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First published online 19 February 2008
doi: 10.1242/jcs.021816

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LRP1 controls biosynthetic and endocytic trafficking of neuronal prion protein

Celia J. Parkyn¹, Esmeralda G. M. Vermeulen¹, Roy C. Mootoosamy¹, Claire Sunyach^1,*, Christian Jacobsen², Claus Oxvig², Søren Moestrup², Qiang Liu³, Guojun Bu³, Angela Jen¹ and Roger J. Morris^1,

¹ King's College London, Wolfson Centre for Age Related Disease, Guy's Campus, London SE1 1UL, UK
² Department of Medical Biochemistry, University of Aarhus, DK-8000 Aarhus C, Denmark
³ Department of Pediatrics, Washington University School of Medicine, St Louis Children's Hospital, St Louis MO 63110, USA

Author for correspondence (e-mail: roger.morris{at}kcl.ac.uk)

Accepted 19 December 2007

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 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 PrP^C in neurons.

Key words: Biosynthesis, Endocytosis, Endoplasmic reticulum, Golgi, LRP, Prion protein

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