Glycosylation of PrP ^C Determines Timing of Neuroinvasion and Targeting in the Brain following Transmissible Spongiform Encephalopathy Infection by a Peripheral Route

Abstract

Transmissible spongiform encephalopathy (TSE) infectivity naturally spreads from site of entry in the periphery to the central nervous system where pathological lesions are formed. Several routes and cells within the host have been identified as important for facilitating the infectious process. Expression of the glycoprotein cellular PrP (PrP C ) is considered a key factor for replication of infectivity in the central nervous system (CNS) and its transport to the brain, and it has been suggested that the infectious agent propagates from cell to cell via a domino-like effect. However, precisely how this is achieved and what involvement the different glycoforms of PrP have in these processes remain to be determined. To address this issue, we have used our unique models of gene-targeted transgenic mice expressing different glycosylated forms of PrP. Two TSE strains were inoculated intraperitoneally into these mice to assess the contribution of diglycosylated, monoglycosylated, and unglycosylated PrP in spreading of infectivity to the brain. This study demonstrates that glycosylation of host PrP has a profound effect in determining the outcome of disease. Lack of diglycosylated PrP slowed or prevented disease onset after peripheral challenge, suggesting an important role for fully glycosylated PrP in either the replication of the infectious agent in the periphery or its transport to the CNS. Moreover, mice expressing unglycosylated PrP did not develop clinical disease, and mice expressing monoglycosylated PrP showed strikingly different neuropathologic features compared to those expressing diglycosylated PrP. This demonstrates that targeting in the brain following peripheral inoculation is profoundly influenced by the glycosylation status of host PrP.

Crucial Role for Prion Protein Membrane Anchoring in the Neuroinvasion and Neural Spread of Prion Infection

“…inoculation might be due to poor spread of PrPres in splanchnic nerves, similar to sciatic and cranial nerves innervating the tongue. Similar results were seen in recent studies of G3 transgenic mice which produce only unglycosylated PrP (15). In G3 mice PrP is GPI anchored to membranes in the Golgi apparatus inside the cell rather than on the plasma membrane.…”

Prion Propagation in Cells Expressing PrP Glycosylation Mutants

“…Glycosylation was shown to influence the incubation period before disease onset and not the neuropathological features in the brain (56). Following inoculation by a peripheral route, however, PrP C glycosylation profoundly influenced both the disease timing and the PrP Sc deposition pattern, and mice without PrP glycosylation were resistant (8). This suggested a role for PrP-attached glycans in the spread of prions within the organism.…”

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.…”