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J. Biol. Chem., Vol. 282, Issue 17, 12725-12733, April 27, 2007

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Perturbation of Endoplasmic Reticulum Homeostasis Facilitates Prion Replication^*

Claudio Hetz¹, Joaquín Castilla, and Claudio Soto²

From the Department of Neurology, University of Texas Medical Branch, Galveston, Texas 77555 and the Institute of Biomedical Science, Fondo de Areas Prioritarias Center for Molecular Studies of the Cell, University of Chile, Independencia 1027, P. O. Box 70086, Santiago, Chile

Prion diseases are fatal and infectious neurodegenerative disorders characterized by the accumulation of an abnormally folded form of the prion protein (PrP), termed PrP^Sc. Prion replication triggers endoplasmic reticulum (ER) stress, neuronal dysfunction, and apoptosis. In this study we analyze the effect of perturbations in ER homeostasis on PrP biochemical properties and prion replication. ER stress led to the generation of a mis-folded PrP isoform, which is detergent-insoluble and protease-sensitive. To understand the mechanism by which ER stress generates PrP misfolding, we assessed the contribution of different signaling pathways implicated in the unfolded protein response. Expression of a dominant negative form of IRE1 or XBP-1 significantly increased PrP aggregation, whereas overexpression of ATF4 or an active mutant form of XBP-1 and ATF6 had the opposite affect. Analysis of prion replication in vitro revealed that the PrP isoform generated after ER stress is more efficiently converted into PrP^Sc compared with the protein extracted from untreated cells. These findings indicate that ER-damaged cells might be more susceptible to prion replication. Because PrP^Sc induces ER stress, our data point to a vicious cycle accelerating prion replication, which may explain the rapid progression of the disease.

Received for publication, December 29, 2006 , and in revised form, February 27, 2007.

^* This work was supported by National Institutes of Health Grants NS049173 and NS050349 (to C. S.), the Fondo Nacional de Ciencia y Desarrollo (FONDECYT) (Grant 1070444 to C. H.), the Fondo de Areas Prioritarias (FONDAP) (Grant 15010006 to C. H.), and a Post Doctoral Fellowship from Damon Runyon Cancer Research Foundation (to C. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Program of Cellular and Molecular Biology, Inst. of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Independencia 1027, P. O. Box 70086, Santiago, Chile. Tel.: 56-2-9786849; Fax: 56-2-9786871; E-mail: chetz{at}med.uchile.cl. ² To whom correspondence may be addressed: Dept. of Neurology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555. Tel.: 409-747-0017; Fax: 409-747-0020; E-mail: clsoto{at}utmb.edu.

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