Abstract
Transmissible spongiform encephalopathies (TSE) are characterized by the conversion of a protease-sensitive host glycoprotein, prion protein or PrP-sen, to a protease-resistant form (PrP-res). PrP-res molecules that accumulate in the brain and lymphoreticular system of the host consist of three differentially glycosylated forms. Analysis of the relative amounts of the PrP-res glycoforms has been used to discriminate TSE strains and has become increasingly important in the differential diagnosis of human TSEs. However, the molecular basis of PrP-res glycoform variation between different TSE agents is unknown. Here we report that PrP-res itself can dictate strain-specific PrP-res glycoforms. The final PrP-res glycoform pattern, however, can be influenced by the cell and significantly altered by subtle changes in the glycosylation state of PrP-sen. Thus, strain-specific PrP-res glycosylation profiles are likely the consequence of a complex interaction between PrP-res, PrP-sen, and the cell and may indicate the cellular compartment in which the strain-specific formation of PrP-res occurs.
Highlights
Multiple strains of Transmissible spongiform encephalopathies (TSE) agent have been identified
Distinct protease-resistant form (PrP-res) Glycosylation Patterns Can Be Produced in Vitro—To study the molecular basis of PrP-res glycoform variation, we focused on four mouse-adapted scrapie strains: 87V, RML, 22L, and ME7 [11]
We have shown that TSE strain glycoforms are primarily determined by PrP-res but can be significantly influenced by PrP-sen
Summary
Multiple strains of TSE agent have been identified. These strains differ biologically by differences in disease incubation times and neuropathology [11]. These size differences are due to strain-specific, conformational changes resulting in the exposure of different proteinase K cleavage sites [17, 18] This size difference could even be transmitted to newly formed PrP-res in vitro, demonstrating that the three-dimensional structure of PrP-res molecules can be self-propagated and suggesting a molecular basis for TSE strains [19]. It is still unclear how conformational differences in the PrP-res molecules may relate to strain-specific disease phenotypes. Based on the fact that the PrP-res glycosylation pattern can be drastically changed depending upon the PrP-sen glycosylation state, our results suggest that it is unlikely that in vivo strainspecific phenotypes are enciphered in the carbohydrate moieties of PrP-res
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