SPECIAL LECTURE - THE SCRAPIE ENIGMA - INSIGHTS FROM RADIATION EXPERIMENTS (REPRINTED FROM RADIATION RESEARCH, VOL 135, PG 283-292, 1993)

Scrapie is the prototype of the Spongiform Encephalopathies (SEs), now often referred to as ''prion diseases.'' They are unique in being bot h familial and transmissible, even between species. Proof of transmiss ibility led to the assumption that the agent was a slow virus, but sta ndard virological techniques failed to determine its size. Using radia tion 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 o f replication cannot involve coding by nucleic acid, nor can the infor mation-conveying component be protein, as some investigators have assu med. Results of radiation chemistry-type experiments provide support f or the Gibbons and Hunter hypothesis that the transmitting agent is a fragment of nerve cell plasma membrane. That hypothesis requires modif ication to take account of recent work on PrP, a plasma membrane prote in originally identified by its co-purification with the agent; but no rmal mammalian nervous tissue also contains PrP. Polymorphisms in the normal PrP amino-acid sequence are associated with the origin of famil ial forms of the SEs, so I postulate that disease arises in the first instance through failure of aberrant PrP to be recognized by its recep tors, with consequent failure to be incorporated into the cell's plasm a membrane. The membrane domain lacking PrP will in its turn fail to r ecognize and incorporate even normal PrP, leading to a cycle of infect ivity and to that accumulation of PrP in the brain which is now known to be the cause of the clinical aspects of the Spongiform Encephalopat hies. (C) 1993 Academic Press, Inc.