NR AUSD
AU Rambold,A.S.; Miesbauer,M.; Rapaport,D.; Bartke,T.; Baier,M.; Winklhofer,K.F.; Tatzelt,J.
TI Recruitment of Bcl-2 to misfolded prion protein is linked to the toxic potential of cytosolic PrP
QU TSE-Forum, 6. Kongress - Nationale TSE-Forschungsplattform, Greifswald 26.6.-28.6.2006, Poster: Pathogenese/Infektion PATH-04
PT Konferenz-Poster
AB Protein misfolding is linked to different neurodegenerative disorders like Alzheimer's disease, polyglutamine and prion diseases. We investigated the cytotoxic effects of aberrant conformers of the prion protein (PrP) and show that toxicity is specifically linked to misfolding of PrP in the cytosolic compartment and involves binding of PrP to the anti-apoptotic protein Bcl-2. PrP targeted to different cellular compartments, including the cytosol, nucleus, and mitochondria, adopted a misfolded and partially proteinase K-resistant conformation. However, only in the cytosol the accumulation of misfolded PrP induced apoptosis. Apoptotic cell death was also induced by two pathogenic mutants of PrP, which are partially mistargeted to the cytosol due to an impaired import into the endoplasmic reticulum. A mechanistic analysis revealed that the toxic potential is linked to an internal domain of PrP and involves co-aggregation of cytosolic PrP with Bcl-2. Increased expression of the chaperones Hsp70 and Hsp40 prevented the formation of PrP/Bcl-2 co-aggregates and interfered with PrP-induced apoptosis. Our study reveals a compartment-specific toxicity of PrP misfolding which involves co-aggregation of Bcl-2 and indicates a protective role of molecular chaperones.
AD Angelika S. Rambold, Margit Miesbauer, Konstanze F. Winklhofer, Jörg Tatzelt, Ludwig-Maximilians-University, Department of Biochemistry, Neurobiochemistry; Doron Rapaport, Institute for Physiological Chemistry, Munich, Germany; Till Bartke, University of Cambridge, UK; Michael Baier, Robert-Koch-Institut, Berlin, Germany
SP englisch
PO Deutschland
OR Tagungsband