NR AWSS
AU Williams,A.; Bate,C.
TI Prion-induced neurodegeneration - a tale of rafts and anchors
QU European Society of Veterinary Pathology, 24th Meeting, Edinburgh, Scotland, 30.8.-2.9.2006, Oral presentation Session 9A : 116
IA http://www.esvp.eu/ESVP_meetings/Proceedings_2006.pdf
PT Oral presentation
AB The conversion of the normal cellular PrPc to the disease-associated PrPsc is a key feature in the pathogenesis of Transmissible Spongiform Encephalopathies (TSEs, or prion diseases). Such PrPsc is a major component of the infectious agent (prion) of TSEs and is neurotoxic via a mechanism that has been shown to be dependent on lipid rafts, specific intracellular trafficking pathways and activation of phospholipase A2. Lipid rafts are specialised membrane microdomains in which GPI-anchored proteins, such as PrPc, are localised. In this study, the process by which aggregated PrPsc molecules cause neuronal damage was addressed by incubating neurones partial GPI analogues to compete with PrP-GPI for second messenger signalling systems. These analogues inhibited the neurotoxic effect of defined PrP peptides and reduced PLA2 activation. In contrast, high concentrations of GPI anchors isolated from PrPc, but not from two other GPI-anchored proteins, Thy-1 or Decay Accelerating Factor (CD55), mimicked two of the effects of prions / PrP peptides on neurones in that the PrP-GPI anchors activated PLA2 and promoted caspase-3 activation in neurones. Collectively, these studies support the concept that PrPsc is neurotoxic as a consequence of the self aggregation of PrPsc in lipid rafts and that the resultant concentration of PrP GPI triggers activation of specific cell signalling pathways associated with prion-induced neuronal death.
AD Alun Williams, Clive Bate, The Royal Veterinary College, UK
SP englisch
PO UK