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J Virol 2010 Apr;84(7):3464-75

Glycosylation of PrPC determines timing of neuroinvasion and targeting in the brain following transmissible spongiform encephalopathies infection by a peripheral route.

Cancellotti E, Bradford BM, Tuzi NL, Hickey RD, Brown D, Brown KL, Barron RM, Kisielewski D, Piccardo P, Manson JC

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 glycoprotein PrP(C) is considered a key factor for replication of infectivity in the 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 the involvement of different glycoforms of PrP in these processes remains 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 intra-peritoneally 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.


Category: Journal Article
PubMed ID: #20106922 DOI: 10.1128/JVI.02374-09
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2011-10-04 Entry Last Modified: 2012-08-29
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