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Prion diseases are neurodegenerative disorders caused by misfolding of the normal prion protein (PrP) into a pathogenic "scrapie" conformation. To better understand the cellular and molecular mechanisms that govern the conformational changes (conversion) of PrP, we compared the dynamics of PrP from mammals susceptible (hamster and mouse) and resistant (rabbit) to prion diseases in transgenic flies. We recently showed that hamster PrP induces spongiform degeneration and accumulates into highly aggregated, scrapie-like conformers in transgenic flies. We show now that rabbit PrP does not induce spongiform degeneration and does not convert into scrapie-like conformers. Surprisingly, mouse PrP induces weak neurodegeneration and accumulates small amounts of scrapie-like conformers. Thus, the expression of three highly conserved mammalian prion proteins in transgenic flies uncovered prominent differences in their conformational dynamics. How these properties are encoded in the amino acid sequence remains to be elucidated.Genetic and biochemical evidence indicates that the prion protein (PrP) 3 is the causative agent in the pathogenesis of prion diseases (1). The pioneers of prion biology successfully transmitted prions to many laboratory animals, including mice, rats, hamsters, and guinea pigs (2, 3). However, rabbits proved resistant to different prion strains from humans and sheep and from mice-adapted scrapie sheep prions. One interpretation of these results is that the cellular environment of the rabbit may lack a conversion factor or express conversion inhibitors that prevent the acquisition of neurotoxic conformers. However, expression of recombinant PrP from sheep and rodents (mouse and bank vole) in rabbit RK13 epithelial cells followed by challenge with autologous prions led to persistent proteinase K-resistant PrP (PrP res or PrP Sc ) replication, indicating that rabbit cells provide a molecular environment consistent with PrP Sc conversion (4, 5). Alternatively, key amino acid substitutions in the sequence of rabbit PrP may impose structural constraints that prevent its conversion. To answer these questions Priola and co-workers (6) expressed rabbit PrP (RaPrP) in prion-infected mouse neuroblastoma cells and showed that RaPrP could not be converted into PrP Sc , indicating that the amino acid sequence of RaPrP prevents its conformational conversion. Thus, understanding the conformational properties of RaPrP can contribute to unraveling the rules governing prion transmission and neuropathology.PrP is a membrane-anchored glycoprotein highly enriched in the brain with the ability to undergo conformational changes. PrP Sc has been postulated as the causative agent in prion diseases, and it is composed of specific folding species of PrP that are replicated by autocatalytic mechanisms (7). However, the structure of PrP Sc has not yet been resolved. Structural studies performed with either purified or recombinant PrP C have confirmed the intrinsic ability of PrP to misfold into conformations that are transmissib...

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