Claus Oxvig

LRP1 controls biosynthetic and endocytic trafficking of neuronal prion protein.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Celia J Parkyn, Denmark
  • Esmeralda G M Vermeulen, Denmark
  • Roy C Mootoosamy, Denmark
  • Claire Sunyach, Denmark
  • Christian Jacobsen, Denmark
  • Claus Oxvig
  • Søren Moestrup
  • Qiang Liu, Denmark
  • Guojun Bu, Denmark
  • Angela Jen, Denmark
  • Roger J Morris, Denmark
  • Department of Medical Biochemistry
  • Department of Molecular Biology
The trafficking of normal cellular prion protein (PrP(C)) is believed to control its conversion to the altered conformation (designated PrP(Sc)) associated with prion disease. Although anchored to the membrane by means of glycosylphosphatidylinositol (GPI), PrP(C) on neurons is rapidly and constitutively endocytosed by means of coated pits, a property dependent upon basic amino acids at its N-terminus. Here, we show that low-density lipoprotein receptor-related protein 1 (LRP1), which binds to multiple ligands through basic motifs, associates with PrP(C) during its endocytosis and is functionally required for this process. Moreover, sustained inhibition of LRP1 levels by siRNA leads to the accumulation of PrP(C) in biosynthetic compartments, with a concomitant lowering of surface PrP(C), suggesting that LRP1 expedites the trafficking of PrP(C) to the neuronal surface. PrP(C) and LRP1 can be co-immunoprecipitated from the endoplasmic reticulum in normal neurons. The N-terminal domain of PrP(C) binds to purified human LRP1 with nanomolar affinity, even in the presence of 1 microM of the LRP-specific chaperone, receptor-associated protein (RAP). Taken together, these data argue that LRP1 controls both the surface, and biosynthetic, trafficking of PrP(C) in neurons.
Udgivelsesdato: 2008-Feb-19
Original languageEnglish
JournalJournal of Cell Science
ISSN0021-9533
DOIs
Publication statusPublished - 2008

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