Abstract
Prion diseases result from conformational alteration of PrPC, a cell surface glycoprotein expressed in brain, spinal cord, and several peripheral tissues, into PrPSc, a protease-resistant isoform that is the principal component of infectious prion particles. Although a great deal is known about the pathogenic role of PrPSc, the physiological function of PrPC has remained a mystery. Several lines of evidence have recently suggested the possibility that PrPC may play a role in the metabolism of copper. To further investigate the interaction of PrPC and copper, we have analyzed the effect of this metal ion on the endocytic trafficking of PrPC in cultured neuroblastoma cells. We report here that copper rapidly and reversibly stimulates endocytosis of PrPC from the cell surface. This effect may be physiologically relevant and suggests the hypothesis that PrPC could serve as a recycling receptor for uptake of copper ions from the extracellular milieu.
Highlights
Prion diseases are neurodegenerative disorders that result from conformational conversion of a normal cell surface glycoprotein (PrPC)1 into a pathogenic isoform (PrPSc) that appears to be infectious in the absence of nucleic acid [1, 2]
We found that at concentrations of 200 M and above, CuSO4 dramatically reduced the amounts of both mouse PrP (moPrP) and chicken PrP (chPrP) on the cell surface (Fig. 1)
Our previous studies have shown that PrPC is constitutively endocytosed from the cell surface via clathrin-coated pits and passes through an early endocytic compartment before being returned to the plasma membrane [29, 25,26,27]
Summary
PrPC, cellular isoform of the prion protein; PrPSc, scrapie isoform of the prion protein; PrP, prion protein; chPrP, chicken prion protein; moPrP, mouse prion protein; PAGE, polyacrylamide gel electrophoresis; PIPLC, phosphatidylinositol-specific phospholipase C; SOD, superoxide dismutase. The total content of copper but not of several other metals is only 20% of normal in crude membranes, synaptosomes, and endosomes derived from the brains of Prn-p0/0 mice that contain a disrupted PrP gene [18]. This result suggests that PrPC may be a major copper-binding protein in brain. Neurons cultured from Prn-p0/0 mice are more sensitive to oxidative insult, perhaps because of reduced SOD activity [21] These observations raise the possibility that PrPC could be involved in delivery of copper ions to SOD and perhaps other cuproenzymes. We report here that copper has a dramatic effect on this cycle
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
