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J. Biol. Chem., Vol. 280, Issue 1, 317-325, January 7, 2005
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¶
From the
Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio 43210 and the Institute of Pathology and Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44120
PrP, a cell surface-localized N-linked glycoprotein, is required for the pathogenesis of prion diseases. Recent studies have revealed that prion protein (PrP) becomes neurotoxic and prone to aggregation when it is in the cytosol, suggesting that cytosolic PrP may play a role in the pathogenesis of prion disease. Retro-translocation of PrP from the endoplasmic reticulum to the cytosol for proteasome degradation offers a natural route for PrP to enter the cytosol, but whether PrP is subject to retrotranslocation is controversial. In this study, we investigated the metabolism of endogenous wild-type PrP in several cell lines and in primary mouse cortical neurons. Our results suggest that a portion of the endogenous wild-type PrP is retro-translocated to the cytosol and degraded by the proteasome. Moreover, we also found that calpain and other cytosolic proteases could degrade PrP in the cytosol when the proteasome activity is compromised. These results provide the foundation for the hypothesis that cytosolic PrP may be involved in the pathogenesis of prion disease.
Received for publication, September 15, 2004 , and in revised form, November 2, 2004.
* This work was supported by a grant from the Ellison Medical Foundation. 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.
¶ To whom correspondence should be addressed. Tel.: 614-688-0408; Fax: 614-292-4118; E-mail: ma.131{at}osu.edu.
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