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

Journal of Cell Science 121, 773-783 (2008)
Published by The Company of Biologists 2008
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Research Article

LRP1 controls biosynthetic and endocytic trafficking of neuronal prion protein

Celia J. Parkyn1, Esmeralda G. M. Vermeulen1, Roy C. Mootoosamy1, Claire Sunyach1,*, Christian Jacobsen2, Claus Oxvig2, Søren Moestrup2, Qiang Liu3, Guojun Bu3, Angela Jen1 and Roger J. Morris1,{ddagger}

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

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

Accepted 19 December 2007

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.

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




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