Increased Proportions of C1 Truncated Prion Protein Protect Against Cellular M1000 Prion Infection (original) (raw)

Prion disease pathogenesis is linked to the cell-associated propagation of misfolded protease-resistant conformers (PrP res) of the normal cellular prion protein (PrP C). Ongoing PrP C expression is the only known absolute requirement for successful prion disease transmission and PrP res propagation. Further typifying prion disease is selective neuronal dysfunction and loss, although the precise mechanisms underlying this are undefined. We utilized a single prion strain (M1000) and a range of neuronal and nonneuronal, PrP C endogenously expressing and transgenically modified overexpressing cell lines, to evaluate whether PrP C glycosylation patterns or constitutive N-terminal cleavage events may be determinants of sustained PrP res propagation. Our data demonstrates that relative proportions of full-length and C1 truncated PrP C are the most important characteristics influencing susceptibility to sustained M1000 prion infection, supporting PrP C >-cleavage as a protective event, which may contribute to the selective neuronal vulnerability observed in vivo.