Inherited
prion disease (IPD) is caused by autosomal-dominant pathogenic mutations in the human
prion protein (PrP) gene (PRNP). A
proline to
leucine substitution at PrP residue 102 (P102L) is classically associated with Gerstmann-Sträussler-Scheinker (GSS) disease but shows marked clinical and neuropathological variability within kindreds that may be caused by variable propagation of distinct
prion strains generated from either PrP 102L or wild type PrP. To-date the transmission properties of
prions propagated in P102L patients remain ill-defined. Multiple mouse models of GSS have focused on mutating the corresponding residue of murine PrP (P101L), however murine PrP 101L, a novel PrP primary structure, may not have the repertoire of pathogenic
prion conformations necessary to accurately model the human disease. Here we describe the transmission properties of
prions generated in human PrP 102L expressing transgenic mice that were generated after primary challenge with ex vivo human GSS P102L or classical CJD
prions. We show that distinct strains of
prions were generated in these mice dependent upon source of the inoculum (either GSS P102L or CJD brain) and have designated these GSS-102L and CJD-102L
prions, respectively. GSS-102L
prions have transmission properties distinct from all
prion strains seen in sporadic and acquired human
prion disease. Significantly, GSS-102L
prions appear incapable of transmitting disease to conventional mice expressing wild type mouse PrP, which contrasts strikingly with the reported transmission properties of
prions generated in GSS P102L-challenged mice expressing mouse PrP 101L. We conclude that future transgenic modeling of IPDs should focus exclusively on expression of mutant human PrP, as other approaches may generate novel experimental
prion strains that are unrelated to human disease.