NR ATHG
AU Schneider,B.; Pietri,M.; Mouillet-Richard,S.; Caprini,A.; Ermonval,M.; Grassi,J.; Kellermann,O.
TI Overstimulation of cellular prion protein-associated signaling pathways by prion peptide 106-126 causes apoptosis of bioaminergic 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-12
PT Konferenz-Poster
AB
Elucidating the molecular and cellular bases of prion-induced neuropathogenesis is great challenge in the TSE field. Increasing evidence support the notion that alterations of cellular prion protein (PrPc) normal function as a result of pathogenic prion (PrPSC) accumulation within a neuronal context may contribute to the deleterious events that lead to neurodegeneration.
Using the 1C11 cell line, endowed with the capacity to differentiate into serotonergic (1C115-HT) or noradrenergic (1C11NE) neurons, we have shown that PrPc responds to antibody-mediated ligation by instructing downstream signal transduction events, including Reactive Oxygen Species (ROS) production through NADPH oxidase recruitment and activation of Extracellular Regulated Kinases 1/2. In 1C11-derived neuronal cells, PrPc fulfils some neuronal-specific function that is sustained by its association with the membrane protein caveolin and the Fyn tyrosine kinase. Our initial studies allowed us to propose that PrPc may take part to the control of the redox equilibrium and cell homeostasis.
The biochemical link between PrPc and intracellular ROS raises the possibility that pathogenic prions might promote oxidative stress conditions through deviation of PrPc-associated signaling function. To challenge this idea, 1C11 neuroepithelial cells and their neuronal progenies were exposed to the amyloidogenic prion peptide 106-126, PrP-(106-126). We establish that PrP-(106-126) induces caspase-dependent apoptosis of 1C115-HT and 1C11NE neuronal cells, while having no effect in 1C11 precursor cells. The neurotoxic effect of PrP-(106-126) relies on the recruitment of PrPc-Cav-Fyn signaling platform, and the overstimulation of NADPH-oxidase activity. ROS accumulation causes oxidative stress conditions, which provoke ERK1/2 long-lasting phosphorylation and recruitment of stress-activated kinase cascades. These data provide evidence that PrP-(106-126)-mediated neuronal death relates to an amplification of PrPc-associated signaling.
AD B.Schneider, M.Pietri, S.Mouillet-Richard, A.Caprini, M.Ermonval, O.Kellermann, CNRS and Institut Pasteur, France; J.Grassi, CEA, France
SP englisch
PO Deutschland