Review article
Perspectives on prion biology, prion disease pathogenesis, and pharmacologic approaches to treatment

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Prion disease fundamentals

Prions are infectious proteins. To date, the only mammalian protein known to behave like an infectious agent is PrP. How can a protein have the characteristics of a conventional infectious agent? Evidence from multiple laboratories indicates that the mature, full-length PrP molecule can exist in at least two conformations without additional chemical modifications: a normal, nonpathogenic isoform that is largely α-helical with little β-sheet content, characteristic of the constitutively

The Prnp0/0 phenotype

Gene-targeting technology made it feasible to disrupt the mouse (Mo) PrP gene (Prnp) by inserting a construct that replaced approximately 75% of the open reading frame (ORF) with an irrelevant promoter and gene complex (Fig. 10). Ablation of both alleles in the first Prnp0/0 mice had no obvious deleterious effects on development, behavior, or life span, but did have a major effect on the understanding of PrP biology [49]. First, neither acute nor chronic exposure of these Prnp0/0 mice to

Role of the N-terminal half of the PrP molecule

The two most important factors that determine whether prion propagation occurs are the PrPSc comprising the infecting prion and the PrPC synthesized by the host. The necessity and specificity of this interaction was first demonstrated in Tg(SHaPrP) mice that express both MoPrPC and SHaPrPC [66], [67]. In contrast to non-Tg mice, which do not become infected with prions composed of SHaPrPSc formed in Syrian hamsters, 100% of Tg(SHaPrP) mice developed disease when inoculated with prions derived

Both PrPSc and PrPC determine prion strain–related differences in the disease phenotype

The existence of prion strains was discovered during laboratory transmission of scrapie in inbred mouse strains [78], [79], [80], [81], [82]. Those studies showed that the disease phenotype is determined partly by the strain of scrapie agent and partly by host genes—as is the case with conventional infectious agents. The parameters used by early investigators to identify prion strains included the host species barrier, incubation time [78], [79], the neuroanatomic distribution of vacuolation

Emerging prion diseases

The first cases of BSE in the United Kingdom were reported in 1986 [122]. In 1994, the first cases of a new, clinically and neuropathologically distinct variant of CJD (vCJD) presented exclusively in subjects with a mean age of 28 years. Subsequent epidemiologic and laboratory studies indicate that vCJD was acquired by ingestion of BSE-contaminated foods [33], [123], [124], [125]. The emergence of BSE in the United Kingdom, the spread of BSE to cattle in many other European countries, and the

Summary

The main goals of this article have been to summarize our current understanding of the biology of PrP, the propagation of prions, and the etiology and pathogenesis of each form of prion disease (familial, sporadic, and infectious); and to review current rational pharmacologic strategies for treatment of prion diseases. Each of these subjects is presented primarily from the perspective of investigations performed by the prion disease research laboratories at the University of California in San

Acknowledgements

This work was supported by grants from the National Institutes of Health (AG02132, AG10770, and NS14069), the Health Assistance Foundation, the G. Harold and Leila Y. Mathers Foundation, and the John D. French Foundation. The authors wish to thank the many colleagues, fellows, and technicians who performed the studies on which this review is based.

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