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

SUMMARY 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.