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J. Biol. Chem., Vol. 282, Issue 31, 22747-22756, August 3, 2007

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Characterization of the Properties and Trafficking of an Anchorless Form of the Prion Protein^*

Vincenza Campana, Anna Caputo, Daniela Sarnataro, Simona Paladino^¶, Simona Tivodar, and Chiara Zurzolo¹

From the Unité de Trafic Membranaire et Pathogénèse, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France and Dipartimento di Biologia e Patologia Cellulare e Molecolare and ^¶Centro di Eccellenza di Ingegneria Genetica, Centro di Biotecnologie Avanzate, Università degli Studi di Napoli "Federico II," via Pansini 5, 80131 Napoli, Italy

Conversion of PrP^C into PrP^Sc is the central event in the pathogenesis of transmissible prion diseases. Although the molecular basis of this event and the intracellular compartment where it occurs are not yet understood, the association of PrP with cellular membranes and in particular its presence in detergent-resistant microdomains appears to be of critical importance. In addition it appears that scrapie conversion requires membrane-bound glycosylphosphatidylinositol (GPI)-linked PrP. The GPI anchor may affect either the conformation, the intracellular localization, or the association of the prion protein with specific membrane domains. However, how this occurs is not known. To understand the relevance of the GPI anchor for the cellular behavior of PrP, we have studied the biosynthesis and localization of a PrP version which lacks the GPI anchor attachment signal (PrPGPI). We found that PrPGPI is tethered to cell membranes and associates to membrane detergent-resistant microdomains but does not assume a transmembrane topology. Differently to PrP^C, this protein does not localize at the cell surface but is mainly released in the culture media in a fully glycosylated soluble form. The cellular behavior of anchorless PrP explains why PrPGPI Tg mice can be infected but do not show the classical signs of the disorder, thus indicating that the plasma membrane localization of PrP^C and/or of the converted scrapie form might be necessary for the development of a symptomatic disease.

Received for publication, February 20, 2007 , and in revised form, June 6, 2007.

^* This work was supported by grants from Ministero dell'Università e della Ricerca Scientifica e Tecnologica (FIRB 2003, PRIN 2006), the Telethon Foundation (GGP0414), European Union (FP6 LSHBCT 2006-019090), and Agence Nationale de la Recherche (NT-05-4 41767) (to C. Z.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed. Tel.: 33-01-45688277; Fax: 33-01-40613238; E-mail: zurzolo{at}pasteur.fr (Institut Pasteur) or Tel.: 39-081-7463237; Fax: 39-081-7701016; E-mail: zurzolo{at}unina.it (Università degli Studi di Napoli "Federico II").

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