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J. Biol. Chem., Vol. 277, Issue 28, 25457-25464, July 12, 2002

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Filipin Prevents Pathological Prion Protein Accumulation by Reducing Endocytosis and Inducing Cellular PrP Release^*

Mathieu Marella, Sylvain Lehmann^§, Jacques Grassi^¶, and Joëlle Chabry

From the  Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 6097, Centre National de la Recherche Scientifique, 660 Route des Lucioles, 06560 Valbonne, France, the ^§ Institut de Génétique Humaine, Centre National de la Recherche Scientifique, 34396 Montpellier, France, and the ^¶ Service de Pharmacologie et d'Immunologie, Commisariat à l'Energie Atomique, 91191 Gif-sur-Yvette, cedex, France

Conversion of the normal membrane-bound prion protein (PrP-sen) to its pathological isoform (PrP-res) is a key event in the pathogenesis of transmissible spongiform encephalopathies. Although the subcellular sites of conversion are poorly characterized, several lines of evidence have suggested the involvement of membrane lipid rafts in the conversion process. Here we report that copper stimulates the endocytosis of PrP-sen via a caveolin-dependent pathway in both microglia and neuroblastoma cells. We show that the polyene antibiotic filipin both limits endocytosis of PrP-sen and dramatically reduces the amount of membrane-bound PrP-sen. This reduction results from a rapid and massive release of full matured PrP-sen into the culture medium. Finally, we demonstrate that filipin is a potent inhibitor of PrP-res formation into chronically infected neuroblastoma cells. Our results reinforce the role of rafts in PrP trafficking and raise the possibility that the release of PrP-sen from the plasma membrane decreases the amount of available substrate PrP-sen at the conversion sites.

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