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

doi:10.1242/jcs.021816

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 journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

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 language	English
Journal	Journal of Cell Science
ISSN	0021-9533
DOIs	https://doi.org/10.1242/jcs.021816
Publication status	Published - 2008

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10.1242/jcs.021816

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@article{e8354010e07d11dc9afb000ea68e967b,

title = "LRP1 controls biosynthetic and endocytic trafficking of neuronal prion protein.",

abstract = "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",

author = "Parkyn, {Celia J} and Vermeulen, {Esmeralda G M} and Mootoosamy, {Roy C} and Claire Sunyach and Christian Jacobsen and Claus Oxvig and S{\o}ren Moestrup and Qiang Liu and Guojun Bu and Angela Jen and Morris, {Roger J}",

year = "2008",

doi = "10.1242/jcs.021816",

language = "English",

journal = "Journal of Cell Science",

issn = "0021-9533",

publisher = "Company of Biologists Ltd",

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TY - JOUR

T1 - LRP1 controls biosynthetic and endocytic trafficking of neuronal prion protein.

AU - Parkyn, Celia J

AU - Vermeulen, Esmeralda G M

AU - Mootoosamy, Roy C

AU - Sunyach, Claire

AU - Jacobsen, Christian

AU - Oxvig, Claus

AU - Moestrup, Søren

AU - Liu, Qiang

AU - Bu, Guojun

AU - Jen, Angela

AU - Morris, Roger J

PY - 2008

Y1 - 2008

N2 - 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

AB - 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

U2 - 10.1242/jcs.021816

DO - 10.1242/jcs.021816

M3 - Journal article

C2 - 18285446

SN - 0021-9533

JO - Journal of Cell Science

JF - Journal of Cell Science

ER -