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. 2008 Jul 25;4(7):e1000113.
doi: 10.1371/journal.ppat.1000113.

Prion protein amino acid determinants of differential susceptibility and molecular feature of prion strains in mice and voles

Umberto Agrimi  1 , Romolo Nonno, Giacomo Dell'Omo, Michele Angelo Di Bari, Michela Conte, Barbara Chiappini, Elena Esposito, Giovanni Di Guardo, Otto Windl, Gabriele Vaccari, Hans-Peter Lipp
Affiliations

Prion protein amino acid determinants of differential susceptibility and molecular feature of prion strains in mice and voles

Umberto Agrimi et al. PLoS Pathog. .

Abstract

The bank vole is a rodent susceptible to different prion strains from humans and various animal species. We analyzed the transmission features of different prions in a panel of seven rodent species which showed various degrees of phylogenetic affinity and specific prion protein (PrP) sequence divergences in order to investigate the basis of vole susceptibility in comparison to other rodent models. At first, we found a differential susceptibility of bank and field voles compared to C57Bl/6 and wood mice. Voles showed high susceptibility to sheep scrapie but were resistant to bovine spongiform encephalopathy, whereas C57Bl/6 and wood mice displayed opposite features. Infection with mouse-adapted scrapie 139A was faster in voles than in C57Bl/6 and wood mice. Moreover, a glycoprofile change was observed in voles, which was reverted upon back passage to mice. All strains replicated much faster in voles than in mice after adapting to the new species. PrP sequence comparison indicated a correlation between the transmission patterns and amino acids at positions 154 and 169 (Y and S in mice, N and N in voles). This correlation was confirmed when inoculating three additional rodent species: gerbils, spiny mice and oldfield mice with sheep scrapie and 139A. These rodents were chosen because oldfield mice do have the 154N and 169N substitutions, whereas gerbil and spiny mice do not have them. Our results suggest that PrP residues 154 and 169 drive the susceptibility, molecular phenotype and replication rate of prion strains in rodents. This might have implications for the assessment of host range and molecular traceability of prion strains, as well as for the development of improved animal models for prion diseases.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Immunoblot of PrPSc from the primary transmission of prion strains to rodent species.
(A) bank voles, (B) field voles, (C) wood mice and (D) C57Bl/6 mice.
Figure 2
Figure 2. Glycoform analysis of PrPSc from rodent species inoculated with SS3, BSE and 139A.
Figure 3
Figure 3. Molecular type of PrPSc produced in rodent species following transmission of prion strains.
Immunoblot of PrPSc from the second passage of BSE to bank voles (lane 1), the primary transmission of 139A to bank voles, field voles, oldfield mice and gerbils (lanes 2, 3, 4, 6), the transmission of 139A to C57Bl/6 mice (lanes 7, 8) and the back passage of vole-adapted 139A to C57Bl/6 mice (lane 5).
Figure 4
Figure 4. Second and third passages of natural scrapie (SS3) and BSE to bank voles and C57Bl/6 mice.
Mean survival times±SD are reported at the top of each bar.
Figure 5
Figure 5. Spongiform change in the cerebellar cortex of rodent species following inoculation of 139A.
(A) bank voles, (B) field voles, (C) oldfield mice, (D) wood mice, (E) gerbils and (F) C57Bl/6 mice. Spongiosis is widespread in both molecular and granular layers of wood mice, gerbils and C57Bl/6 mice. In contrast, the cerebellar cortex is quite completely spared in the other three rodent species in which occasional vacuoles were observed only in the granular layer. Bar = 50 µm.
Figure 6
Figure 6. Prion protein amino acid sequences alignment of the rodent species under study.
The sequence numbers of C57Bl/6 mouse (Mus musculus) amino acids are shown in the upper line and refer to the residue under the first digit. In the other rodent species, residues identical to the mouse are indicated as dots. The amino acid residues that were identified as potentially important for the different susceptibility of vole- and mouse-related species are boxed (154 and 169). Blank spaces at the N or C termini of the sequences represent presently undetermined amino acid residues.
Figure 7
Figure 7. Position of amino acid residues Y154 (green) and S169 (red) in the NMR-structure of the globular domain of mouse PrPC.
Different secondary structure elements are drawn in different colours (purple: α-helix, yellow: β-sheet, green: loop).
Figure 8
Figure 8. Taxonomic tree of the Muroidea superfamily comprising the rodent species used in the study.
All species with Y154–S169 residues (gerbil, C57Bl/6, wood and spiny mouse) fall in the family of Muridae, while species with 154N–169N (oldfiled mouse, bank and field vole) fall in the family of Cricetidae.
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