Glycosylphosphatidylinositol anchor analogues sequester cholesterol and reduce prion formation.
A hallmark of prion diseases is the conversion of the host-encoded prion protein (PrP(C) where C is cellular) into an alternatively folded, disease-related isoform (PrP(Sc), where Sc is scrapie), the accumulation of which is associated with synapse degeneration and ultimately neuronal death. The formation of PrP(Sc) is dependent upon the presence of PrP(C) in specific, cholesterol-sensitive membrane microdomains, commonly called lipid rafts. PrP(C) is targeted to these lipid rafts because it is attached to membranes via a glycosylphosphatidylinositol anchor. Here, we show that treatment of prion-infected neuronal cell lines (ScN2a, ScGT1, or SMB cells) with synthetic glycosylphosphatidylinositol analogues, glucosamine-phosphatidylinositol (glucosamine-PI) or glucosamine 2-O-methyl inositol octadecyl phosphate, reduced the PrP(Sc) content of these cells in a dose-dependent manner. In addition, ScGT1 cells treated with glucosamine-PI did not transmit infection following intracerebral injection to mice. Treatment with glucosamine-PI increased the cholesterol content of ScGT1 cell membranes and reduced activation of cytoplasmic phospholipase A(2) (PLA(2)), consistent with the hypothesis that the composition of cell membranes affects key PLA(2)-dependent signaling pathways involved in PrP(Sc) formation. The effect of glucosamine-PI on PrP(Sc) formation was also reversed by the addition of platelet-activating factor. Glucosamine-PI caused the displacement of PrP(C) from lipid rafts and reduced expression of PrP(C) at the cell surface, putative sites for PrP(Sc) formation. We propose that treatment with glucosamine-PI modifies local micro-environments that control PrP(C) expression and activation of PLA(2) and subsequently inhibits PrP(Sc) formation.
Bate
Clive
C
Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts AL9 7TA, United Kingdom. c.bate@rvc.ac.uk
Tayebi
Mourad
M
Williams
Alun
A
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005944:Glucosamine / Q000494:pharmacology; D017261:Glycosylphosphatidylinositols / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D054467:Phospholipases A2 / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology; D018621:PrPC Proteins / Q000737:chemistry / Q000378:metabolism; D018620:PrPSc Proteins / Q000378:metabolism*
D017261:Glycosylphosphatidylinositols; D010972:Platelet Activating Factor; D018621:PrPC Proteins; D018620:PrPSc Proteins; D002784:Cholesterol; D054467:Phospholipases A2; D005944:Glucosamine