NR AHVY

AU Marella,M.; Lehmann,S.; Grassi,J.; Chabry,J.

TI Filipin prevents pathological prion protein accumulation by reducing endocytosis and inducing cellular PrP release

QU The Journal of Biological Chemistry 2002 Jul 12; 277(28): 25457-64

PT journal article

AB Conversion of the normal membrane-bound prion protein (PrP-sen) to its pathological isoform (PrPres) 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 PrPres 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.

MH Cell Line; Chlorpromazine/metabolism; Endocytosis/*physiology; Filipin/*metabolism; Human; Iodine Radioisotopes; Microglia/cytology/metabolism; Nystatin/pharmacology; Prions/*physiology; Subcellular Fractions/metabolism; Support, Non-U.S. Gov't

AD Institut de Pharmacologie Moleculaire et Cellulaire, Unite Mixte de Recherche 6097, Centre National de la Recherche Scientifique, 660 Route des Lucioles, 06560 Valbonne, France.

SP englisch

PO USA

EA pdf-Datei

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