Abstract
Atypical scrapie or Nor98 has been identified as a transmissible spongiform encephalopathy (TSE) that is clearly distinguishable from classical scrapie and BSE, notably regarding the biochemical features of the protease-resistant prion protein PrPres and the genetic factors involved in susceptibility to the disease. In this study we transmitted the disease from a series of 12 French atypical scrapie isolates in a transgenic mouse model (TgOvPrP4) overexpressing in the brain ∼0.25, 1.5 or 6× the levels of the PrPARQ ovine prion protein under the control of the neuron-specific enolase promoter. We used an approach based on serum PrPc measurements that appeared to reflect the different PrPc expression levels in the central nervous system. We found that transmission of atypical scrapie, much more than in classical scrapie or BSE, was strongly influenced by the PrPc expression levels of TgOvPrP4 inoculated mice. Whereas TgOvPrP4 mice overexpressing ∼6× the normal PrPc level died after a survival periods of 400 days, those with ∼1.5× the normal PrPc level died at around 700 days. The transmission of atypical scrapie in TgOvPrP4 mouse line was also strongly influenced by the prnp genotypes of the animal source of atypical scrapie. Isolates carrying the AF141RQ or AHQ alleles, associated with increased disease susceptibility in the natural host, showed a higher transmissibility in TgOvPrP4 mice. The biochemical analysis of PrPres in TgOvPrP4 mouse brains showed a fully conserved pattern, compared to that in the natural host, with three distinct PrPres products. Our results throw light on the transmission features of atypical scrapie and suggest that the risk of transmission is intrinsically lower than that of classical scrapie or BSE, especially in relation to the expression level of the prion protein.
Highlights
Transmissible Spongiform Encephalopathies (TSEs) are fatal neuro-degenerative diseases that affect humans and animals, and include bovine spongiform encephalopathy (BSE) in cattle, scrapie in small ruminants, chronic wasting disease (CWD) in cervids, and Creutzfeldt-Jakob disease (CJD) in humans
Characterization of the infectious agents involved in TSEs has historically required transmission in inbred wild-type mice, such as C57Bl, VM or RIII [4,22,23]
The strain-specific molecular diversity of the classical scrapie or BSE sources was faithfully reproduced in the TgOvPrP4 ovine transgenic mouse model that we have developed
Summary
Transmissible Spongiform Encephalopathies (TSEs) are fatal neuro-degenerative diseases that affect humans and animals, and include bovine spongiform encephalopathy (BSE) in cattle, scrapie in small ruminants, chronic wasting disease (CWD) in cervids, and Creutzfeldt-Jakob disease (CJD) in humans. TSEs are transmissible in their species of origin, but can cross species barriers and induce infection and/or disease after long incubation periods in other mammalian species, notably mice [4]. In this context transgenic mice expressing the prion protein of the natural host of the disease are very useful in TSEs transmission studies, as has been shown for scrapie using ovine transgenic mice [5,6]. This disease, designated Nor or atypical scrapie clearly differs from classical scrapie, notably with regard to the molecular and biochemical characteristics of the corresponding PrPres and to the genetic factors involved in susceptibility [14,15,16]
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