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  • The EMBO Journal (2001) 20, 3957 - 3966
  • doi:10.1093/emboj/20.15.3957

Intracellular re-routing of prion protein prevents propagation of PrPSc and delays onset of prion disease

Sabine Gilch1, Konstanze F. Winklhofer2, Martin H. Groschup3, Max Nunziante1, Ralf Lucassen4, Christian Spielhaupter1, Walter Muranyi1, Detlev Riesner4, Jörg Tatzelt2,5 and Hermann M. Schätzl1,5

  1. Gene Center Munich, Max von Pettenkofer-Institute for Virology, Ludwig-Maximilians-University of Munich, Feodor-Lynen-Strasse 25, D-81377 Munich, Germany
  2. Max Planck-Institute for Biochemistry, Department of Cellular Biochemistry, Am Klopferspitz 18a, D-82152 Martinsried, Germany
  3. Federal Research Center for Virus Diseases of Animals, D-72001 Tübingen, Germany
  4. Institute of Physical Biology, University of Düsseldorf, D-40225 Düsseldorf, Germany
  5. J.Tatzelt and H.M.Schätzl should be considered the senior authors of this work.

Correspondence to:

Hermann M. Schätzl, E-mail: schaetzl@lmb.uni-muenchen.de

Received 9 April 2001; Accepted 15 June 2001; Revised 7 June 2001

Prion diseases are fatal and transmissible neurodegenerative disorders linked to an aberrant conformation of the cellular prion protein (PrPc). We show that the chemical compound Suramin induced aggregation of PrP in a post-ER/Golgi compartment and prevented further trafficking of PrPc to the outer leaflet of the plasma membrane. Instead, misfolded PrP was efficiently re-routed to acidic compartments for intracellular degradation. In contrast to PrPSc in prion-infected cells, PrP aggregates formed in the presence of Suramin did not accumulate, were entirely sensitive to proteolytic digestion, had distinct biophysical properties, and were not infectious. The prophylactic potential of Suramin-induced intracellular re-routing was tested in mice. After intraperitoneal infection with scrapie prions, peripheral application of Suramin around the time of inoculation significantly delayed onset of prion disease. Our data reveal a novel quality control mechanism for misfolded PrP isoforms and introduce a new molecular mechanism for anti-prion compounds.

  • Keywords:

    • aggregation,
    • prion protein,
    • quality control,
    • re-routing,
    • Suramin