A modified host protein model of scrapie

The scrapie agent is still not completely characterized biochemically and ultrastructurally, but its requirement for a functional protein has been established. Purification of the scrapie agent by methods using digestion with proteinase K yields a glycoprotein with an apparent mass of 27-30 kDa (PrP 27-30). In contrast, a 33-37 kDa glycoprotein, called Sp33-37, is the major protein component isolated from scrapie-affected brain when protease digestion is not used. Sp33-37 is the product of a normal host gene and is a larger form of PrP 27-30. We propose a model in which Sp33-37, a modified host protein, is the critical component of the scrapie agent; a non-host nucleic acid is not part of the agent. We postulate that Sp33-37, perhaps in concert with other unidentified host components, is capable of inducing the disease and directing the production of more of itself by acting on the normal protein directly or by affecting one of the steps in protein processing. Agent replication requires that: 1) a constant supply of the substrate protein Cp33-37 is available, 2) aggregates of Sp33-37 are resistant to degradation and accumulate in cells or cell membranes, and 3) membrane damage and cell death facilitate spread to adjacent cells. The model predicts that disease can be transmitted by the scrapie agent or initiated by a spontaneous metabolic error resulting in accumulation of the abnormal protein.