Prions and the transmissible spongiform encephalopathies

Abstract

The purpose of this chapter is to highlight the prion protein, which is expressed in a wide range of tissues and most likely has a variety of important cellular functions, and its role in producing the neurodegenerative diseases known as the transmissible spongiform encephalopathies (TSEs). The protein is a normal cellular protein; however, it possess a unique property, so that when the normal α-helix-rich conformation is converted to a misfolded, β-sheet-rich conformation, the resultant particulate protein is infectious and produces a TSE, whose clinical features vary somewhat depending on the species (e.g., cow, sheep, human, etc.). The basic mechanism of infectivity remains mostly unknown, but it seems to be correctly thought of as a slowly progressing type of chain reaction. This model is often described as recruitment and conversion. The resultant TSEs are akin to other neurodegenerative diseases in that the TSEs are extraordinarily slow progressing diseases in humans and animals. In humans, after presymptomatic periods of as long as several decades, they are fatal and incurable. The unique primary and higher-order structure of the prion proteins of each species imparts a unique character to the TSEs of each species. Additionally, allelic variation at key structural sites appears to impart a unique character to the resultant disease. Variances in the character of disease resultant from these structural differences appear to account for the concept of prion strains. While most of the TSEs are relatively rare, a recent epidemic (1986-2000) of the prion disease known as bovine spongiform encephalopathy (BSE), or mad cow, thrust the TSEs into the public awareness, especially since the consumption of beef contaminated with infectious central nervous system (CNS) tissue seems to have transmitted the mad cow disease to humans (Will et al., 1996; Collinge et al., 1996; Bruce et al., 1997; Will et al., 1999). The original event that triggered the BSE epidemic will not likely ever be known with certainty; however, it is generally thought to be from the introduction in 1926 in the United Kingdom (BSE Inquiry, 2000) of cattle feed containing offals (including brain and spinal cord) and -mammalian meat and bone meal (MBM) animal by-products. It is thought that at some point the process was contaminated with infectious prion material, possibly sheep offals infected with scrapie, which precipitated the mad cow epidemic (BSE Inquiry, 2000). Scrapie disease in sheep is also a TSE, and it has been epidemic in sheep in the United Kingdom for 200 years. The removal of offals and mammalian meat and bone meal additives appeared to end the epidemic, which supports the offal-scrapie theory for the origin of the epidemic; however, there are other theories (Chesebro, 2004). There are also indications that the epidemic may have featured multiple strains of the prion protein (Capobianco et al., 2007). The transmitted disease in humans is known as a new variant of the Creutzfledt-Jacob disease (vCJD). The mad cow outbreak peaked in 1992 and all but disappeared in the United Kingdom by 2000. Because the incubation period for the TSEs is typically extraordinarily long, years or even decades, speculation abounds as to whether vCJD in humans has already peaked or remains dormant in the form of a future epidemic waiting to emerge (Brown, 2001).