NR AURA
AU Strom,A.; Wang,G.S.; Reimer,R.; Scott,F.W.
TI Age Dependent Cytosolic Aggregation of Cellular Prion Protein In Vivo
QU TSE-Forum, 6. Kongress - Nationale TSE-Forschungsplattform, Greifswald 26.6.-28.6.2006, Vortrag V-19
PT Konferenz-Vortrag
AB The cellular prion protein (PrPc) plays a major role in the pathogenesis of a group of neurodegenerative disorders also known as prion diseases. Despite decades of effort, the mechanism by which PrPc causes fatal neurodegenerative diseases remains unclear. It was suggested that the pathogenic PrP isoform (PrPsc, Sc-scrapie) might arise de novo in sporadic and familial forms of the prion diseases on the rare occasions when unfolded or misfolded PrPc accumulates in the cytosol. Thus far, cytosolic PrP aggregates have been reported only in studies performed in vitro by manipulating cell metabolism using protease inhibitors [Kristiansen M. et al., JBC 2005; Ma J. and Lindquist S., PNAS 2001] or cyclosporine A [Cohen E. and Taraboulos A., EMBO J., 2003]. Whether PrPc, a cell-surface N-linked glycoprotein, would ever exist in vivo in cytoplasm under normal circumstances has been a fundamental question. In this presentation we show for the first time in vivo the accumulation of PrPc in cytosolic inclusions in rats. These cellular structures expressed different molecular characteristics from the aggresome-like PrP inclusions described in vitro. Further, the frequency of the cytosolic PrPc inclusions was increased and more pronounced with age reaching a size of >4 micrometer and dependent on metabolic cell conditions. Such cytosolic PrPc deposits could play an important role in familial and sporadic forms of prion diseases in humans, by providing "prion seeds" required for the initiation of the disease. The observed increase in the frequency of PrPc aggregates with age correlates with the fact that, sporadic and familial forms of prion diseases appear in the later stages of life. Thus, our findings may contribute to the understanding of the initial steps of prion disorders in humans.
AD Alexander Strom, Gen-Sheng Wang, Fraser W. Scott, Molecular Medicine, Ottawa Health Research Institute, Ottawa, Ontario, Canada; Rudolph Reimer, Electron Microscopy and Micro-Technology Group, Heinrich-Pette-Institute, Hamburg, Germany
SP englisch
PO Deutschland
OR Tagungsband