LRP1 controls biosynthetic and endocytic trafficking of neuronal prion protein

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.