NR AXIY
AU Bate,C.; Williams,A.
TI Role of Glycosylphosphatidylinositol Anchors in the Neurotoxicity of PrPsc
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Pathology and Pathogenesis P03.97
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
There is increasing interest in the mechanisms by which PrPsc leads to neurodgeneration. The majority of PrPc molecules are linked to membranes via a glycosylphosphatidylinositol (GPI) anchor. The self-aggregation of PrPsc results in the clustering of GPI anchors in lipid raft micro-domains that are enriched in signalling molecules. We demonstrate that the addition of GPI anchors isolated from PrPc or PrPsc mimics some of the effects of PrPsc on neurones, namely activation of phospholipase A2 (PLA2), a key enzyme in the process by which PrPsc kills some neurones, and induction of caspase-3 (Bate & Williams, 2004). The GPIs isolated from PrP in hamster brains are unusual in that they contain high amounts of galactose, mannose and sialic acid (Stahl et al., 1992). Although is not known whether PLA2 activation is a unique property of GPIs attached to PrP, GPI anchors isolated from Thy1, decay-accelerating factor (DAF) or CD14 did not activate PLA2 indicating that this activity is not shared by all GPIs.
High concentrations of GPI anchors were required to activate PLA2, perhaps reproducing the locally high concentration of GPI anchors that occurs following the aggregation of PrPsc molecules, or the cross-linkage of PrPc by specific mabs (Solforosi et al., 2004). The activity of GPIs was dependent on a phosphatidylinositol moiety, on ester-linked acyl chains and on a glycan component. There were no obvious physical differences between GPIs isolated from PrPc or PrPsc, nor any differences in their activity. Pre-treatment with glucosamine-phosphatidylinositol (PI) reduced activation of PLA2 by PrPsc and protected neurones against the toxicity of PrPsc. These results are consistent with the hypothesis that glucosamine-PI competes with the GPI anchors of PrPsc for cellular receptors involved in signal transduction. While neuronal death in prion diseases is undoubtedly a complex process, these observations provide insight into the signalling processes that result in PrPsc-induced neuronal loss.
AD C. Bate, A. Williams, Royal Veterinary College, Pathology and Infectious Diseases, UK
SP englisch
PO Schottland