NR AOYY
AU Schneider,B.; Pietri,M.; Mutel,V.; Ermonval,M.; Mouillet-Richard,S.; Kellermann,O.
TI NADPH oxidase and Extracellular Regulated Kinases 1/2 are intracellular targets activated upon prion protein stimulation in neuronal and non-neuronal cells
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - BR-112
PT Konferenz-Poster
AB
TSE are fatal neurodegenerative diseases that involve misfolding of the cellular prion protein (PrPc) leading to the accumulation of protease-resistant insoluble deposits in the brain. PrPc is ubiquitously expressed, but its function still remains enigmatic. While PrPc knock-out mice fail to exhibit an obvious phenotype, they display an increased sensitivity to oxidative stress, suggesting that PrPc takes part to the cellular redox equilibrium.
To investigate the role of PrPc, we used the 1C11 inducible neuroectodermal cell line, that differentiates into serotonergic (1C115-HT) or noradrenergic (1C11NE) cells. Antibody-mediated ligation of PrPc allowed us to identify a caveolin-1-dependent coupling of PrPc to the Fyn tyrosine kinase, which is restricted to fully differentiated bioaminergic neurons. We thus assigned for the first time signaling properties to PrPc.
Based on this experimental approach, we sought to assess the functional link between PrPc and redox equilibrium. Antibody-mediated ligation of PrPc promoted a reactive oxygen species (ROS) production via the NADPH oxidase enzymic system. Strikingly, this activation was observed not only in 1C115-HT and 1C11NE cells but also in the 1C11 progenitor and T lymphocytes. These results thus argue for an ubiquitous function of PrPc in cell redox homeostasis.
The ROS generated upon PrPc stimulation were found to act as " second message " signal, controling the phosphorylation of Extracellular Regulated Kinases 1/2 (ERK 1/2). In 1C11 precursor cells and T lymphocytes, PrPc-dependent ROS totally governed ERK 1/2 activation, while in 1C115-HT and 1C11NE cells they partly contributed to ERK 1/2 phosphorylation. Furthermore, in 1C11-derived bioaminergic neurons, we reasserted the neuronal specificity of the PrPc-caveolin-Fyn complex since Fyn inhibition failed to induce both PrPc-dependent ROS production and ERK 1/2 activation. In view of the key role of ERKs as mediators of cell survival, our results strenghten the idea that PrPc signaling may participate to the survival of neurons and may also play a role in lymphoid cell homeostasis.
AD B. Schneider, M. Pietri, M. Ermonval, S. Mouillet-Richard, O. Kellermann, CNRS UPR 1983 Institut André Lwoff, France; V. Mutel, F. Hoffmann-La-Roche, Switzerland
SP englisch
PO Deutschland