NR ATHO
AU Kristiansen,M.; Messenger,M.J.; Klöhn,P.C.; Brandner,S.; Wadsworth,J.D.F.; Collinge,J.; Tabrizi,S.J.
TI Disease-related prion protein forms aggresomes in neuronal cells
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Cell Biology of PrPc and PrPsc CELL-20
PT Konferenz-Poster
AB The molecular basis for neuronal death in prion disease is not established but putative pathogenic roles for both disease-related prion protein (PrPsc) and accumulated cytosolic PrPc have been proposed. Here we report that only prion-infected neuronal cells become apoptotic after mild inhibition of the proteasome, and this is strictly dependent upon sustained propagation of PrPsc. While cells overexpressing PrPc developed cytosolic PrPc aggregates, this did not cause cell death. In contrast, only in prion-infected cells, mild proteasome impairment resulted in the formation of large cytosolic perinuclear aggresomes that contained PrPsc, Hsc 70, ubiquitin, proteasome subunits, vimentin and tubulin. Evidence for similar structures were found in the brains of prion-infected mice. PrPsc aggresome formation was directly associated with activation of caspase 3 and 8 resulting in apoptosis. These data suggest that neuronal propagation of prions invokes a neurotoxic mechanism involving intracellular formation of PrPsc aggresomes. This in turn triggers caspase-dependent apoptosis, and further implicates proteasome dysfunction in the pathogenesis of prion diseases.
AD Mark Kristiansen, Marcus Messenger, Peter Kloehn, Sebastian Brandner, Jonathon Wadsworth, John Collinge, Sarah J. Tabrizi, MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG
SP englisch
PO Deutschland