Abstract
Prion diseases are fatal neurodegenerative diseases caused by misfolding of the prion protein (PrP). These conditions affect humans and animals, including endemic forms in sheep and deer. Bovine, rodents, and many zoo mammals also developed prion diseases during the "mad-cow" epidemic in the 1980's. Interestingly, rabbits, horses, and dogs show unusual resistance to prion diseases, suggesting that specific sequence changes in the corresponding endogenous PrP prevents the accumulation of pathogenic conformations. In vitro misfolding assays and structural studies have identified S174, S167, and D159 as the key residues mediating the stability of rabbit, horse, and dog PrP, respectively. Here, we expressed the WT forms of rabbit, horse, and dog PrP in transgenic Drosophila and found that none of them is toxic. Replacing these key residues with the corresponding amino acids in hamster PrP showed that mutant horse (S167D) and dog (D159N) PrP are highly toxic, whereas mutant rabbit (S174 N) PrP is not. These results confirm the impact of S167 and D159 in local and long-range structural features in the globular domain of PrP that increase its stability, while suggesting the role of additional residues in the stability of rabbit PrP. Identifying these protective amino acids and the structural features that stabilize PrP can contribute to advance the field towards the development of therapies that halt or reverse the devastating effects of prion diseases.
