LRP1 controls biosynthetic and endocytic trafficking of neuronal prion protein.
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 muM 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.
Parkyn
Celia J
CJ
King's College London, Wolfson Centre for Age Related Disease, Guy's Campus, London SE1 1UL, UK.
Vermeulen
Esmeralda G M
EG
Mootoosamy
Roy C
RC
Sunyach
Claire
C
Jacobsen
Christian
C
Oxvig
Claus
C
Moestrup
Søren
S
Liu
Qiang
Q
Bu
Guojun
G
Jen
Angela
A
Morris
Roger J
RJ
D000818:Animals; D002462:Cell Membrane / Q000737:chemistry; D004705:Endocytosis / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D018832:Molecular Chaperones / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D009475:Neurons, Afferent / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D018621:PrPC Proteins / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D018832:Molecular Chaperones; D018621:PrPC Proteins