Host PrP Glycosylation: A Major Factor Determining the Outcome of Prion Infection

Abstract

The expression of the prion protein (PrP) is essential for transmissible spongiform encephalopathy (TSE) or prion diseases to occur, but the underlying mechanism of infection remains unresolved. To address the hypothesis that glycosylation of host PrP is a major factor influencing TSE infection, we have inoculated gene-targeted transgenic mice that have restricted N-linked glycosylation of PrP with three TSE strains. We have uniquely demonstrated that mice expressing only unglycosylated PrP can sustain a TSE infection, despite altered cellular location of the host PrP. Moreover we have shown that brain material from mice infected with TSE that have only unglycosylated PrPSc is capable of transmitting infection to wild-type mice, demonstrating that glycosylation of PrP is not essential for establishing infection within a host or for transmitting TSE infectivity to a new host. We have further dissected the requirement of each glycosylation site and have shown that different TSE strains have dramatically different requirements for each of the glycosylation sites of host PrP, and moreover, we have shown that the host PrP has a major role in determining the glycosylation state of de novo generated PrPSc.

Sequence-dependent Prion Protein Misfolding and Neurotoxicity

“…However, conversion is not observed in transgenic mice expressing unglycosylated PrP, indicating important differences in the behavior of the protein in vivo. Although recent results demonstrate that prion transmission can take place regardless of PrP glycosylation (40), it seems to be important for the transmission of certain strains (41). Thus, mono-and unglycosylated PrP seem to be better substrates for conversion than diglycosylated PrP.…”

Dramatic Reduction of PrPCLevel and Glycosylation in Peripheral Nerves following PrP Knock-Out from Schwann Cells Does Not Prevent Transmissible Spongiform Encephalopathy Neuroinvasion

“…Again the alterations observed via the intraperitoneal route would at best argue for the peripheral nerves being only a minor component of the route to the CNS. We have established in parallel studies that while mice expressing only unglycosylated PrP can become infected with a TSE agent following intracerebral challenge (Tuzi et al, 2008), they are not capable of TSE neuroinvasion following peripheral routes of inoculation (EC, BMB and JCM unpublished data) thus implicating glycosylated PrP as important in the peripheral phases of infection (replication and/or transport). It may be the case that fully glycosylated PrP is a requirement for agent replication in the periphery but is not a requirement for agent transport, or vice versa.…”

Prion Protein Glycosylation Is Not Required for Strain-Specific Neurotropism

“…Interestingly, different ratios of PrP C glycoforms are found in different brain regions (2,10,32), and different prion strains produce distinctive ratios of PrP Sc glycoforms upon serial passage (9). Studies of transgenic mice show that PrP C glycosylation influences patterns of prion neurotropism in a strain-dependent manner (11,35). Studies with human brain specimens have shown that the regional distribution of PrP Sc glycoforms is heterogenous in the sporadic but not the variant form of Creutzfeldt-Jakob disease (21).…”