NR AOZR
AU Tatzelt,J.; Heller,U.; Heske,J.; Winklhofer,K.F.
TI Misfolding of the prion protein in the cytosol and in the endoplasmic reticulum
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Oral sessions OS-10
PT Konferenz-Vortrag
AB
Prion diseases in humans and animals are characterized by the accumulation of PrPsc, a partially protease-resistant isoform of the cellular prion protein PrPc. Studies in transgenic animals revealed that PrP aggregates in the cytosol, or aberrant transmembrane topologies in the endoplasmic reticulum (ER) can induce neurodegeneration in the absence of PrPsc. We are using yeast and neuronal cells to study the mechanism of PrP folding and the formation of pathogenic conformations in vivo. We specifically investigate folding events during and shortly after import into the ER and showed that the putative transmembrane domain can induce misfolding of PrP during post-translational targeting to the ER. As a consequence, misfolded PrP molecules with uncleaved signal peptides associate with the ER membrane and interfere with cell viability. After import into the ER the putative TM domain is dispensable for maturation of PrPc, however, deletion or destabilization of helix 1 interferes with the complex glycosylation and glycosylphosphatidylinositol (GPI) anchor attachment. These misfolded PrP mutants are not subjected to retrograde transport and subsequent proteasomal degradation in the cytosol, but are transported through the secretory pathway and secreted.
(This work was supported by grants from the Deutsche Forschungsgemeinschaft, and the Bavarian Government)
References:
Winklhofer et al. (2003). J. Biol. Chem., 278, 14961-14970.
Winklhofer et al. (2003) Traffic, 4, 313-322.
Heller et al. (2003) J. Biol. Chem., Jul 8
AD Jörg Tatzelt, Ulrich Heller, Johanna Heske, Konstanze F. Winklhofer, Max-Planck-Institute for Biochemistry, Germany
SP englisch
PO Deutschland