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Prion Diseases pp 239-249 | Cite as

Function of PrPC as a copper-binding protein at the synapse

  • H. A. Kretzschmar
  • T. Tings
  • A. Madlung
  • A. Giese
  • J. Herms
Chapter
Part of the Archives of Virology. Supplementa book series (ARCHIVES SUPPL, volume 16)

Summary

The prion protein (PrPC) shows cooperative copper binding of the N-terminal octarepeat (PHGGGWGO) ×4. In brain homogenates, PrPC is found in highest concentration in synaptosomal fractions. Mice devoid of PrPC (Prnp0/0 mice) show synaptosomal copper concentrations diminished by 50% as compared to normal mice. PrPC in the synaptic cleft may serve as a copper buffer. Alternatively it may play a role in the reuptake of copper into the presynapse or may be of structural importance for the N-terminus and thus may influence binding of PrPC to other proteins.

Keywords

Purkinje Cell Synaptic Vesicle Prion Protein Synaptic Plasma Membrane Cellular Prion Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Brenner HR, Herczeg A, Oesch B (1992) Normal development of nerve-muscle synapses in mice lacking the prion protein gene. Proc R Soc London 250: 151–156CrossRefGoogle Scholar
  2. 2.
    Brose N, Huntley GW, Stern-Bach A, Sharma G, Morrison JH, Heinemann SF (1994) Differential assembly of coexpressed glutamate receptor subunits in neurons of rat cerebral cortex. J Biol Chem 269: 16780–16784PubMedGoogle Scholar
  3. 3.
    Brose N, Petrenko AG, Südhof TC, Jahn R (1992) Synaptotagmin: a calcium sensor on the synaptic vesicle surface. Science 256: 1021–1025PubMedCrossRefGoogle Scholar
  4. 4.
    Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser P, Kruck T, von Bohlen A, Schulz-Schaeffer W, Giese A, Westaway D, Kretzschmar H (1997) The cellular prion protein binds copper in vivo. Nature 390: 684–687PubMedCrossRefGoogle Scholar
  5. 5.
    Büeler H, Fischer M, Lang Y, Bluethmann H, Lipp HP, DeArmond SJ, Prusiner SB, Aguet M, Weissmann C (1992) Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356: 577–582PubMedCrossRefGoogle Scholar
  6. 6.
    Chishti MA, Strome R, Carlson GA, Westaway D (1997) Syrian hamster prion protein (PrPc) is expressed in photoreceptor cells of the adult retina. Neurosci Lett 234: 11–14PubMedCrossRefGoogle Scholar
  7. 7.
    Colling SB, Collinge J, Jefferys JGR (1996) Hippocampal slices from prion protein null mice: disrupted Ca2+ activated K+ currents. Neurosci Lett 209: 49–52PubMedCrossRefGoogle Scholar
  8. 8.
    Collinge J, Whittington MA, Sidle KCL, Smith CJ, Palmer MS, Clarke AR, Jefferys JGR (1994) Prion protein is necessary for normal synaptic function. Nature 370: 295–297PubMedCrossRefGoogle Scholar
  9. 9.
    Doreulee N, Yanovsky A, Haas HL (1997) Suppression of long-term potentiation in hippocampal slices by copper. Hippocampus 7: 666–669PubMedCrossRefGoogle Scholar
  10. 10.
    Edenhofer F, Rieger R, Famulok M, Wendler W, Weiss S, Winnacker E-L (1996) Prion protein PrPc interacts with molecular chaperones of the Hsp6O family. J Virol 70: 4724–4728PubMedGoogle Scholar
  11. 11.
    Fischer M, Rülicke T, Raeber A, Sailer A, Moser M, Oesch B, Brandner S, Aguzzi A, Weissmann C (1996) Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J 15: 1255–1264PubMedGoogle Scholar
  12. 12.
    Fournier J-G, Escaig-Haye F, De Villemeur TB, Robain O (1995) Ultrastructural localization of cellular prion protein (PrPc) in synaptic boutons of normal hamster hippocampus. C R Acad Sci Paris 318: 339–344PubMedGoogle Scholar
  13. 13.
    Harris DA, Falls DL, Johnson FA, Fischbach GD (1991) A prion-like protein from chicken brain copurifies with an acetylcholin receptor-inducing activity. Proc Natl Acad Sci USA 88: 7664–7668PubMedCrossRefGoogle Scholar
  14. 14.
    Hartter DE, Barnea A (1988) Evidence for release of copper in the brain: depolarisation-induced release of newly taken-up 67 copper. Synapse 2: 412–415PubMedCrossRefGoogle Scholar
  15. 15.
    Herms J, Tings T, Gall S, Madlung A, Giese A, Siebert H, Schurmann P, Windl O, Brose N, Kretzschmar H (1999) Evidence of presynaptic location and function of the prion protein. J Neurosci 19: 8866–8875PubMedGoogle Scholar
  16. 16.
    Herms JW, Kretzschmar HA, Titz S, Keller BU (1995) Patch-clamp analysis of synaptic transmission to cerebellar Purkinje cells of prion protein knockout mice. Eur J Neurosci 7: 2508–2512PubMedCrossRefGoogle Scholar
  17. 17.
    Hornshaw MP, McDermott JR, Candy JM (1995) Copper binding to the N-terminal tandem repeat regions of mammalian and avian prion protein. Biochem Biophys Res Commun 207: 621–629PubMedCrossRefGoogle Scholar
  18. 18.
    Hornshaw MP, McDermott JR, Candy JM, Lakey JH (1995) Copper binding to the N-terminal tandem repeat region of mammalian and avian prion protein: Structural studies using synthetic peptides. Biochem Biophys Res Commun 214: 993–999PubMedCrossRefGoogle Scholar
  19. 19.
    Huttner WB, Schiebler W, Greengard P, De Camilli P (1983) Synapsin I (protein I), a nerve terminal-specific phosphoprotein. III. Its association with synaptic vesicles studied in a highly purified synaptic vesicle preparation. J Cell Biol 96: l374–1388CrossRefGoogle Scholar
  20. 20.
    Kardos J, Kovács I, Hajós F, Kálmán M, Simonyi M (1989) Nerve endings from rat brain tissue release copper upon depolarization. A possible role in regulating neuronal excitability. Neurosci Lett 103: 139–144PubMedCrossRefGoogle Scholar
  21. 21.
    Krasemann S, Groschup MH, Harmeyer S, Hunsmann G, Bodemer W (1996) Generation of monoclonal antibodies against human prion proteins in PrP0/0 mice. Mol Med 2: 725–734PubMedGoogle Scholar
  22. 22.
    Kurschner C, Morgan JI (1995) The cellular prion protein (PrP) selectively binds to Bcl-2 in the yeast two-hybrid system. Mol Brain Res 30: 165–167PubMedCrossRefGoogle Scholar
  23. 23.
    Kurschner C, Morgan JI (1996) Analysis of interaction sites in homo- and heteromeric complexes containing Bcl-2 family members and the cellular prion protein. Mol Brain Res 37: 249–258PubMedCrossRefGoogle Scholar
  24. 24.
    Llano I, Marty A, Armstrong CM, A Konnerth (1991) Synaptic- and agonist-induced excitatory currents of Purkinje cells in rat cerebellar slices. J Physiol 434: 183–213PubMedGoogle Scholar
  25. 25.
    L1edo PM, Tremblay P, DeArmond SJ, Prusiner SB, Nicoll RA (1996) Mice deficient for prion protein exhibit normal neuronal excitability and synaptic transmission in the hippocampus. Proc Natl Acad Sci USA 93: 2403–2407CrossRefGoogle Scholar
  26. 26.
    Manson JC, Clarke AR, McBride PA, McConnell I, Hope J (1994) PrP gene dosage determines the timing but not the final intensity or distribution of lesions in scrapie pathology. Neurodegeneration 3: 331–340PubMedGoogle Scholar
  27. 27.
    Manson JC, Hope J, Clarke AR, Johnston A, Black C, MacLeod N (1995) PrP gene dosage and long term potentiation. Neurodegeneration 4: 113–115PubMedCrossRefGoogle Scholar
  28. 28.
    Marcotte EM, Eisenberg D (1999) Chicken prion tandem repeats form a stable, protease-resistant domain. Biochemistry 38: 667–676PubMedCrossRefGoogle Scholar
  29. 29.
    Martins VR, Graner E, Garcia-Abreu J, deSouza SJ, Mercadante AF, Veiga SS, Zanata SM, Neto VM, Brentani RR (1998) Complementary hydropathy identifies a cellular prion protein receptor. Nature Med 3: 1376–1382Google Scholar
  30. 30.
    McArthur AJ, Gillette MU, Prosser RA (1991) Melatonin directly resets the rat suprachiasmatic circadian clock in vitro. Brain Res 565: 158–161PubMedCrossRefGoogle Scholar
  31. 31.
    Miura T, Hori-i A, Takeuchi H (1996) Metal-dependent a-helix formation promoted by the glycine-rich octapeptide region of prion protein. FEBS Lett 396: 248–252PubMedCrossRefGoogle Scholar
  32. 32.
    Moore RC, Hope J, McBride PA, McConnell I, Selfridge J, Melton DW, Manson JC (1998) Mice with gene targetted prion protein alterations show that Prnp, Sinc and Prni are congruent. Nature Genet 18: 118–125PubMedCrossRefGoogle Scholar
  33. 33.
    Moore RC, Lee IY, Silverman GL, Harrison PM, Strome R, Heinrich C, Karunaratne A, Pasternak SH, Chishti MA, Liang Y, Mastrangelo P, Wang K, Smit AFA, Katamine S, Carlson GA, Cohen FE, Prusiner SB, Melton DW, Tremblay P, Hood LE, Westaway D (1999) Ataxia in prion protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein doppel. J Mol Biol 292: 797–818PubMedCrossRefGoogle Scholar
  34. 34.
    Nam SC, Hockberger PE (1992) Divalent ions released from stainless steel hypodermic needles reduce neuronal calcium currents. Pflugers Arch 420: 106–108PubMedCrossRefGoogle Scholar
  35. 35.
    Nishida N, Tremblay P, Sugimoto T, Shigematsu K, Shirabe S, Petromilli C, Erpel SP, Nakaoke R, Atarashi R, Houtani T, Torchia M, Sakaguchi S, De Armond S, Prusiner SB, Katamine S (1999) A mouse prion protein transgene rescues mice deficient for the prion protein gene from Purkinje cell degeneration and demyelination. Lab Invest 79: 689–697PubMedGoogle Scholar
  36. 36.
    Oesch B, Teplow TB, Stahl N, Serban D, Hood LE, Prusiner SB (1990) Identification of cellular proteins binding to the scrapie prion protein. Biochemistry 29: 5848–5855PubMedCrossRefGoogle Scholar
  37. 37.
    Oxenkrug GF, Requintina P (1998) The effect of MAO-A inhibition and cold-immobilization stress on N-acetylserotonin and melatonin in SHR and WKY rats. J Neural Transm Suppl 52: 333–336CrossRefGoogle Scholar
  38. 38.
    Pauly PC, Harris DA (1998) Copper stimulates endocytosis of the prion protein. J Biol Chem 273: 33107–33110PubMedCrossRefGoogle Scholar
  39. 39.
    Rieger R, Edenhofer F, Lasmézas CI, Weiss S (1998) The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells. Nature Med 3: 1383–1388Google Scholar
  40. 40.
    Sakaguchi S, Katamine S, Nishida N, Moriuchi R, Shigematsu K, Sugimoto T, Nakatani A, Kataoka Y, Houtani T, Shirabe S, Okada H, Hasegawa S, Miyamoto T, Noda T (1996) Loss of cerebellar Purkinje cells in aged mice homozygous for a disrupted PrP gene. Nature 380: 528–531PubMedCrossRefGoogle Scholar
  41. 41.
    Salés N, Rodolfo K, Hässig R, Faucheux B, Di Giamberardino L, Moya KL (1998). Cellular prion protein localization in rodent and primate brain. Eur J Neurosci 10: 2464–2471PubMedCrossRefGoogle Scholar
  42. 42.
    Schätzl HM, Da Costa M, Taylor L, Cohen FE, Prusiner SB (1995) Prion protein gene variation among primates. J Mol Biol 245: 362–374PubMedCrossRefGoogle Scholar
  43. 43.
    Sharonova IN, Vorobjev VS, Haas HL (1998) High-affinity copper block of GABAA-receptor-mediated currents in acutely isolated cerebellar Purkinje cells of the rat. Eur J Neurosci 10: 522–528PubMedCrossRefGoogle Scholar
  44. 44.
    Shyng SL, Heuser JE, Harris DA (1994) A glycolipid-anchored prion protein is endocytosed via clathrin-coated pits. J Cell Biol 125: 1239–1250PubMedCrossRefGoogle Scholar
  45. 45.
    Stahl N, Borchelt DR, Hsiao K, Prusiner SB (1987) Scrapie prion protein contains a phospatidylinositol glycolipid. Cell 51: 229–240PubMedCrossRefGoogle Scholar
  46. 46.
    Tobler I, Deboer T, Fischer M (1997) Sleep and sleep regulation in normal and prion protein-deficient mice. J Neurosci 17: 1869–1879PubMedGoogle Scholar
  47. 47.
    Tobler I, Gaus SE, Deboer T, Achermann P, Fischer M, Rülicke T, Moser M, Oesch B, McBride PA, Manson JC (1996) Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature 380: 639–642PubMedCrossRefGoogle Scholar
  48. 48.
    Tremblay P, Meiner Z, Galou M, Heinrich C, Petromilli C, Lisse T, Cayetano J, Torchia M, Mobley W, Bujard H, De Armond S, Prusiner SB (1998) Doxycycline control of prion protein transgene expression modulates prion disease in mice. Proc Natl Acad Sei USA 95: 12580–12585CrossRefGoogle Scholar
  49. 49.
    Viles JH, Cohen FE, Prusiner SB, Goodin DB, Wright PE, Dyson HJ (1999) Copper binding to the prion protein: structural implications of four identical cooperative binding sites. Proc Natl Acad Sci USA 96: 2042–2047PubMedCrossRefGoogle Scholar
  50. 50.
    Walz W, Amaral OB, Rockenback IC, Roesler R, Izquierdo I, Cavalheiro EA, Martins VR, Brentani RR (1999) Increased sensitivity to seizures in mice lacking cellular prion protein. Epilepsis 40: 1679–1682CrossRefGoogle Scholar
  51. 51.
    Weissmann C (1996) PrP effects clarified. Curr Biol 6: 1369CrossRefGoogle Scholar
  52. 52.
    Whatley SA, Powell JF, Politopoulou G, Campbell IC, Brammer MJ, Percy NS (1995) Regulation of intracellular free calcium levels by the cellular prion protein. Neuroreport 6: 2333–2337PubMedCrossRefGoogle Scholar
  53. 53.
    Yehiely F, Bamborough P, DaCosta M, Perry BJ, Thinakaran G, Cohen FE, Carlson GA, Prusiner SB (1997) Identification of candidate proteins binding to prion protein. Neurobiol Dis 3: 339–355PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2000

Authors and Affiliations

  • H. A. Kretzschmar
    • 1
    • 2
  • T. Tings
    • 1
  • A. Madlung
    • 1
  • A. Giese
    • 1
  • J. Herms
    • 1
  1. 1.Institute of NeuropathologyUniversity of GöttingenGöttingenGermany
  2. 2.Department of NeuropathologyUniversity of MunichMünchenGermany

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