NR AUQZ
AU Montrasio,F.
TI The cellular prion protein: its role in neuronal differentiation and neurotoxicity
QU TSE-Forum, 6. Kongress - Nationale TSE-Forschungsplattform, Greifswald 26.6.-28.6.2006, Vortrag V-18
PT Konferenz-Vortrag
AB
The cellular prion protein (PrPc) is a glycosylphosphatidylinositol-anchored cell-surface protein whose biological function is largely unknown. In order to develop in vitro models for studying prion protein-dependent pathways, we have first generated a novel PrP knockout cell line called PrP0/0 ML, which does express neither the prion protein nor doppel. Here we show that the PrP0/0 ML cell line is a unipotent neuronal precursor line which can specifically differentiate into mature neurons when cultivated under specific culture conditions and that PrPc expression induces neuronal differentiation. Furthermore we show that the N-terminal domain containing the octapeptide repeat region of the prion protein is not necessary for the activation of the neuronal differentiation pathway.
PrPc plays a fundamental role in the pathogenesis of transmissible spongiform encephalopathies, a group of fatal neurodegenerative disorders. However, the processes leading to neuronal degeneration in the central nervous system upon prion infections are still not identified. In the recent past, it has been proposed that neuronal death might be triggered by accumulation of PrP in the cytosol. In order to elucidate the molecular mechanisms leading to cytotoxic effects of cytosolic PrP, we used transiently transfected Neuro-2a cell lines conditionally expressing either wild-type or cytosolic PrP. In contrast to previously reported data, here we show that cytosolic PrP expression per se is not sufficient to trigger cytotoxicity in N2a cells independently of proteasome inhibition. Interestingly, cytosolic PrP accumulates in fine foci when expressed at high levels and colocalises with the cytosolic chaperone Hsc70 in EEA-1 positive endocytic vesicles. We therefore propose that the chaperone Hsc70 acts as a regulator for the controlled formation of amorphous cytosolic PrP aggregates and their transport to endosomal/lysosomal vesicles. This Hsc70-dependent mechanism may confer protection to N2a cells against cytoplasmatic toxic accumulation of Cy-PrP.
AD Montrasio,F., Prion Research Group, Paul-Ehrlich-Institut, Langen, Germany
SP englisch
PO Deutschland
OR Tagungsband