Copper Stimulates Endocytosis of the Prion Protein

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 PrPCmay 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. 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 PrPCmay 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. Prion diseases are neurodegenerative disorders that result from conformational conversion of a normal cell surface glycoprotein (PrPC) 1The abbreviations used are: 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. 1The abbreviations used are: 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. into a pathogenic isoform (PrPSc) that appears to be infectious in the absence of nucleic acid (1Prusiner S.B. Science. 1997; 278: 245-251Crossref PubMed Scopus (852) Google Scholar, 2Prusiner S.B. Scott M.R. DeArmond S.J. Cohen F.E. Cell. 1998; 93: 337-348Abstract Full Text Full Text PDF PubMed Scopus (819) Google Scholar). Although a wealth of information is now available about the role of PrPSc in the disease process, relatively little is known about the normal, physiological function of PrPC. PrPC is expressed in neurons and glia of the brain and spinal cord and at lower levels in several peripheral tissues and in leukocytes (3Bendheim P.E. Brown H.R. Rudelli R.D. Scala L.J. Goller N.L. Wen G.Y. Kascsak R.J. Cashman N.R. Bolton D.C. Neurology. 1992; 42: 149-156Crossref PubMed Google Scholar, 4Manson J. West J.D. Thomson V. McBride P. Kaufman M.H. Hope J. Development. 1992; 115: 117-122PubMed Google Scholar, 5Harris D.A. Lele P. Snider W.D. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4309-4313Crossref PubMed Scopus (74) Google Scholar, 6Moser M. Colello R.J. Pott U. Oesch B. Neuron. 1995; 14: 509-517Abstract Full Text PDF PubMed Scopus (271) Google Scholar, 7Dodelet V.C. Cashman N.R. Blood. 1998; 91: 1556-1561Crossref PubMed Google Scholar). Its localization on the cell surface would be consistent with roles in cell adhesion and recognition, ligand uptake, or transmembrane signaling. Mice in which the endogenous PrP gene has been ablated do not display any gross anatomical or developmental defects (8Büeler H. Fischer M. Lang Y. Fluethmann H. Lipp H.-P. DeArmond S.J. Prusiner S.B. Aguet M. Weissmann C. Nature. 1992; 356: 577-582Crossref PubMed Scopus (1432) Google Scholar) but are reported in some studies to have electrophysiological and structural abnormalities in the hippocampus (9Collinge J. Whittington M.A. Sidle K.C. Smith C.J. Palmer M.S. Clarke A.R. Jefferys J.G. Nature. 1994; 370: 295-297Crossref PubMed Scopus (686) Google Scholar, 10Manson J.C. Hope J. Clarke A.R. Johnston A. Black C. MacLeod N. Neurodegen. 1995; 4: 113-114Crossref PubMed Google Scholar, S.B. J. Jefferys PubMed Scopus Google Scholar, S.B. M. J. Jefferys 1997; PubMed Scopus Google of S. S. N. A. Y. S. H. S. Nature. PubMed Scopus Google or in and P. Fischer M. M. Oesch B. McBride J.C. Nature. PubMed Scopus Google Scholar). to the normal function of PrPC is the function of PrPC may be in the of prion of this function as a result of conversion to PrPSc may some of the of that PrPC may play a role in the metabolism of copper. the of PrPC a of and that are of copper or PrP the copper with a of and of the metal conformational in the 1995; PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar, A. H. PubMed Scopus Google Scholar, A. J. P.E. A. A. H. Nature. 1997; PubMed Scopus Google Scholar, J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar). of and of PrPSc J. J. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the of copper but not of several is of normal in and from the that a PrP gene A. J. P.E. A. A. H. Nature. 1997; PubMed Scopus Google Scholar). This result suggests that PrPC may be a in superoxide from is and copper the from normal the is for from that PrPC B. 1997; PubMed Scopus Google Scholar, A. J. 1998; PubMed Scopus Google Scholar). cultured are to of B. 1997; PubMed Scopus Google Scholar). the possibility that PrPC could be in of copper ions to and for to copper have of PrPC, a role for the in or of copper B. J. 1998; PubMed Scopus Google copper and PrPC are is at possibility is that copper as for as of PrPC, as in as and of Google Scholar). of on the cell PrPC could function as a for of extracellular copper ions or as a for uptake and of copper ions to of information that may on the interaction of PrPC and copper is the metal the cellular localization and trafficking of PrPC. We have that PrPC is from the and to the cell surface D.A. J. 1993; Full Text PDF PubMed Google Scholar, D.A. J. 1994; PubMed Scopus Google Scholar, A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, D.A. A. S. Google Scholar). We report here that copper has a effect on this have the cellular trafficking of PrPC lines of mouse neuroblastoma that have been to or D.A. P. 1993; PubMed Scopus Google Scholar, D.A. J. 1993; Full Text PDF PubMed Google Scholar, D.A. J. 1994; PubMed Scopus Google Scholar, A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). We used to the of copper on the cellular of PrPC. To copper the of PrPC on the cell we for with and with a of PrP PrP from cell the on and of the gel with and We that at of and the of and on the cell surface the of surface PrP to not PrPC in is from the D.A. J. 1993; Full Text PDF PubMed Google Scholar, D.A. J. 1994; PubMed Scopus Google we the effect of copper on the of surface PrPC could be a effect on To we at to to and the of PrP that to phosphatidylinositol-specific phospholipase a that the for PrP to the this we that rapidly of and and in PrP could be as little as of and of the with in cells. of endocytosis could be to surface PrP this the of to in and this endocytosis of chPrP, but effect with or at effect of copper on PrP not to a in endocytosis of surface not of stimulates endocytosis of at and to for the of in the or absence of with at and from the and cell and analyzed and the of PrP of the gel and the of PrP expressed as a of the of PrP at of in absence of copper is in in D.A. J. 1993; Full Text PDF PubMed Google of in the of the at and to for in the of the of with at and from the and cell and of gel with and the of PrP of the gel in and the of PrP expressed as a of the of PrP at copper in this are of at that the effect of copper rapidly of of the PrP to from the to the of the as to and a at which about of the about the that is endocytosis in the absence of copper D.A. J. 1993; Full Text PDF PubMed Google Scholar). This of the is to the of PrPC to to surface of are D.A. J. 1993; Full Text PDF PubMed Google Scholar). To this recycling process, we for at in the of to of PrP and surface PrP with at and the in the of to into the this we that copper from the of the PrP to the surface with a of consistent with the of B. copper in the PrP to the in the absence of metal This result that copper stimulates the of PrP has effect on the of studies have the of and chicken PrP in copper 1995; PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar, A. J. P.E. A. A. H. Nature. 1997; PubMed Scopus Google Scholar, J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar). We have that this of the is for endocytosis of PrP A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). We the effect of copper on endocytosis of of a surface D.A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). of the of the the effect of copper, the some the of the of the or the but not of PrP, that the copper of are in to of and of expressed in surface as in the to C. of PrP at in to expressed as a of the of PrP the of to studies have that PrPC is from the cell surface and endocytic to the D.A. P. 1993; PubMed Scopus Google Scholar, D.A. J. 1993; Full Text PDF PubMed Google Scholar, D.A. J. 1994; PubMed Scopus Google Scholar, A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). We here that copper ions rapidly and reversibly the endocytic of this is to that this effect is to of copper ions to PrPC, of PrP have been to copper the 1995; PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar, A. J. P.E. A. A. H. Nature. 1997; PubMed Scopus Google Scholar, J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar). to PrPC, copper N. Prusiner S.B. Sci. 1992; PubMed Scopus Google Scholar). with a effect of copper on the of PrPC, we that of that are some or of the are the in to extracellular copper. hypothesis to of copper could endocytosis of PrPC is that the the of PrPC, the of the for a endocytic receptor that PrPC in PrPC is to the cell surface a a that could to the of We have the of a transmembrane receptor extracellular PrPC and for with and A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, D.A. A. S. Google of PrPC copper in the of which is the for of copper to PrP and PrP in 1995; PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar, A. J. P.E. A. A. H. Nature. 1997; PubMed Scopus Google Scholar, J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar). This may be in to of copper ions to as that are in the used for a that would lower the of copper. is that the effect of copper on endocytosis to on PrPC that are from the on or PrP or to on in any the copper in brain has been to be and may be in brain J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar, Smith of the Scholar). the endocytic we have here is relevant from a physiological hypothesis is that PrPC as a receptor for uptake of copper ions from the extracellular milieu. PrPC copper ions on the cell surface and to endocytic which the ions from PrPC and are to that the ions into the PrPC would to the cell surface to This function for PrPC is to that of the receptor in uptake of A. A. J. Full Text PDF PubMed Google with the that the metal ions to the receptor in the of PrPC to a with Although copper and copper have been in and Science. 1997; 278: PubMed Scopus Google the of copper uptake is S. 1995; PubMed Scopus Google Scholar). of the interaction PrPC and copper ions at the cellular may on this Prion diseases are neurodegenerative disorders that result from conformational conversion of a normal cell surface glycoprotein (PrPC) 1The abbreviations used are: 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. 1The abbreviations used are: 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. into a pathogenic isoform (PrPSc) that appears to be infectious in the absence of nucleic acid (1Prusiner S.B. Science. 1997; 278: 245-251Crossref PubMed Scopus (852) Google Scholar, 2Prusiner S.B. Scott M.R. DeArmond S.J. Cohen F.E. Cell. 1998; 93: 337-348Abstract Full Text Full Text PDF PubMed Scopus (819) Google Scholar). Although a wealth of information is now available about the role of PrPSc in the disease process, relatively little is known about the normal, physiological function of PrPC. PrPC is expressed in neurons and glia of the brain and spinal cord and at lower levels in several peripheral tissues and in leukocytes (3Bendheim P.E. Brown H.R. Rudelli R.D. Scala L.J. Goller N.L. Wen G.Y. Kascsak R.J. Cashman N.R. Bolton D.C. Neurology. 1992; 42: 149-156Crossref PubMed Google Scholar, 4Manson J. West J.D. Thomson V. McBride P. Kaufman M.H. Hope J. Development. 1992; 115: 117-122PubMed Google Scholar, 5Harris D.A. Lele P. Snider W.D. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4309-4313Crossref PubMed Scopus (74) Google Scholar, 6Moser M. Colello R.J. Pott U. Oesch B. Neuron. 1995; 14: 509-517Abstract Full Text PDF PubMed Scopus (271) Google Scholar, 7Dodelet V.C. Cashman N.R. Blood. 1998; 91: 1556-1561Crossref PubMed Google Scholar). Its localization on the cell surface would be consistent with roles in cell adhesion and recognition, ligand uptake, or transmembrane signaling. Mice in which the endogenous PrP gene has been ablated do not display any gross anatomical or developmental defects (8Büeler H. Fischer M. Lang Y. Fluethmann H. Lipp H.-P. DeArmond S.J. Prusiner S.B. Aguet M. Weissmann C. Nature. 1992; 356: 577-582Crossref PubMed Scopus (1432) Google Scholar) but are reported in some studies to have electrophysiological and structural abnormalities in the hippocampus (9Collinge J. Whittington M.A. Sidle K.C. Smith C.J. Palmer M.S. Clarke A.R. Jefferys J.G. Nature. 1994; 370: 295-297Crossref PubMed Scopus (686) Google Scholar, 10Manson J.C. Hope J. Clarke A.R. Johnston A. Black C. MacLeod N. Neurodegen. 1995; 4: 113-114Crossref PubMed Google Scholar, S.B. J. Jefferys PubMed Scopus Google Scholar, S.B. M. J. Jefferys 1997; PubMed Scopus Google of S. S. N. A. Y. S. H. S. Nature. PubMed Scopus Google or in and P. Fischer M. M. Oesch B. McBride J.C. Nature. PubMed Scopus Google Scholar). to the normal function of PrPC is the function of PrPC may be in the of prion of this function as a result of conversion to PrPSc may some of the Several of that PrPC may play a role in the metabolism of copper. the of PrPC a of and that are of copper or PrP the copper with a of and of the metal conformational in the 1995; PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar, A. H. PubMed Scopus Google Scholar, A. J. P.E. A. A. H. Nature. 1997; PubMed Scopus Google Scholar, J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar). of and of PrPSc J. J. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the of copper but not of several is of normal in and from the that a PrP gene A. J. P.E. A. A. H. Nature. 1997; PubMed Scopus Google Scholar). This result suggests that PrPC may be a in superoxide from is and copper the from normal the is for from that PrPC B. 1997; PubMed Scopus Google Scholar, A. J. 1998; PubMed Scopus Google Scholar). cultured are to of B. 1997; PubMed Scopus Google Scholar). the possibility that PrPC could be in of copper ions to and for to copper have of PrPC, a role for the in or of copper B. J. 1998; PubMed Scopus Google Scholar). copper and PrPC are is at possibility is that copper as for as of PrPC, as in as and of Google Scholar). of on the cell PrPC could function as a for of extracellular copper ions or as a for uptake and of copper ions to of information that may on the interaction of PrPC and copper is the metal the cellular localization and trafficking of PrPC. We have that PrPC is from the and to the cell surface D.A. J. 1993; Full Text PDF PubMed Google Scholar, D.A. J. 1994; PubMed Scopus Google Scholar, A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, D.A. A. S. Google Scholar). We report here that copper has a effect on this have the cellular trafficking of PrPC lines of mouse neuroblastoma that have been to or D.A. P. 1993; PubMed Scopus Google Scholar, D.A. J. 1993; Full Text PDF PubMed Google Scholar, D.A. J. 1994; PubMed Scopus Google Scholar, A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). We used to the of copper on the cellular of PrPC. To copper the of PrPC on the cell we for with and with a of PrP PrP from cell the on and of the gel with and We that at of and the of and on the cell surface the of surface PrP to not PrPC in is from the D.A. J. 1993; Full Text PDF PubMed Google Scholar, D.A. J. 1994; PubMed Scopus Google we the effect of copper on the of surface PrPC could be a effect on To we at to to and the of PrP that to phosphatidylinositol-specific phospholipase a that the for PrP to the this we that rapidly of and and in PrP could be as little as of and of the with in cells. of endocytosis could be to surface PrP this the of to in and this endocytosis of chPrP, but effect with or at effect of copper on PrP not to a in endocytosis of surface not of that the effect of copper rapidly of of the PrP to from the to the of the as to and a at which about of the about the that is endocytosis in the absence of copper D.A. J. 1993; Full Text PDF PubMed Google Scholar). This of the is to the of PrPC to to surface of are D.A. J. 1993; Full Text PDF PubMed Google Scholar). To this recycling process, we for at in the of to of PrP and surface PrP with at and the in the of to into the this we that copper from the of the PrP to the surface with a of consistent with the of B. copper in the PrP to the in the absence of metal This result that copper stimulates the of PrP has effect on the of studies have the of and chicken PrP in copper 1995; PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar, A. J. P.E. A. A. H. Nature. 1997; PubMed Scopus Google Scholar, J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar). We have that this of the is for endocytosis of PrP A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). We the effect of copper on endocytosis of of a surface D.A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). of the of the the effect of copper, the some the of the of the or the but not of PrP, that the copper of are in to of and of expressed in surface as in the to C. of PrP at in to expressed as a of the of PrP the of to We have the cellular trafficking of PrPC lines of mouse neuroblastoma that have been to or D.A. P. 1993; PubMed Scopus Google Scholar, D.A. J. 1993; Full Text PDF PubMed Google Scholar, D.A. J. 1994; PubMed Scopus Google Scholar, A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). We used to the of copper on the cellular of PrPC. To copper the of PrPC on the cell we for with and with a of PrP PrP from cell the on and of the gel with and We that at of and the of and on the cell surface the of surface PrP to not PrPC in is from the D.A. J. 1993; Full Text PDF PubMed Google Scholar, D.A. J. 1994; PubMed Scopus Google we the effect of copper on the of surface PrPC could be a effect on To we at to to and the of PrP that to phosphatidylinositol-specific phospholipase a that the for PrP to the this we that rapidly of and and in PrP could be as little as of and of the with in cells. of endocytosis could be to surface PrP this the of to in and this endocytosis of chPrP, but effect with or at effect of copper on PrP not to a in endocytosis of surface not of We that the effect of copper rapidly of of the PrP to from the to the of the as to and a at which about of the about the that is endocytosis in the absence of copper D.A. J. 1993; Full Text PDF PubMed Google Scholar). This of the is to the of PrPC to to surface of are D.A. J. 1993; Full Text PDF PubMed Google Scholar). To this recycling process, we for at in the of to of PrP and surface PrP with at and the in the of to into the this we that copper from the of the PrP to the surface with a of consistent with the of B. copper in the PrP to the in the absence of metal This result that copper stimulates the of PrP has effect on the of studies have the of and chicken PrP in copper 1995; PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar, A. J. P.E. A. A. H. Nature. 1997; PubMed Scopus Google Scholar, J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar). We have that this of the is for endocytosis of PrP A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). We the effect of copper on endocytosis of of a surface D.A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). of the of the the effect of copper, the some the of the of the or the but not of PrP, that the copper studies have that PrPC is from the cell surface and endocytic to the D.A. P. 1993; PubMed Scopus Google Scholar, D.A. J. 1993; Full Text PDF PubMed Google Scholar, D.A. J. 1994; PubMed Scopus Google Scholar, A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). We here that copper ions rapidly and reversibly the endocytic of this is to that this effect is to of copper ions to PrPC, of PrP have been to copper the 1995; PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar, A. J. P.E. A. A. H. Nature. 1997; PubMed Scopus Google Scholar, J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar). to PrPC, copper N. Prusiner S.B. Sci. 1992; PubMed Scopus Google Scholar). with a effect of copper on the of PrPC, we that of that are some or of the are the in to extracellular copper. hypothesis to of copper could endocytosis of PrPC is that the the of PrPC, the of the for a endocytic receptor that PrPC in PrPC is to the cell surface a a that could to the of We have the of a transmembrane receptor extracellular PrPC and for with and A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, D.A. A. S. Google of PrPC copper in the of which is the for of copper to PrP and PrP in 1995; PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar, A. J. P.E. A. A. H. Nature. 1997; PubMed Scopus Google Scholar, J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar). This may be in to of copper ions to as that are in the used for a that would lower the of copper. is that the effect of copper on endocytosis to on PrPC that are from the on or PrP or to on in any the copper in brain has been to be and may be in brain J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar, Smith of the Scholar). the endocytic we have here is relevant from a physiological hypothesis is that PrPC as a receptor for uptake of copper ions from the extracellular milieu. PrPC copper ions on the cell surface and to endocytic which the ions from PrPC and are to that the ions into the PrPC would to the cell surface to This function for PrPC is to that of the receptor in uptake of A. A. J. Full Text PDF PubMed Google with the that the metal ions to the receptor in the of PrPC to a with Although copper and copper have been in and Science. 1997; 278: PubMed Scopus Google the of copper uptake is S. 1995; PubMed Scopus Google Scholar). of the interaction PrPC and copper ions at the cellular may on this studies have that PrPC is from the cell surface and endocytic to the D.A. P. 1993; PubMed Scopus Google Scholar, D.A. J. 1993; Full Text PDF PubMed Google Scholar, D.A. J. 1994; PubMed Scopus Google Scholar, A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). We here that copper ions rapidly and reversibly the endocytic of this is to that this effect is to of copper ions to PrPC, of PrP have been to copper the 1995; PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar, A. J. P.E. A. A. H. Nature. 1997; PubMed Scopus Google Scholar, J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar). to PrPC, copper N. Prusiner S.B. Sci. 1992; PubMed Scopus Google Scholar). with a effect of copper on the of PrPC, we that of that are some or of the are the in to extracellular copper. hypothesis to of copper could endocytosis of PrPC is that the the of PrPC, the of the for a endocytic receptor that PrPC in PrPC is to the cell surface a a that could to the of We have the of a transmembrane receptor extracellular PrPC and for with and A. D.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, D.A. A. S. Google Scholar). of PrPC copper in the of which is the for of copper to PrP and PrP in 1995; PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar, A. J. P.E. A. A. H. Nature. 1997; PubMed Scopus Google Scholar, J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar). This may be in to of copper ions to as that are in the used for a that would lower the of copper. is that the effect of copper on endocytosis to on PrPC that are from the on or PrP or to on in any the copper in brain has been to be and may be in brain J. J. Cohen F.E. Prusiner S.B. 1998; PubMed Scopus Google Scholar, Smith of the Scholar). the endocytic we have here is relevant from a physiological hypothesis is that PrPC as a receptor for uptake of copper ions from the extracellular milieu. PrPC copper ions on the cell surface and to endocytic which the ions from PrPC and are to that the ions into the PrPC would to the cell surface to This function for PrPC is to that of the receptor in uptake of A. A. J. Full Text PDF PubMed Google with the that the metal ions to the receptor in the of PrPC to a with Although copper and copper have been in and Science. 1997; 278: PubMed Scopus Google the of copper uptake is S. 1995; PubMed Scopus Google Scholar). of the interaction PrPC and copper ions at the cellular may on this We for of copper metabolism and of the for on the