The prion/lipid hypothesis - further evidence to support the molecular basis for transmissible spongiform encephalopathy risk assessment

Abstract

Summary Defining the molecular structure of the transmissible spongiform encephalopathy (TSE) agent is important both for underpinning risk assessments and for developing and understanding decontamination strategies. Recent studies have shown that oligomeric particles comprising 14–28 prion protein (PrP) molecules are much more infectious than larger fibrils (prion rods) or indeed smaller oligomers (trimers) and PrP monomers. Here, results from deactivation studies (with alkali, heat, hexane or formaldehyde) are interpreted in terms of the infectious nucleation seed comprising 14–28 PrP molecules held together by interactions with amphipathic phospholipid (PL) or more probably sphingolipid (SL) from the host. According to the PrP/lipid hypothesis, the strength of the protein/lipid interactions accounts for the high thermostability of TSE infectivity and for differences in thermostability between strains. The implications of the molecular biophysics data for environmental TSE risk assessments are discussed with respect to behaviour in soil. While formaldehyde appears to cause inactivation of scrapie infectivity by increasing the ID50, the dose–response is complicated by apparent heterogeneity between hamster subpopulations in susceptibility. The process of inactivation by formaldehyde may be due to cross‐linking the highly infectious 14–28 PrP oligomers into larger, but less infectious aggregates. This process appears more reversible in some hamster subpopulations than others.

Isolation of phosphatidylethanolamine as a solitary cofactor for prion formation in the absence of nucleic acids

“…(iii) Polar organic solvents that are able to extract polar lipids such 2-choroethanol inactivate prions, whereas nonpolar solvents such as hexane do not (16,17). (iv) Variations in the strength of interaction between PrP and phospholipids correlate with differences in the thermostability of various prion strains (18,19). (v) Radio inactivation studies suggest the presence of essential lipid molecules within infectious prions (20).…”

Toward a Mechanism of Prion Misfolding and Structural Models of PrPSc: Current Knowledge and Future Directions

“…A general feature of protein amyloid is an increased exposure of hydrophobic groups that are sequestered in the protein interior in the native state, so the presence of lipids in PrP Sc may help to lessen the energetic unfavorability of surface hydrophobic groups. It was postulated that the thermostability of PrP Sc is due to the strength of protein/lipid associations in the aggregate (Gale, 2007), but lipids (mainly sphingomyelin, α-hydroxycerebroside, and cholesterol) are believed to comprise only around 1% of the mass of purified prions (Klein et al, 1998); this would entail approximately one lipid molecule for every one or two PrP monomers. High titer, more infectious samples contained about 40 PrP to 1 lipid molecule.…”