Dextran sulphate inhibits an association of prions with plasma membrane at the early phase of infection

Abstract

The defining characteristic of prion diseases is conversion of a cellular prion protein (PrP^C) to an abnormal prion protein (PrP^Sc). The exogenous attachment of PrP^Sc to the surface of a target cell is critical for infection. However, the initial interaction of PrP^Sc with the cell surface is poorly characterized. In the current study, we specifically focused on the association of PrP^Sc with cells during the early phase of infection, using an acute infection model. First, we treated mouse neuroblastoma N2a-58 cells with prion strain 22 L-infected brain homogenates and revealed that PrP^Sc was associated with membrane fractions within three hours, a short exposure time. These results were also observed in PrP^C-deficient hippocampus cell lines. We also demonstrate here that PrP^Sc from 22 L-infected brain homogenates was associated with lipid rafts during the early phase of infection. Furthermore, we revealed that DS500, a glycosaminoglycan mimetic, inhibited both the attachment of PrP^Sc to membrane fractions and subsequent prion transmission, suggesting that the early association of prions with cell surface is important for prion infection.

Keywords: Abnormal prion protein; Cellular prion protein; Endocytosis; Lipid rafts; Prion diseases.