B. Caughey

Prion Biochemistry and Therapeutics

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are caused by infectious agents that are unusually hard to decontaminate and can resist more heat and radiation than other pathogens. These characteristics led to proposals, during the 1960s, that they might lack nucleic-acid genomes. The first recognized TSE disease was scrapie, a widespread infection of sheep that can persist in pastures for years after removal of infected animals. Similarities between scrapie and human kuru, which was spread by cannibalistic mortuary feasts amongst the Fore tribe in Papua New Guinea, contributed to widespread interest in these fatal neurodegenerative diseases. Since then, the impact of TSEs has been greatly amplified by the recognition of more common human forms, such as Creutzfelt-Jakob disease (CJD), and the epidemics of bovine spongiform encephalopathy (BSE) and cervid chronic-wasting disease (CWD).

The Formation of Scrapie-Associated Prion Protein In Vitro

The formation of the abnormal protease-resistant, amyloidogenic isoform of PrP (PrP-res) appears to play a central role in the pathogenesis of scrapie and other transmissible spongiform encephalopathies (TSEs). Thus, it is important to understand the process by which the normal, protease-sensitive PrP (PrP-sen) is converted to the protease-resistant state. To define the cellular and molecular details of this process and how it might be inhibited, we have performed in vitro studies using both scrapie-infected tissue culture cells and cell-free reactions. This chapter summarizes the recent results from these studies.