The nature of the scrapie agent: the virus theory

Abstract

All spongiform encephalopathies (SEs) are slow virus-transmissible infectious disorders of the brain. Tubulofilamentous particles/scrapie-associated fibrils (SAF) are ultrastructural markers, while protease-resistant protein (PrP) is a protein marker. The PrP molecules aggregate to form SAF, which occurs as an internal part of the tubulofilamentous particle termed nemavirus (NVP). Each NVP consists of three layers: (i) an outer protein coat, (ii) an intermediate ssDNA layer, and (iii) inner PrP/SAF. A chronological study of scrapie-infected hamster brain revealed that NVP and SAF are seen 10 days postinoculation from the inoculated right side of the brain and from 18 days postinoculation from both sides of the brain. The existence of at least 20 stable strains of SEs implies that a nucleic acid molecule serves as the information molecule. This is incompatible with the hypothesis that PrP by itself or a specific point mutation is the agent. It appears that an "accessory protein" coded by the ssDNA of the nemavirus interacts with normal PrPc molecules, resulting in their conversion to PrPsc/SAF. The pathogenesis process in infected animals with increasing incubation periods reveals that larger amounts of normal PrP molecules are modified to form SAF. This interferes with the normal supply of PrP to cell membranes, which become disrupted and eventually fragment, resulting in the vacuoles typical of those found in the SEs.