Possible origin of the scrapie genome in small endogenous RNAs; studies on eight candidate species in 263K scrapie infected hamster brain

Abstract

The identity of the etiologic agent of the transmissible spongiform encephalopathies (TSEs), including bovine spongiform encephalopathy (BSE), scrapie and Creutzfeldt-Jakob disease (CJD), remains unknown. While much attention has been given to the hypothesis that the TSEs may be caused by a proteinaceous infectious agent or prion, there is considerable evidence to suggest that this hypothesis is incomplete. We have pursued an alternative contention: that the etiologic agent comprises in part a modified and replicating form of an endogenous nucleic acid, probably RNA. The endovirus hypothesis contends that the parental molecule is most likely to be a small and highly-structured cellular RNA that can convert to a replicating molecule by a finite number of nucleotide sequence changes. We have begun a systematic analysis of candidate molecular species present in hamster brain infected with scrapie strain 263K. Initial work focussed on the 7S group of small RNAs. Examination of 7-2, 7SK and 7SL failed to reveal differences in abundance and/or sequence between normal and scrapie (263K)-infected hamster brain. Inspection of other possible candidates, including U3, H1/8-2 and novel molecules KR1, nu1 and nu2, similarly failed to provide evidence for scrapie-specific molecular variants; alterations to the KR1 sequence failed to correlate with disease. We present sequences of hamster RNAs 7-2, 7SK, 7SL, H1/8-2, U3, nu1, nu2 and KR1. Together our data so far fail to contradict or confirm the hypothesis, while arguing that the major species of these 8 RNA molecules are unlikely to correspond to the etiologic agent of the TSEs.