NR ARDC
AU Kiachopoulos,S.; Rambold,A.S.; Heske,J.; Winklhofer,K.F.; Tatzelt,J.
TI Mistargeting of the prion protein to the cytosol; mechanism and pathophysiological consequences
QU TSE-Forum, 4. Kongress - Nationale TSE-Forschungsplattform, Düsseldorf 28.10.-29.10.2004, Vortrag V-19
PT Konferenz-Vortrag
AB
Structural studies with recombinantly expressed PrP revealed a large flexibly disordered N-terminal region and a structured C-terminal globular domain. A crucial step in the biogenesis of PrPc is its import into the endoplasmic reticulum (ER). Aberrant regulation at this step can lead to the formation of a transmembrane topology like CtmPrP, or, in the case of unproductive import, to the generation of cytosolic PrP. Both PrP species have been described to induce neurodegeneration in transgenic mice in the absence of PrPsc: A possible pathogenic role of misfolded PrP conformers at or in the ER membrane was emphasized by a study from our group using a yeast model. We could show that PrP misfolding occurred during post-translational targeting to the ER membrane and interfered with cell growth (Heller et al., 2003). Recently, we have examined the import of PrP into the (ER) of neuronal cells and showed that information present in the C-terminal globular domain is required for ER import of the N-terminus (Heske et al., 2004). As a consequence, two PrP mutants linked to inherited prion disease in humans, PrP-W145Stop and PrP-Q160Stop, were partially retained in the cytosol. The cytosolic fraction was characterized by an uncleaved N-terminal signal peptide and was degraded by the proteasome. We have now determined the elements required for a productive import of PrPc into the ER and are analyzing the cytotoxic potential of misfolded PrP.
References:
Heller, U., Winklhofer, K.F., Heske, J., Reintjes, A. and Tatzelt, J. (2003). J Biol Chem, 278, 36139-36147.
Heske, J., Heller, U., Winklhofer, K.F. and Tatzelt, J. (2004). J Biol Chem, 279, 5435-5443.
AD Sophia Kiachopoulos, Angelika Rambold, Johanna Heske, Konstanze F. Winklhofer and Jörg Tatzelt, Max-Planck-Institut für Biochemie, Am Klopferspitz 18, 82152 Martinsried
SP englisch
PO Deutschland
OR Tagungsband