Prion protein structure and pathology of transmissible spongiform encephalopathies (TSE)

Abstract

Transmissible spongiform encephalopathies (TSE) are neurodegenerative diseases for which it has been proposed that they are related to a novel infectious agent, the prion [1,2]. TSEs have been reported to occur as infectious, inherited, and spontaneous diseases. Following the ‘protein-only hypothesis’ [2,3] the causative agent is a pathogenic conformation of the prion protein (PrP). PrP is ubiquitous in mammalian cells in a benign, cellular conformation ( PrPC) . In rare cases it may be transformed into the infectious scrapie conformation (PrP Sc ), which has been observed in the form of insoluble, protease-resistant aggregates in the brain of affected individuals [4, 5]. The most widely discussed TSEs are Creutzfeldt–Jakob disease (CJD) in humans, scrapie in sheep, and bovine spongiform encephalopathy (BSE). Other human prion diseases include kuru, the Gerstmann–Straussler–Scheinker syndrome (GSS) and fatal familial insomnia (FFI). The ‘mad cow crisis’ in Europe has greatly added to public concern about TSEs and raised keen interest in the biological foundations of TSE pathology and TSE transmission. Thus, questions relating to the ‘species barrier’ [4, 5], i,e., the relative ease of infection between individuals of different species relative to that between individuals of the same species, have attracted intensive interest, in particular regarding possible transmission of BSE from cows to humans through the food chain [6, 7]. Another focus are the pointmutations in human PrP that have been linked with inherited prion diseases, i.e., GSS, FFI and certain forms of CJD [1]. To provide a foundation for discussions of these phenomena on the molecular level, we undertook to solve the three-dimensional structure of the cellular form of the prion protein in solution, using nuclear magnetic resonance (NMR) spectroscopy.