Variable Protease-Sensitive Prionopathy Transmission to Bank Voles.

Romolo Nonno,Jody Lavrich,Laura Pirisinu,Ilaria Vanni,Silvio Notari,Ignazio Cali,Umberto Agrimi,Claudia D’Agostino,Diane Kofskey,Laura Cracco,Piero Parchi,Michele Angelo Di Bari,Pierluigi Gambetti

doi:10.3201/eid2501.180807

Abstract

Variably protease-sensitive prionopathy (VPSPr), a recently described human sporadic prion disease, features a protease-resistant, disease-related prion protein (resPrPD) displaying 5 fragments reminiscent of Gerstmann-Sträussler-Scheinker disease. Experimental VPSPr transmission to human PrP–expressing transgenic mice, although replication of the VPSPr resPrPD profile succeeded, has been incomplete because of second passage failure. We bioassayed VPSPr in bank voles, which are susceptible to human prion strains. Transmission was complete; first-passage attack rates were 5%–35%, and second-passage rates reached 100% and survival times were 50% shorter. We observed 3 distinct phenotypes and resPrPD profiles; 2 imitated sporadic Creutzfeldt-Jakob disease resPrPD, and 1 resembled Gerstmann-Sträussler-Scheinker disease resPrPD. The first 2 phenotypes may be related to the presence of minor PrPD components in VPSPr. Full VPSPr transmission confirms permissiveness of bank voles to human prions and suggests that bank vole PrP may efficiently reveal an underrepresented native strain but does not replicate the complex VPSPr PrPD profile.

Highlights

Protease-sensitive prionopathy (VPSPr), a recently described human sporadic prion disease, features a protease-resistant, disease-related prion protein displaying 5 fragments reminiscent of Gerstmann-SträusslerScheinker disease
The permissiveness of bank vole PrP or cellular human PrP (PrPC) is well known [15,16,18,21,22,23,24,25,26,27]; it is exemplified by the observation that, despite the mere 8-aa PrPC divergence between bank voles and mice, a variety of human and animal prion diseases not transmissible to mice are infectious to bank voles and transgenic mice expressing bank vole prion protein (PrP) [15,16,18,22,24]
This striking permissiveness has been attributed to the presence of several asparagine and glutamine residues in and around the β2–α2 loop that would result in a PrPC conformation compatible with the conformations of a large number of PrPD strains [21]

Summary

Introduction

Protease-sensitive prionopathy (VPSPr), a recently described human sporadic prion disease, features a protease-resistant, disease-related prion protein (resPrPD) displaying 5 fragments reminiscent of Gerstmann-SträusslerScheinker disease. Sporadic prion diseases are classified according to phenotype as well as the pairing of the prion protein (PrP) genotype at the methionine (M)/valine (V) polymorphic codon 129 and the conformational characteristics of the abnormal or disease-associated PrP (PrPD) These characteristics include electrophoretic mobility and the ratio of the PrPD fragments that are resistant to proteinase K (PK) digestion (Appendix Table 1, https://wwwnc.cdc.gov/EID/article/25/1/18-0807App1.pdf) [1]. Additional variances concerning immunoreactivity characteristics, ratios of PK-resistant and PK-sensitive PrPD species, and conformational properties including aggregate size, have been observed [6,7,8] These distinctive properties point to VPSPr PrPD as a prion strain different from those of other. The presence of small amounts of sCJD-like 3-band resPrPD has been signaled in VPSPr [6,11,12]

Methods

Results

Conclusion