Media coverage of “Mad Cow” disease has struck fear into the hearts of beef-loving consumers. However, the unorthodox biological properties of the prion protein (PrP) responsible for the disease have elicited both scepticism and surprise among many scientists. Prion diseases comprise a number of distinct neurodegenerative disorders, including scrapie of sheep and goats, bovine spongiform encephalopathy (BSE), and, in humans, Creutzfeldt-Jakob disease (CJD), kuru, and Gerstmann-Straussler-Scheinker (GSS) disease. In the past decade, these rare disorders have been thrust into the spotlight by the emergence of a new form of CJD in the UK and Europe. The occurrence of variant CJD (vCJD) followed an outbreak of BSE, and evidence suggests that human BSE infection is the cause of vCJD. The pathogenic agent of prion diseases is not a virus or a bacterium, but a protein called PrP. PrP was identified in the early 1980s by purification of infectious matter from scrapie-affected brain lysates. The great surprise was that it was not a foreign, virally encoded protein, but rather an endogenous, mammalian, chromosomally encoded protein. This finding prompted the proposal of an atypical “protein only” mechanism of disease transmission and the coining of the term “prion” to denote a new type of pathogen. The aminoacid sequence of PrP isolated from organisms affected by acquired prion diseases, such as scrapie, BSE, and vCJD, is identical to that of PrP found in unaffected organisms. What, therefore, is the basis of prion infectivity? The key to this puzzle lies in the threedimensional conformation of PrP. The PrP polypeptide can adopt two distinct three-dimensional structures: the normal cellular form, PrP, and the scrapie-associated form, PrP. The former is a detergent-soluble, proteasesensitive, membrane protein, while the latter forms insoluble aggregates that are resistant to protease digestion. During the course of disease progression, infective PrP particles probably catalyse the conformational conversion of PrP to PrP. This structural switch is ultimately toxic through a mechanism that is still not properly understood by scientists. When the prion concept was first proposed, it represented a radical departure from traditional notions of infectious disease mechanisms. The idea of a rogue protein that could adopt an infectious shape seemed akin to science fiction. Two decades later, the theory is widely accepted, but some challenges remain. In particular, how can the “protein only” hypothesis explain the existence of multiple prion strains that are associated with distinct patterns of disease progression? For a virus, strain variations are caused by mutations in the viral genome that result in expression of polymorphic viral proteins. In the case of prions, disease progression depends on endogenous PrP, but, remarkably, different strains can be serially propagated in genetically identical animals. How can the same protein produce multiple disease phenotypes? To resolve this dilemma, an idea that is perhaps even more heretical has been proposed: that every prion strain represents a different PrP conformation. PrP must, therefore, be an extremely flexible molecule that is able to adopt multiple stable forms that can each propagate through conversion of PrP (figure). Although this notion is difficult to test in mammalian systems, biochemical data support the conformational basis of strain identity. Several assays that report indirectly on protein conformation can be used to group prion strains into classes that correlate with clinical distinctions. These types of data provided the telltale signs that BSE and vCJD were most likely caused by the same prion strain. The most direct evidence in favour of the “multiple conformations, multiple strains” hypothesis has come from budding yeast Saccharomyces cerevisiae in which several proteins display prion-like behaviour. Experiments with a yeast prion have shown a direct correlation between its ability to adopt two distinct conformations and to exhibit differential strain characteristics. The conversion of PrP into disease-causing forms is only one example of the broader pathological role of protein misfolding. The mechanisms by which aberrantly folded proteins generate cellular toxicity are just beginning to be explored. Protein misfolding is a common feature of diseases that affect the nervous system. Neurodegenerative conditions such as Alzheimer’s, Parkinson’s, and Huntington’s disease show aggregation of proteins specific to each disease and the formation of characteristic fibrils referred to as amyloid. These amyloid fibres resemble the PrP form of the prion protein, however, unlike PrP, none of them have shown evidence of being transmitted from one organism to another in an infectious manner. Thus, although prion diseases might be unique in their infectivity and their multiplicity of strains, other features of their pathology are likely to be generally applicable to a wide spectrum of diseases. Conformational basis of prion strains PrP can adopt multiple pathogenic conformations. Two such conformations are denoted PrP and PrP. Once established, these strains maintain their identities and propagate by converting more PrP to their particular conformation. This leads to the development of strain-specific diseases, such as BSE/vCJD and scrapie.
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Nov 7, 2002
Christl A Donnelly + 3
Open Access
