A simplified recipe for prions

Abstract

As long ago as the 1960s, it was proposed that the infectious agent of the transmissible spongiform encephalopathies (TSEs), or prion diseases, was composed of protein with no essential nucleic acid component. From the beginning, one basic idea was that the causative agent was a corrupted and pathological form of a host protein that could propagate itself by causing its normal homolog to convert to the pathological form (1). This concept, now commonly known as the “prion hypothesis” (2), has been extremely difficult to prove (3). Fungi were shown to have conceptually analogous protein-only prion pathogens (4), but TSE infectivity eluded clear biochemical characterization for decades. Complicating matters were the inherent difficulties in purifying TSE infectivity, which forms sticky, insoluble aggregates that are not amenable to rigorous purification techniques. Consistent with the prion hypothesis, the major component of infectious isolates was found to be an aberrant, partially protease-resistant form of the host's prion protein (PrPSc or PrP-res) (2). However, various other molecules, including nucleic acids, could often be found in even the purest preparations (e.g., refs. 5 and 6). Because there were typically ≈100,000 PrPSc molecules per infectious unit, it was difficult to exclude the possibility that other essential components of infectivity might be much less abundant. A standard approach to establishing the essential ingredients of any biological activity is the reconstitution of the activity from defined ingredients in vitro. However, despite the seductive simplicity and apparent plausibility of the prion hypothesis, many laboratories were frustrated for years in their attempts to assemble infectivity in defined cell-free reactions. Recently, striking progress has been made toward this goal, and, as reported by Supattapone and colleagues in this issue of PNAS (7), a defined recipe for producing robust mammalian prions is at hand.