Polythiophenes inhibit prion propagation by stabilizing prion protein (PrP) aggregates

Journal of Biological Chemistry

Volumn 287, Issue 23, 2012, Pages 18872-18887

  Margalith, Ilan ^a   Suter, Carlo ^a   Ballmer, Boris ^a   Schwarz, Petra ^a   Tiberi, Cinzia ^a   Sonati, Tiziana ^a   Falsig, Jeppe ^a   Nyström, Sofie ^b   Hammarström, Per ^b   Åslund, Andreas ^b   Nilsson, K Peter R ^b   Yam, Alice ^c   Whitters, Eric ^c   Hornemann, Simone ^a   Aguzzi, Adriano ^a  

^a UNIVERSITY HOSPITAL ZURICH   (Switzerland)

^b LINKÖPING UNIVERSITY   (Sweden)

^c Novartis Diagnostics   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTI-PRION AGENTS; BRAIN HOMOGENATES; IN-VITRO; ISOFORMS; LUMINESCENT CONJUGATED POLYMERS; MODE OF ACTION; POLY(THIOPHENE-3-ACETIC ACID); PRION PROPAGATION; PRION PROTEIN; PROTEIN AGGREGATES;

ASSAYS; MAMMALS; OLIGOMERS; PROTEINS; THIOPHENE;

AGGREGATES;

AMPHOLYTE; ANION; CATION; ISOPROTEIN; OLIGOMER; POLY(THIOPENE 3 ACETIC ACID); POLYMER; POLYTHIOPENE DERIVATIVE; PRION PROTEIN; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; BRAIN HOMOGENATE; CEREBELLUM; CONTROLLED STUDY; ENZYME LINKED IMMUNOSORBENT ASSAY; IN VITRO STUDY; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN CONFORMATION; PROTEIN DEGRADATION; PROTEIN DETERMINATION; PROTEIN STABILITY; PROTEIN STRUCTURE; PROTEIN TRANSPORT; TISSUE CULTURE;

ANIMALS; CEREBELLUM; MICE; PEPTIDE FRAGMENTS; POLYMERS; PRIONS; PROTEIN STABILITY; PROTEIN STRUCTURE, TERTIARY; PROTEOLYSIS; PRPSC PROTEINS; THIOPHENES;

EID: 84861748092     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M112.355958     Document Type: Article

References (81)

1. Mastrianni, J. A. (2010) The genetics of prion diseases. Genet. Med. 12, 187-195
2. Edgeworth, J. A., Gros, N., Alden, J., Joiner, S., Wadsworth, J. D., Linehan, J., Brandner, S., Jackson, G. S., Weissmann, C., and Collinge, J. (2010) Spontaneous generation of mammalian prions. Proc. Natl. Acad. Sci. U.S.A. 107, 14402-14406
3. Weissmann, C., Enari, M., Klöhn, P. C., Rossi, D., and Flechsig, E. (2002) Transmission of prions. J. Infect. Dis. 186, S157-S165 (Pubitemid 35370476)
4. Aguzzi, A., and Polymenidou, M. (2004) Mammalian prion biology. One century of evolving concepts. Cell 116, 313-327 (Pubitemid 38167320)
5. Haybaeck, J., Heikenwalder, M., Klevenz, B., Schwarz, P., Margalith, I., Bridel, C., Mertz, K., Zirdum, E., Petsch, B., Fuchs, T. J., Stitz, L., and Aguzzi, A. (2011) Aerosols transmit prions to immunocompetent and immunodeficient mice. PLoS Pathog. 7, e1001257
6. Prusiner, S. B. (1998) Prions. Proc. Natl. Acad. Sci. U.S.A. 95, 13363-13383
7. Weissmann, C. (2004) The state of the prion. Nat. Rev. Microbiol. 2, 861-871
8. Aguzzi, A., and Calella, A. M. (2009) Prions. Protein aggregation and infectious diseases. Physiol. Rev. 89, 1105-1152
9. Aguzzi, A. (2009) Cell biology. Beyond the prion principle. Nature 459, 924-925
10. Appleby, B. S., and Lyketsos, C. G. (2011) Rapidly progressive dementias and the treatment of human prion diseases. Expert Opin. Pharmacother. 12, 1-12
11. Korth, C., May, B. C., Cohen, F. E., and Prusiner, S. B. (2001) Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc. Natl. Acad. Sci. U.S.A. 98, 9836-9841 (Pubitemid 32769390)
12. Pocchiari, M., Schmittinger, S., and Masullo, C. (1987) Amphotericin B delays the incubation period of scrapie in intracerebrally inoculated hamsters. J. Gen. Virol. 68, 219-223 (Pubitemid 17207202)
13. Collinge, J., Gorham, M., Hudson, F., Kennedy, A., Keogh, G., Pal, S., Rossor, M., Rudge, P., Siddique, D., Spyer, M., Thomas, D., Walker, S., Webb, T., Wroe, S., and Darbyshire, J. (2009) Safety and efficacy of quinacrine in human prion disease (PRION-1 study). A patient-preference trial. Lancet Neurol. 8, 334-344
14. Martínez-Lage, J. F., Rábano, A., Bermejo, J., Martíez Pérez, M., Guerrero, M. C., Contreras, M. A., and Lunar, A. (2005) Creutzfeldt-Jakob disease acquired via a dural graft. Failure of therapy with quinacrine and chlorpromazine. Surg. Neurol. 64, 542-545 (Pubitemid 41635236)
15. Benito-León, J. (2004) Combined quinacrine and chlorpromazine therapy in fatal familial insomnia. Clin. Neuropharmacol. 27, 201-203
16. Ingrosso, L., Ladogana, A., and Pocchiari, M. (1995) Congo red prolongs the incubation period in scrapie-infected hamsters. J. Virol. 69, 506-508 (Pubitemid 24378829)
17. Tagliavini, F., McArthur, R. A., Canciani, B., Giaccone, G., Porro, M., Bugiani, M., Lievens, P. M., Bugiani, O., Peri, E., Dall'Ara, P., Rocchi, M., Poli, G., Forloni, G., Bandiera, T., Varasi, M., Suarato, A., Cassutti, P., Cervini, M. A., Lansen, J., Salmona, M., and Post, C. (1997) Effectiveness of anthracycline against experimental prion disease in Syrian hamsters. Science 276, 1119-1122 (Pubitemid 27218121)
18. Caspi, S., Halimi, M., Yanai, A., Sasson, S. B., Taraboulos, A., and Gabizon, R. (1998) The anti-prion activity of Congo red. Putative mechanism. J. Biol. Chem. 273, 3484-3489 (Pubitemid 28109769)
19. Ouidja, M. O., Petit, E., Kerros, M. E., Ikeda, Y., Morin, C., Carpentier, G., Barritault, D., Brugère-Picoux, J., Deslys, J. P., Adjou, K., and Papy-Garcia, D. (2007) Structure-activity studies of heparan mimetic polyanions for anti-prion therapies. Biochem. Biophys. Res. Commun. 363, 95-100 (Pubitemid 47440153)
20. Tsuboi, Y., Doh-Ura, K., and Yamada, T. (2009) Continuous intraventricular infusion of pentosan polysulfate. Clinical trial against prion diseases. Neuropathology 29, 632-636
21. Terada, T., Tsuboi, Y., Obi, T., Doh-ura, K., Murayama, S., Kitamoto, T., Yamada, T., and Mizoguchi, K. (2010) Less protease-resistant PrP in a patient with sporadic CJD treated with intraventricular pentosan polysulfate. Acta Neurol. Scand. 121, 127-130
22. MacGregor, I. R., Dawes, J., Pepper, D. S., Prowse, C. V., and Stocks, J. (1985) Metabolism of sodium pentosan polysulfate in man measured by a new competitive binding assay for sulfated polysaccharides. Comparison with effects upon anticoagulant activity, lipolysis, and platelet α-granule proteins. Thromb. Haemost. 53, 411-414 (Pubitemid 15055642)
23. Supattapone, S., Piro, J. R., and Rees, J. R. (2009) Complex polyamines. Unique prion disaggregating compounds. CNS Neurol. Disord. Drug Targets 8, 323-328
24. Nilsson, K. P., Herland, A., Hammarström, P., and Inganäs, O. (2005) Conjugated polyelectrolytes. Conformation-sensitive optical probes for detection of amyloid fibril formation. Biochemistry 44, 3718-3724 (Pubitemid 40358024)
25. Herland, A., Nilsson, K. P., Olsson, J. D., Hammarström, P., Konradsson, P., and Inganäs, O. (2005) Synthesis of a regioregular zwitterionic conjugated oligoelectrolyte, usable as an optical probe for detection of amyloid fibril formation at acidic pH. J. Am. Chem. Soc. 127, 2317-2323 (Pubitemid 40270535)
26. Nilsson, K. P., Hammarström, P., Ahlgren, F., Herland, A., Schnell, E. A., Lindgren, M., Westermark, G. T., and Inganäs, O. (2006) Conjugated polyelectrolytes. Conformation-sensitive optical probes for staining and characterization of amyloid deposits. ChemBioChem. 7, 1096-1104 (Pubitemid 44049445)
27. Nilsson, K. P., Ikenberg, K., Aslund, A., Fransson, S., Konradsson, P., Röcken, C., Moch, H., and Aguzzi, A. (2010) Structural typing of systemic amyloidoses by luminescent-conjugated polymer spectroscopy. Am. J. Pathol. 176, 563-574
28. Sigurdson, C. J., Nilsson, K. P., Hornemann, S., Manco, G., Polymenidou, M., Schwarz, P., Leclerc, M., Hammarström, P., Wüthrich, K., and Aguzzi, A. (2007) Prion strain discrimination using luminescent conjugated polymers. Nat. Methods 4, 1023-1030 (Pubitemid 350201774)
29. Gottlieb, H. E., Kotlyar, V., and Nudelman, A. (1997)NMRchemical shifts of common laboratory solvents as trace impurities. J. Org. Chem. 62, 7512-7515
30. Nilsson, K. P., Aslund, A., Berg, I., Nyström, S., Konradsson, P., Herland, A., Inganäs, O., Stabo-Eeg, F., Lindgren, M., Westermark, G. T., Lannfelt, L., Nilsson, L. N., and Hammarström, P. (2007) Imaging distinct conformational states of amyloid-β fibrils in Alzheimer's disease using novel luminescent probes. ACS Chem. Biol. 2, 553-560 (Pubitemid 350011326)
31. Aslund, A., Herland, A., Hammarström, P., Nilsson, K. P., Jonsson, B. H., Inganäs, O., and Konradsson, P. (2007) Studies of luminescent conjugated polythiophene derivatives. Enhanced spectral discrimination of protein conformational states. Bioconjug. Chem. 18, 1860-1868 (Pubitemid 350219985)
32. Ho, H. A., Boissinot, M., Bergeron, M. G., Corbeil, G., Doré, K., Boudreau, D., and Leclerc, M. (2002) Colorimetric and fluorometric detection of nucleic acids using cationic polythiophene derivatives. Angew. Chem. Int. Ed. Engl. 41, 1548-1551 (Pubitemid 34534396)
33. Nilsson, K. P., Rydberg, J., Baltzer, L., and Inganäs, O. (2003) Self-assembly of synthetic peptides control conformation and optical properties of a zwitterionic polythiophene derivative. Proc. Natl. Acad. Sci. U.S.A. 100, 10170-10174 (Pubitemid 37071851)
34. Nilsson, K. P., and Inganäs, O. (2003) Chip and solution detection of DNA hybridization using a luminescent zwitterionic polythiophene derivative. Nat. Mater. 2, 419-424
35. Aslund, A., Sigurdson, C. J., Klingstedt, T., Grathwohl, S., Bolmont, T., Dickstein, D. L., Glimsdal, E., Prokop, S., Lindgren, M., Konradsson, P., Holtzman, D. M., Hof, P. R., Heppner, F. L., Gandy, S., Jucker, M., Aguzzi, A., Hammarström, P., and Nilsson, K. P. (2009) Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses. ACS Chem. Biol. 4, 673-684
36. Aslund, A., Nilsson, K. P., and Konradsson, P. (2009) Fluorescent oligo and poly-thiophenes and their utilization for recording biological events of diverse origin-when organic chemistry meets biology. J. Chem. Biol. 2, 161-175
37. Ding, L., Jonforsen, M., Roman, L. S., Andersson, M., and Inganäs, O. (2000) Synth. Met. 110, 133-140
38. Falsig, J., and Aguzzi, A. (2008) The prion organotypic slice culture assay, POSCA. Nat. Protoc. 3, 555-562 (Pubitemid 351516751)
39. Falsig, J., Julius, C., Margalith, I., Schwarz, P., Heppner, F. L., and Aguzzi, A. (2008) A versatile prion replication assay in organotypic brain slices. Nat. Neurosci. 11, 109-117
40. Klöhn, P. C., Stoltze, L., Flechsig, E., Enari, M., and Weissmann, C. (2003) A quantitative, highly sensitive cell-based infectivity assay for mouse scrapie prions. Proc. Natl. Acad. Sci. U.S.A. 100, 11666-11671 (Pubitemid 37205992)
41. Lau, A. L., Yam, A. Y., Michelitsch, M. M., Wang, X. Gao, C., Goodson, R. J., Shimizu, R., Timoteo, G., Hall, J., Medina-Selby, A., Coit, D., McCoin, C., Phelps, B., Wu, P., Hu, C., Chien, D., and Peretz, D. (2007) Characterization of prion protein (PrP)-derived peptides that discriminate fulllength PrPSc from PrPC. Proc. Natl. Acad. Sci. U.S.A. 104, 11551-11556 (Pubitemid 47175050)
42. Polymenidou, M., Moos, R., Scott, M., Sigurdson, C., Shi, Y. Z., Yajima, B., Hafner-Bratkovic, I., Jerala, R., Hornemann, S., Wuthrich, K., Bellon, A., Vey, M., Garen, G., James, M. N., Kav, N., and Aguzzi, A. (2008) ThePOM monoclonals. A comprehensive set of antibodies to nonoverlapping prion protein epitopes. PLoS One 3, e3872
43. Zahn, R., Liu, A., Lührs, T., Riek, R., von Schroetter, C., López García, F., Billeter, M., Calzolai, L., Wider, G., and Wüthrich, K. (2000) NMR solution structure of the human prion protein. Proc. Natl. Acad. Sci. U.S.A. 97, 145-150 (Pubitemid 30055798)
44. Lysek, D. A., and Wüthrich, K. (2004) Prion protein interaction with the C-terminal SH3 domain of Grb2 studied usingNMRand optical spectroscopy. Biochemistry 43, 10393-10399 (Pubitemid 39079313)
45. Hornemann, S., Christen, B., von Schroetter, C., Pérez, D. R., and Wüthrich, K. (2009) Prion protein library of recombinant constructs for structural biology. FEBS J. 276, 2359-2367
46. Apetri, A. C., Vanik, D. L., and Surewicz, W. K. (2005) Polymorphism at residue 129 modulates the conformational conversion of the D178N variant of human prion protein 90-231. Biochemistry 44, 15880-15888 (Pubitemid 41746918)
47. Almstedt, K., Nyström, S., Nilsson, K. P., and Hammarström, P. (2009) Amyloid fibrils of human prion protein are spun and woven from morphologically disordered aggregates. Prion 3, 224-235
48. Polymenidou, M., Prokop, S., Jung, H. H., Hewer, E., Peretz, D., Moos, R., Tolnay, M., and Aguzzi, A. (2011) Atypical prion protein conformation in familial prion disease with PRNP P105T mutation. Brain Pathol. 21, 209-214
49. Kranich, J., Krautler, N. J., Falsig, J., Ballmer, B., Li, S., Hutter, G., Schwarz, P., Moos, R., Julius, C., Miele, G., and Aguzzi, A. (2010) Engulfment of cerebral apoptotic bodies controls the course of prion disease in a mouse strain-dependent manner. J. Exp. Med. 207, 2271-2281
50. Fischer, M., Rülicke, T., Raeber, A., Sailer, A., Moser, M., Oesch, B., Brandner, S., Aguzzi, A., and Weissmann, C. (1996) Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J. 15, 1255-1264 (Pubitemid 26093461)
51. Peretz, D., Scott, M. R., Groth, D., Williamson, R. A., Burton, D. R., Cohen, F. E., and Prusiner, S. B. (2001) Strain-specified relative conformational stability of the scrapie prion protein. Protein Sci. 10, 854-863 (Pubitemid 32240511)
52. Otzen, D. E. (2010) Amyloid formation in surfactants and alcohols. Membrane mimetics or structural switchers? Curr. Protein Pept. Sci. 11, 355-371
53. Breyer, J., Wemheuer, W. M., Wrede, A., Graham, C., Benestad, S. L., Brenig, B., Richt, J. A., and Schulz-Schaeffer, W. J. (2012) Detergents modify proteinase K resistance of PrP(Sc) in different transmissible spongiform encephalopathies (TSEs). Vet. Microbiol. 157, 23-31
54. Milhavet, O., Mangé, A., Casanova, D., and Lehmann, S. (2000) Effect of Congo red on wild-type and mutated prion proteins in cultured cells. J. Neurochem. 74, 222-230 (Pubitemid 30012772)
55. Rangachari, V., Reed, D. K., Moore, B. D., and Rosenberry, T. L. (2006) Secondary structure and interfacial aggregation of amyloid-β(1-40) on sodium dodecyl sulfate micelles. Biochemistry 45, 8639-8648 (Pubitemid 44078884)
56. Tew, D. J., Bottomley, S. P., Smith, D. P., Ciccotosto, G. D., Babon, J., Hinds, M. G., Masters, C. L., Cappai, R., and Barnham, K. J. (2008) Stabilization of neurotoxic soluble β-sheet-rich conformations of the Alzheimer's disease amyloid-β peptide. Biophys. J. 94, 2752-2766
57. Terzi, E., Hölzemann, G., and Seelig, J. (1995) Self-association of β-amyloid peptide(1-40) in solution and binding to lipid membranes. J. Mol. Biol. 252, 633-642
58. Bokvist, M., Lindström, F., Watts, A., and Gröbner, G. (2004) Two types of Alzheimer's β-amyloid(1-40) peptide membrane interactions. Aggregation preventing transmembrane anchoring versus accelerated surface fibril formation. J. Mol. Biol. 335, 1039-1049 (Pubitemid 38091609)
59. Wahlström, A., Hugonin, L., Perálvarez-Marín, A., Jarvet, J., and Gräslund, A. (2008) Secondary structure conversions of Alzheimer Aβ(1-40) peptide induced by membrane-mimicking detergents. FEBS J. 275, 5117-5128
60. Lendel, C., Bolognesi, B., Wahlström, A., Dobson, C. M., and Gräslund, A. (2010) Detergent-like interaction of Congo red with the amyloid β peptide. Biochemistry 49, 1358-1360
61. Abelein, A., Bolognesi, B., Dobson, C. M., Gräslund, A., and Lendel, C. (2012) Hydrophobicity and conformational change as mechanistic determinants for nonspecific modulators of amyloid β self-assembly. Biochemistry 51, 126-137
62. Knowles, T. P., Waudby, C. A., Devlin, G. L., Cohen, S. I., Aguzzi, A., Vendruscolo, M., Terentjev, E. M., Welland, M. E., and Dobson, C. M. (2009) An analytical solution to the kinetics of breakable filament assembly. Science 326, 1533-1537
63. Caughey, B., and Lansbury, P. T. (2003) Protofibrils, pores, fibrils, and neurodegeneration. Separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26, 267-298 (Pubitemid 37064935)
64. Wang, Y. Q., Buell, A. K., Wang, X. Y., Welland, M. E., Dobson, C. M., Knowles, T. P., and Perrett, S. (2011) Relationship between prion propensity and the rates of individual molecular steps of fibril assembly. J. Biol. Chem. 286, 12101-12107
65. Gabizon, R., McKinley, M. P., and Prusiner, S. B. (1987) Purified prion proteins and scrapie infectivity copartition into liposomes. Proc. Natl. Acad. Sci. U.S.A. 84, 4017-4021 (Pubitemid 17090866)
66. Silveira, J. R., Raymond, G. J., Hughson, A. G., Race, R. E., Sim, V. L., Hayes, S. F., and Caughey, B. (2005) The most infectious prion protein particles. Nature 437, 257-261 (Pubitemid 41294488)
67. Tixador, P., Herzog, L., Reine, F., Jaumain, E., Chapuis, J., Le Dur, A., Laude, H., and Béringue, V. (2010) The physical relationship between infectivity and prion protein aggregates is strain-dependent. PLoS Pathog. 6, e1000859
68. Shaked, G. M., Fridlander, G., Meiner, Z., Taraboulos, A., and Gabizon, R. (1999) Protease-resistant and detergent-insoluble prion protein is not necessarily associated with prion infectivity. J. Biol. Chem. 274, 17981-17986
69. Lasmézas, C. I., Deslys, J. P., Robain, O., Jaegly, A., Beringue, V., Peyrin, J. M., Fournier, J. G., Hauw, J. J., Rossier, J., and Dormont, D. (1997) Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 275, 402-405 (Pubitemid 27051621)
70. Sklaviadis, T. K., Manuelidis, L., and Manuelidis, E. E. (1989) Physical properties of the Creutzfeldt-Jakob disease agent. J. Virol. 63, 1212-1222 (Pubitemid 19061363)
71. Hsiao, K. K., Groth, D., Scott, M., Yang, S. L., Serban, H., Rapp, D., Foster, D., Torchia, M., Dearmond, S. J., and Prusiner, S. B. (1994) Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. Proc. Natl. Acad. Sci. U.S.A. 91, 9126-9130
72. Piccardo, P., Manson, J. C., King, D., Ghetti, B., and Barron, R. M. (2007) Accumulation of prion protein in the brain that is not associated with transmissible disease. Proc. Natl. Acad. Sci. U.S.A. 104, 4712-4717 (Pubitemid 47186290)
73. Barron, R. M., Campbell, S. L., King, D., Bellon, A., Chapman, K. E., Williamson, R. A., and Manson, J. C. (2007) High titers of transmissible spongiform encephalopathy infectivity associated with extremely low levels of PrPSc in vivo. J. Biol. Chem. 282, 35878-35886 (Pubitemid 350277109)
74. Chiesa, R., Piccardo, P., Quaglio, E., Drisaldi, B., Si-Hoe, S. L., Takao, M., Ghetti, B., and Harris, D. A. (2003) Molecular distinction between pathogenic and infectious properties of the prion protein. J. Virol. 77, 7611-7622 (Pubitemid 36734531)
75. Shyng, S. L., Lehmann, S., Moulder, K. L., and Harris, D. A. (1995) Sulfated glycans stimulate endocytosis of the cellular isoform of the prion protein, PrPC, in cultured cells. J. Biol. Chem. 270, 30221-30229
76. Enari, M., Flechsig, E., and Weissmann, C. (2001) Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody. Proc. Natl. Acad. Sci. U.S.A. 98, 9295-9299 (Pubitemid 32743910)
77. Perrier, V., Solassol, J., Crozet, C., Frobert, Y., Mourton-Gilles, C., Grassi, J., and Lehmann, S. (2004) Anti-PrP antibodies block PrPSc replication in prion-infected cell cultures by accelerating PrPC degradation. J. Neurochem. 89, 454-463 (Pubitemid 38495993)
78. Peretz, D., Williamson, R. A., Kaneko, K., Vergara, J., Leclerc, E., Schmitt- Ulms, G., Mehlhorn, I. R., Legname, G., Wormald, M. R., Rudd, P. M., Dwek, R. A., Burton, D. R., and Prusiner, S. B. (2001) Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature 412, 739-743 (Pubitemid 32771997)
79. Hijazi, N., Shaked, Y., Rosenmann, H., Ben-Hur, T., and Gabizon, R. (2003) Copper binding to PrPC may inhibit prion disease propagation. Brain Res. 993, 192-200
80. Pauly, P. C., and Harris, D. A. (1998) Copper stimulates endocytosis of the prion protein. J. Biol. Chem. 273, 33107-33110 (Pubitemid 29005676)
81. Brown, L. R., and Harris, D. A. (2003) Copper and zinc cause delivery of the prion protein from the plasma membrane to a subset of early endosomes and the Golgi. J. Neurochem. 87, 353-363 (Pubitemid 37255243)