The scrapie enigma: insights from radiation experiments.

Scrapie is the prototype of the Spongiform Encephalopathies (SEs), now often referred to as "prion diseases." They are unique in being both familial and transmissible, even between species. Proof of transmissibility led to the assumption that the agent was a slow virus, but standard virological techniques failed to determine its size. Using radiation target theory, we found that, if the agent were nucleic acid, it is too small to code for even a single protein. Concurrently we found that the agent was effectively transparent to germicidal UV radiation. Our subsequently constructed action spectrum confirms that the mode of replication cannot involve coding by nucleic acid, nor can the information-conveying component be protein, as some investigators have assumed. Results of radiation chemistry-type experiments provide support for the Gibbons and Hunter hypothesis that the transmitting agent is a fragment of nerve cell plasma membrane. That hypothesis requires modification to take account of recent work on PrP, a plasma membrane protein originally identified by its co-purification with the agent; but normal mammalian nervous tissue also contains PrP. Polymorphisms in the normal PrP amino-acid sequence are associated with the origin of familial forms of the SEs, so I postulate that disease arises in the first instance through failure of aberrant PrP to be recognized by its receptors, with consequent failure to be incorporated into the cell's plasma membrane. The membrane domain lacking PrP will in its turn fail to recognize and incorporate even normal PrP, leading to a cycle of infectivity and to that accumulation of PrP in the brain which is now known to be the cause of the clinical aspects of the Spongiform Encephalopathies.