NR ATFZ
AU Tatzelt,J.
TI Misfolding of PrP in the cytosol: mechanism of toxicity and the role of molecular chaperones
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Oral sessions ORAL-30
PT Konferenz-Vortrag
AB A hallmark of prion diseases is the conversion of the cellular prion protein PrPc into PrPsc, a misfolded and proteinase K-resistant isoform, which is the main component of infectious prions. In the majority of prion diseases neurodegeneration is tightly linked to the propagation of infectious prions. However, transgenic mouse models revealed that misfolding or mistargeting of PrPc can induce neuronal cell death in the absence of infectious prions. For example, Lindquist and coworkers showed that mice expressing a PrP mutant with a deleted N-terminal ER targeting signal (cytoPrP) acquired severe ataxia due to cerebellar degeneration and gliosis. So far, mutations within the N-terminal signal sequence of PrP, which could affect the efficiency of ER import, have not been identified in patients suffering from prion diseases. However, we found that mutations in the C-terminal globular domain can interfere with the import of PrP into the ER. As a consequence, Q160Stop and W145Stop, two pathogenic mutants linked to inherited prion diseases in humans, are partially mistargeted to the cytosol. We have now performed a mechanistic analysis and compared the cytotoxic effects of misfolded PrP present in different cellular compartments. In addition, we identified cellular proteins which interact with cytoPrP and could play a role in PrP-mediated cell death.
AD J.Tatzelt, Max-Planck-Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
SP englisch
PO Deutschland