and trafficking in neurons.

  • The concept of the generation of neurotoxic forms of PrP, designated 'PrPL' (PrP lethal), during prion replication, which might involve soluble oligomers of misfolded PrP, is emphasized. The rationale for focussing on therapeutic strategies that target normal PrPC rather than PrPSc itself, where stabilizing the native form will prevent the generation of toxic intermediates, is explained.The balance between the production and clearance of PrPL (and PrPSc) in prion infection in determining ultimate neurotoxicity is discussed, with particular relevance for therapeutic intervention.

  • Other therapeutic strategies, including targeting PrPSc and immunotherapeutic modulation, are considered, as well as potential future strategies, such as gene silencing by RNA interference and, ultimately, stem cell therapy for the repair of damaged tissue.

  • Consideration is given to human therapeutic studies and the need for advances in the early diagnosis of prion infection.

Abstract

Prions — pathogens that are lethal to humans and other animals — are thought to be conformational isomers of the cellular prion protein. Their unique biology, and the potential for a wider pathobiological significance of prion-like mechanisms, has motivated much research into understanding prion neurodegeneration. Moreover, concerns that extensive dietary exposure to bovine spongiform encephalopathy (BSE) prions might have infected many individuals — who might eventually develop its human counterpart, variant Creutzfeldt–Jakob disease (vCJD) — has focused much interest on therapeutics. The challenge of interrupting this aggressive, diffuse and uniformly fatal neurodegenerative process is daunting. However, the recent finding that the onset of clinical disease in established neuroinvasive prion infection in a mouse model can be halted and early pathology reversed is a source for considerable optimism. A therapeutic focus on the cellular prion protein, rather than prions themselves, which might not be directly neurotoxic, is suggested.

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Figure 1: A model of prion propagation.
Figure 2: Hypothetical mechanisms of prion neurotoxicity
Figure 3: Model of late-onset PrP depletion in mice by Cre-mediated recombination.
Figure 4: PrPC depletion in neurons of mice with established CNS prion infection reverses early spongiosis and prevents neuronal loss.
Figure 5: Survival of prion-infected mice after PrPC depletion.

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Acknowledgements

We thank R. Young for help with graphics and C. Trevitt for critical comments on the manuscript.

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Authors and Affiliations

  1. Medical Research Council Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK

    Giovanna Mallucci & John Collinge

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  1. Giovanna Mallucci
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  2. John Collinge
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Correspondence to John Collinge.

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John Collinge is a director and shareholder of DGen Ltd, an academic spin-off company.

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DATABASES

Entrez

BCL2

DPL

PrP

TNF-α

TP53

TTR

OMIM

Alzheimer's disease

CJD

Gerstmann–Sträussler–Scheinker disease

kuru

FURTHER INFORMATION

Current Controlled Trials — Quinacrine for human prion disease

Consumer workshop on clinical trials for CJD

Glossary

PRION

The transmissible agent that is responsible for prion diseases, which, according to the 'protein-only' hypothesis, lacks an agent-specific nucleic acid genome and is composed principally or entirely of a conformational isomer of cellular prion protein. A term that was originally coined by Prusiner from 'proteinaceous infectious particle'.

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

(Prion diseases). Transmissible neurodegenerative diseases of mammals that are characterized by neuronal loss, astrocytosis, spongiform vacuolation and accumulation of the disease-associated isoform of prion protein (PrPSc), sometimes with the formation of amyloid deposits. They are transmissible both within and between species.

PrPC

The normal cellular isoform of mature prion protein. It is a glycosyl phosphatidylinositol (GPI)-anchored cell surface molecule that is highly expressed in neurons, and often associated with raft-like structures in the outer leaflet of the plasma membrane. It consists of a globular, predominantly α-helical, carboxy-terminal domain and an amino-terminal tail that is unstructured in conditions used for solution structure determination.

PrPSc

The disease-associated isoform of prion protein (PrP), which was originally distinguished from PrPC by its biochemical properties — its relative resistance to proteolysis and detergent insolubility. It is isolated from infected animals as highly aggregated material that appears rich in β-sheet secondary structure. Although it is sometimes used as shorthand for the infectious agent, neither PrPSc nor the infectious agent itself have yet been clearly defined at the atomical level.

β-PrP

A β-sheet-rich monomeric form of prion protein (PrP) that can be generated from disulphide-reduced PrP in acidic conditions in vitro. β-PrP has PrPSc-like properties and rapidly aggregates and then forms fibrillary structures in physiological salt concentrations.

SUB-CLINICAL PRION INFECTION

Prion diseases are typically associated with prolonged, clinically silent incubation periods before overt neurological disease occurs. However, asymptomatic carrier states of prion infection — sub-clinical infections — have been described in animal models in which animals do not develop clinical prion disease during their lifespan despite high prion titres in the brain.

CONDITIONAL KNOCKOUT

A process by which a gene or its product is knocked out using conditional genetic or recombinant DNA technology. Temporal and spatial features of the knockout are determined by promoter and other elements that control the expression of the protein that is expressed to delete it, such as the phage P1 enzyme Cre recombinase.

ENDOPLASMIC RETICULUM-ASSOCIATED DEGRADATION

(ERAD). A quality control mechanism for protein synthesis in the endoplasmic reticulum (ER). Misfolded proteins are directed by the ER to proteasomes in the cytoplasm for degradation.

Cre RECOMBINASE

Phage P1-derived DNA recombinase that excises DNA sequences that are flanked by loxP sequences with the same orientation. It is effective in mammalian cells in vitro and in vivo.

loxP SEQUENCE

A 34-base-pair sequence for recognition by Cre recombinase. One loxP site remains after Cre-mediated excision.

RNA INTERFERENCE

(RNAi). Describes the use of double-stranded RNA to target specific messenger RNAs for degradation, thereby silencing their expression. RNAi is one of several RNA-silencing phenomena that occur in plants, animals and fungi.

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Mallucci, G., Collinge, J. Rational targeting for prion therapeutics. Nat Rev Neurosci 6, 23–34 (2005). https://doi.org/10.1038/nrn1584

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