Progress toward an ultimate proof of the prion hypothesis.

Abstract

Early indications that the infectious agent responsible for scrapie did not contain nucleic acid (1) led to several insightful hypotheses to explain this conundrum (2). Eventually considerable data came to support one of these ideas, dubbed the prion hypothesis, also shown to be applicable to related fatal transmissible spongiform encephalopathies including Creutzfeldt–Jakob and mad cow disease (3). According to the prion hypothesis, the prion protein (PrP) can exist in the normal cellular form (PrPC), or in an “infectious” prion form (PrPSc) that causes disease by converting the cellular form into the prion form. Whereas PrPC is soluble and easily digested by protease K, PrPSc is rich in β-sheets, aggregates into fibrils, and has a protease K-resistant core that forms amyloid. The prion hypothesis has now been extended to explain phenomena involving other proteins (4). Using genetic criteria, Wickner (4) identified the non-Mendelian yeast elements [URE3] (5) and [PSI+] (6), as prions of the Ure2 and Sup35 proteins, respectively. A great deal of additional genetic and biochemical evidence now supports this hypothesis (reviewed in refs. 7 and 8). Evidence for other yeast prions (9–11), as well as for [Het-s] of Podospora anserina (12–16), is now emerging. Although the evidence for the prion hypothesis is compelling, a direct demonstration that infectious activity is caused by pure protein when in the prion form has been lacking. Using the [Het-s] prion, Maddelein et al. (17) in a recent issue of PNAS have now come tantalizingly close to achieving that aim.