LRP1 controls biosynthetic and endocytic trafficking of neuronal prion protein

Celia J. Parkyn, Esmeralda G.M. Vermeulen, Roy C. Mootoosamy, Claire Sunyach, Christian Jacobsen, Claus Oxvig, Søren Moestrup, Qiang Liu, Guojun Bu, Angela Jen, Roger J. Morris

Research output: Contribution to journalArticlepeer-review

85 Scopus citations


The trafficking of normal cellular prion protein (PrPC) is believed to control its conversion to the altered conformation (designated PrPSc) associated with prion disease. Although anchored to the membrane by means of glycosylphosphatidylinositol (GPI), PrPC 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 PrPC during its endocytosis and is functionally required for this process. Moreover, sustained inhibition of LRP1 levels by siRNA leads to the accumulation of PrPC in biosynthetic compartments, with a concomitant lowering of surface PrPC, suggesting that LRP1 expedites the trafficking of PrPC to the neuronal surface. PrPC and LRP1 can be co-immunoprecipitated from the endoplasmic reticulum in normal neurons. The N-terminal domain of PrPC binds to purified human LRP1 with nanomolar affinity, even in the presence of 1 μM of the LRP-specific chaperone, receptor-associated protein (RAP). Taken together, these data argue that LRP1 controls both the surface, and biosynthetic, trafficking of PrPC in neurons.

Original languageEnglish (US)
Pages (from-to)773-783
Number of pages11
JournalJournal of cell science
Issue number6
StatePublished - Mar 15 2008


  • Biosynthesis
  • Endocytosis
  • Endoplasmic reticulum
  • Golgi
  • LRP
  • Prion protein

ASJC Scopus subject areas

  • Cell Biology


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