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

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2006 May 19

PMID 16707568

Citations 42

Authors

Angelika S Rambold

Margit Miesbauer

Doron Rapaport

Till Bartke

Michael Baier

Konstanze F Winklhofer

Jorg Tatzelt

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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