Fig 1.
Model of how PrP PTMs may impact HS-mediated prion conversion.
Prion conversion of GPI-anchored prions occurs at the cellular membrane or intracellularly within the endolysosomal pathway. GPI-anchored prions bind inefficiently to HS and form diffuse and small plaque-like aggregates containing a mixture of di-, mono-, and unglycosylated PrPSc. Prion conversion of GPI-anchorless prions may occur extracellularly, as approximately 10% to 15% of the cellular prion protein (PrPC) is constitutively cleaved from the plasma membrane by ADAM10 [40]. Shed, ADAM10-cleaved PrPC traffics through the interstitial fluid by bulk flow and binds HS chains in the extracellular matrix and vascular basement membrane. PrPSc also binds HS; thus, HS potentially facilitates PrPC and PrPSc interaction and scaffolds assembly (curved arrows). Poorly glycosylated PrP (mono- and unglycosylated) binds to HS and is enriched in prion fibrils. ADAM10, A-disintegrin-and-metalloproteinase domain-containing protein 10; GPI, glycosylphosphatidylinositol; HS, heparan sulfate; PrP, prion protein; PrPC, cellular prion protein; PrPSc, misfolded and aggregated prion protein.