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Originally published as MBC in Press, 10.1091/mbc.E06-01-0083 on May 17, 2006

Vol. 17, Issue 8, 3356-3368, August 2006

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Association of Bcl-2 with Misfolded Prion Protein Is Linked to the Toxic Potential of Cytosolic PrP

Angelika S. Rambold*, Margit Miesbauer*, Doron Rapaport{dagger}, Till Bartke{ddagger}, Michael Baier§, Konstanze F. Winklhofer*,||, and Jörg Tatzelt*,||

*Department of Biochemistry, Neurobiochemistry, Ludwig-Maximilians-Universität München, D-80336 München, Germany; {dagger}Institut für Physiologische Chemie, Ludwig-Maximilians-Universität München, D-81377 München, Germany; {ddagger}Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and §Robert-Koch-Institut, D-13353 Berlin, Germany

Submitted January 27, 2006; Revised April 17, 2006; Accepted May 10, 2006
Monitoring Editor: Jonathan Weissman

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 did the accumulation of misfolded PrP induce apoptosis. Apoptotic cell death was also induced by two pathogenic mutants of PrP, which are partially localized in the cytosol. A mechanistic analysis revealed that the toxic potential is linked to an internal domain of PrP (amino acids 115–156) and involves coaggregation of cytosolic PrP with Bcl-2. Increased expression of the chaperones Hsp70 and Hsp40 prevented the formation of PrP/Bcl-2 coaggregates and interfered with PrP-induced apoptosis. Our study reveals a compartment-specific toxicity of PrP misfolding that involves coaggregation of Bcl-2 and indicates a protective role of molecular chaperones.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-01-0083) on May 17, 2006.

|| These authors contributed equally to this work.

Address correspondence to: Jörg Tatzelt ( Joerg.Tatzelt{at}med.uni-muenchen.de)




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