The glycosylphosphatidylinositol anchor is a major determinant of prion binding and replication

Clive Bate (1) , Mourad Tayebi , Alun Williams

1 Pathology and Infectious Diseases

The prion diseases occur following the conversion of the cellular prion protein (PrPC) into an alternatively folded, disease-related isoform (PrPSc). However, the spread of PrPSc from cell to cell is poorly understood. Here we report that soluble PrPSc bound to and replicated within both GT1 neuronal cells and primary cortical neurones. The capacity of PrPSc to bind and replicate within cells was significantly reduced by enzymatic modification of its glycosylphosphatidylinositol (GPI) anchor. Thus, PrPSc that had been digested with phosphatidylinositol-phospholipase C bound poorly to GT1 cells or cortical neurones and did not result in PrPSc formation in recipient cells. PrPSc that had been digested with phospholipase A2 (PrPSc-G-lyso-PI) bound readily to GT1 cells and cortical neurones but replicated less efficiently than mock treated PrPSc. Whereas the addition of PrPSc increased cellular cholesterol levels and was predominantly found within lipid raft micro-domains, PrPSc-G-lyso-PI did not alter cholesterol levels and most of it was found outside lipid rafts. We conclude that the nature of the GPI anchor attached to PrPSc affected the binding of PrPSc to neurones, its localisation to lipid rafts and its ability to convert endogenous PrPC.

Mots clés: Life Sciences

Clive Bate, Mourad Tayebi, Alun Williams. The glycosylphosphatidylinositol anchor is a major determinant of prion binding and replication. Biochemical Journal, 2010, 428 (1), pp.95-101. ⟨10.1042/BJ20091469⟩. ⟨hal-00479259⟩