Prion Protein and the Transmissible Spongiform Encephalopathy Diseases

is not known, but biophysical measurements indicate a Transmissible spongiform encephalopathy (TSE) dishigh amount of b sheet structure. Furthermore, PrP-res eases or prion diseases are rare fatal neurodegenerative often forms fibrils that show birefringence after binding diseases of humans and other animals. In the past deof Congo red. This property is a well-known characteriscade, a high awareness of TSE diseases has developed tic of b sheet–rich non-PrP amyloid proteins found in due to the appearance of bovine spongiform encephaamyloidosis associated with other diseases, such as lopathy (BSE) or “mad cow disease” in the United Kingtype II diabetes, Alzheimer’s disease, tuberculosis, rheudom. Due to the potential for human infection, in Europe matoid arthritis, and various cancers. BSE has influenced medical, agricultural, economic, and The generation of PrP-res from PrP-sen has been political issues, perhaps even to a greater extent than studied in scrapie-infected mouse cells as well as under has AIDS. cell-free conditions in test tubes (Caughey and ChesePrimary symptoms of TSE diseases in humans are bro, 1997). The PrP-res generated in these cell-free labodementia and ataxia. These diseases are usually characratory studies mimics closely the material produced in terized by spongiform degeneration of the brain acbrains of scrapie-infected animals and humans. Howcompanied by appearance of activated astrocytes and ever, because these cell-free experiments contain large accumulation of abnormal aggregates consisting of proamounts of infectivity associated with the PrP-res used tease-resistant prion protein (PrP), which sometimes to initiate the conversion process, it has not yet been forms amyloid-like plaques. TSE diseases are transmispossible to prove that the abnormal PrP formed in vitro sible by inoculation or ingestion of infected tissues. Inis actually infectious. cubation periods prior to clinical symptoms range from The normal function of PrP-sen is not known. PrP is months to years, and in the case of some kuru patients not essential for viability, as some lines of PrP knockout may have been as long as 40 years. mice are fertile and neurologically normal, although TSE diseases in humans can be divided into three some sleep abnormalities have been observed. Other groups: sporadic, familial, and iatrogenic (or infectious) lines of PrP knockout mice have shown cerebellar de(Brown et al., 1994). Sporadic Creutzfeldt-Jakob disease generation, but this difference may be due to disruption (CJD) is not associated with any known mutations and of adjacent genes. Interestingly, expression of PrP-sen occurs world-wide at an incidence of around 1 per 2 is required for susceptibility to TSE diseases, and propamillion. The source of this disease is completely ungation of infectivity is eliminated or drastically reduced known. Familial TSE diseases are all associated with in the absence of the PrP gene (Weissmann, 1999). This different mutations in the PrP gene, and include familial has been interpreted to imply that PrP is either a receptor CJD, Gerstmann-Sträussler-Scheinker syndrome (GSS), for the infectious agent or a component of the agent. and fatal familial insomnia (FFI). Infectious or iatrogenic Natural and Experimental Scrapie in Sheep TSE diseases include kuru, which was spread by ritual Scrapie has been recognized as a disease in sheep for cannibalism in New Guinea tribesmen, CJD, which is over 2 centuries, and was the first TSE disease to be spread by transplantation or inoculation with brain tisshown as experimentally transmissible. Thus, sheep sues or extracts from unsuspected CJD patients, and scrapie provides an unusual opportunity to compare variant CJD (vCJD), which is apparently due to infection natural and experimental TSE disease processes. Alof humans with the agent of BSE. though in animals there are no known genetic cases of Prion Protein (PrP) TSE disease comparable to those seen in humans, allelic Besides transmissibility, the other hallmark of TSE disvariations in the sheep PrP sequence do occur, and eases is the presence of abnormal protease-resistant variation at several residues in the PrP sequence influPrP (PrP-res, also known as PrP), detectable by immuences susceptibility to both natural and experimental noblot or immunohistochemistry in the brains of afflicted scrapie infection. The mechanism of these effects is individuals. PrP-res is believed to be responsible for the not known, but these data show clearly that PrP is an pathogenic effects in the TSE diseases, either by direct important susceptibility factor for TSE diseases. A simitoxicity or indirect effects due to interactions with the lar effect may also occur in humans, where variation at normal PrP expressed on many brain cells. PrP-res is PrP codon 129 does not induce a familial TSE disease generated posttranslationally by an unknown mechabut instead appears to influence susceptibility to sponism from normal protease-sensitive PrP (PrP-sen, also radic CJD. known as PrP), which is expressed as a GPI-linked cell Although the infectious nature of sheep scrapie has