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

The Roslin Institute and R(D)SVS University of Edinburgh, Roslin, Midlothian EH25 9PS, Scotland, United Kingdom.
Journal of Virology (Impact Factor: 4.44). 04/2010; 84(7):3464-75. DOI: 10.1128/JVI.02374-09
Source: PubMed


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.

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    • "Inoculation of ME7 resulted in only a slight lengthening of incubation time in G2 mice but showed no transmission in either G1 or G3 mice (Cancellotti et al. 2010 ) . Transmission of TSE agents to these mice thus established that glycosylation of host PrP has a major in fl uence on the outcome of disease (Tuzi et al. 2008 ; Cancellotti et al. 2010 ) . "
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    ABSTRACT: Although the prion protein (PrP) was discovered in the early 1980s, there is still a considerable lack of knowledge of the normal function of the PrP protein and its precise role in the infectious process of transmissible spongiform encephalopathies (TSEs) or prion diseases. The production and use of a multitude of transgenic mice expressing different forms of PrP has enabled us to increase our knowledge of PrP in health and disease. Using mice expressing PrP from different species, we are able to define the strain of TSE agent infecting a wide range of hosts and model the transmission potential of each agent within and between species. Transgenic mouse models are also utilised in investigating the normal function of PrP, the impact of differential glycosylation in PrP biology and the genetics underlying disease susceptibility. Advances in transgenic technologies have enabled us to control both spatial and temporal expression of PrP, allowing us to define the mechanisms and routes of disease pathogenesis. Transgenic mice also play a vital role in understanding the mechanisms of neurodegeneration in the TSEs, which may also lead to a better understanding of the other protein misfolding diseases such as Alzheimer’s disease.
    11/2013: chapter 10: pages 155-169; Springer New York., ISBN: 9781461453376
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    • "Intra-cranial infection of these mice with multiple prion strains indicates dramatically different requirements for occupation of each of the glycosylation sites of host PrP for infection. However, since disease outcomes are significantly modulated following peripheral infection of glycosylation-deficient, genetargeted mice, our data also suggest that glycosylation of PrP is important for either peripheral replication of PrP Sc or for trafficking of the infection to the CNS (Cancellotti, et al., 2010). The glycans present at either site are highly heterogeneous (Ritchie et al., 2002, Rudd et al., 1999, Stimson et al., 1999); at least 60 different glycan moieties can be present on the protein and genetic removal of glycosylation does not distinguish between individual glycan structures. "

    Miscellanea on Encephalopathies, 04/2012; , ISBN: 978-953-51-0499-5
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    ABSTRACT: A novel thermolysin digestion method for the molecular strain-typing of ruminant TSEs has been developed which resulted in the clearance of cellular prion protein (PrP C) from healthy sheep or cattle brain homogenates, while digestion of scrapie or BSE infected samples resulted in the generation of the full-length disease-related isoform, PrP Sc . Using antibodies against the amino terminal region of PrP it was possible to distinguish ovine scrapie from ovine BSE, permitting the potential identification of BSE infected sheep within the UK flock. The identification of a disease-associated, endogenously-generated fragment of PrP (termed C2) in scrapie infected sheep is also described. Absent in healthy brain homogenates, the neuroanatomical distribution of both C2 fragments and thermolysin-resistant PrP Sc permitted the classification of four groups within a sample of natural scrapie cases which may be representative of scrapie strain heterogeneity in the UK.
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