NR AXVQ
AU Saghafi,S.; Spilman,P.R.; Prusiner,S.B.; DeArmond,S.J.; Lingappa,V.R.
TI Gain and Loss of PrPc-mediated Functions in Infectious Prion Disease
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Pathology and Pathogenesis P03.188
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Substantial evidence indicates that the cellular prion protein (PrPc) plays a central role in the pathogenesis of transmissible prion diseases. However, it remains unresolved if its role results from gain or loss of PrPc-mediated functions. We propose a hypothesis by which both gain and loss of PrPc functions can occur in infectious disease. At the basis of our hypothesis is the detection of two topological isoforms of PrPc in wildtype mice and the isolation of their respective functions: Fully secreted SecPrP reveals a neuroprotective function against reactive oxygen species (ROS) whereas transmembrane CtmPrP triggers caspase-3 - mediated apoptosis. To identify the roles of both CtmPrP and SecPrP in prion disease pathogenesis, transgenic mice favoring expression of either the CtmPrP or SecPrP isoform were inoculated with PrPsc. Mice favoring CtmPrP expression develop symptoms within 7 weeks and show pathology
for both apoptosis and oxidative stress-mediated neurodegeneration. In contrast, despite substantial accumulation of protease-resistant PrP, mice favoring expression in the SecPrP form develop symptoms after ~50 weeks with indications of oxidative stress and non-apoptotic cell loss. Our data suggest PrPsc accumulation leads to upregulation of CtmPrP, which triggers apoptosis. Additionally, the SecPrP-to-PrPsc conversion leads to a loss of the neuroprotective function of SecPrP, resulting in a higher susceptibility of infected cells to ROS. Therefore, pathophysiology of infectious prion disease is likely facilitated by both the apoptotic effects of CtmPrP and the loss of the protective effects of SecPrP.
AD S. Saghafi, V.R. Lingappa, University of California, Physiology, USA; P.R. Spilman, S.J. DeArmond, University of California, Pathology; S.B. Prusiner, University of California, Institute for Neurodegenerative Disease
SP englisch
PO Schottland