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Prions and their partners in crime

Nature volume 443, pages 803810 (19 October 2006) | Download Citation

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Abstract

Prions, the infectious agents of transmissible spongiform encephalopathies (TSEs), have defied full characterization for decades. The dogma has been that prions lack nucleic acids and are composed of a pathological, self-inducing form of the host's prion protein (PrP). Recent progress in propagating TSE infectivity in cell-free systems has effectively ruled out the involvement of foreign nucleic acids. However, host-derived nucleic acids or other non-PrP molecules seem to be crucial. Interactions between TSE-associated PrP and its normal counterpart are also pathalogically important, so the physiological functions of normal PrP and how they might be corrupted by TSE infections have been the subject of recent research.

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References

  1. 1.

    , & Prion protein and the molecular features of transmissible spongiform encephalopathy agents. Curr. Top. Microbiol. Immunol. 284, 1–50 (2004).

  2. 2.

    , & Protease-resistant prion protein produced in vitro lacks detectable infectivity. J. Gen. Virol. 80, 11–14 (1999).

  3. 3.

    et al. Synthetic mammalian prions. Science 305, 673–676 (2004).

  4. 4.

    et al. Strain-specified characteristics of mouse synthetic prions. Proc. Natl Acad. Sci. USA 102, 2168–2173 (2005).

  5. 5.

    et al. Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. Proc. Natl Acad. Sci. USA 91, 9126–9130 (1994).

  6. 6.

    et al. Immunodetection of disease-associated mutant PrP, which accelerates disease in GSS transgenic mice. EMBO J. 24, 2472–2480 (2005).

  7. 7.

    , , & In vitro generation of infectious scrapie prions. Cell 121, 195–206 (2005).

  8. 8.

    et al. Protease-resistant prion protein amplification reconstituted with partially purified substrates and synthetic polyanions. J. Biol. Chem. 280, 26873–26879 (2005).

  9. 9.

    et al. Sulfated glycans and elevated temperature stimulate PrPSc dependent cell-free formation of protease-resistant prion protein. EMBO J. 20, 377–386 (2001).

  10. 10.

    et al. Heparan sulfate is a cellular receptor for purified infectious prions. J. Biol. Chem. 280, 17062–17067 (2005).

  11. 11.

    , , & PrPSc incorporation to cells requires endogenous glycosaminoglycan expression. J. Biol. Chem. 280, 17057–17061 (2005).

  12. 12.

    et al. Cellular heparan sulfate participates in the metabolism of prions. J. Biol. Chem. 278, 40041–40049 (2003).

  13. 13.

    , , , & Reconstitution of prion infectivity from solubilized protease-resistant PrP and nonprotein components of prion rods. J. Biol. Chem. 276, 14324–14328 (2001).

  14. 14.

    A unified theory of prion propagation. Nature 352, 679–683 (1991).

  15. 15.

    & The hypothesis of the catalytic action of nucleic acid on the conversion of prion protein. Protein Pept. Lett. 12, 251–255 (2005).

  16. 16.

    et al. The 37 kDa/67 kDa laminin receptor is required for PrPSc propagation in scrapie-infected neuronal cells. EMBO Rep. 4, 290–295 (2003).

  17. 17.

    et al. The most infectious prion protein particles. Nature 437, 257–261 (2005).

  18. 18.

    & Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26, 267–298 (2003).

  19. 19.

    et al. Anchorless prion protein results in infectious amyloid disease without clinical scrapie. Science 308, 1435–1439 (2005).

  20. 20.

    et al. Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 379, 339–343 (1996).

  21. 21.

    et al. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302, 871–874 (2003).

  22. 22.

    et al. Disease-related prion protein forms aggresomes in neuronal cells leading to caspase activation and apoptosis. J. Biol. Chem. 280, 38851–38861 (2005).

  23. 23.

    et al. The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity. J. Neurosci. 25, 2793–2802 (2005).

  24. 24.

    et al. Astrocyte-specific expression of hamster prion protein (PrP) renders PrP knockout mice susceptible to hamster scrapie. EMBO J. 16, 6057–6065 (1997).

  25. 25.

    , , & Scrapie-specific neuronal lesions are independent of neuronal PrP expression. Ann. Neurol. 55, 781–792 (2004).

  26. 26.

    et al. Pathological prion protein exposure switches on neuronal mitogen-activated protein kinase pathway resulting in microglia recruitment. J. Biol. Chem. 280, 1529–1534 (2005).

  27. 27.

    & New insights into prion structure and toxicity. Neuron 50, 353–357 (2006).

  28. 28.

    , & Is loss of function of the prion protein the cause of prion disorders? Trends Mol. Med. 9, 237–243 (2003).

  29. 29.

    & Rational targeting for prion therapeutics. Nature Rev. Neurosci. 6, 23–34 (2005).

  30. 30.

    & Prion diseases: what is the neurotoxic molecule? Neurobiol. Dis. 8, 743–763 (2001).

  31. 31.

    & Cellular prion protein neuroprotective function: implications in prion diseases. J. Mol. Med. 83, 3–11 (2005).

  32. 32.

    et al. Cellular prion protein: on the road for functions. FEBS Lett. 512, 25–28 (2002).

  33. 33.

    & The prion protein and neuronal zinc homeostasis. Trends Biochem. Sci. 28, 406–410 (2003).

  34. 34.

    & Cellular prion protein function in copper homeostasis and redox signalling at the synapse. J. Neurochem. 86, 538–544 (2003).

  35. 35.

    , , & Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth. J. Cell Biol. 169, 341–354 (2005).

  36. 36.

    et al. Interaction of cellular prion and stress-inducible protein 1 promotes neuritogenesis and neuroprotection by distinct signaling pathways. J. Neurosci. 25, 11330–11339 (2005).

  37. 37.

    , , , & Axonal transport of the cellular prion protein is increased during axon regeneration. J. Neurochem. 92, 1044–1053 (2005).

  38. 38.

    , , , & Recombinant prion protein induces rapid polarization and development of synapses in embryonic rat hippocampal neurons in vitro. J. Neurochem. 95, 1373–1386 (2005).

  39. 39.

    et al. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature 380, 639–642 (1996).

  40. 40.

    et al. Prion protein is necessary for normal synaptic function. Nature 370, 295–297 (1994).

  41. 41.

    et al. Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons. Neurobiol. Dis. 19, 255–265 (2005).

  42. 42.

    et al. The cellular prion protein binds copper in vivo. Nature 390, 684–687 (1997).

  43. 43.

    et al. Overexpression of PrPC by adenovirus-mediated gene targeting reduces ischemic injury in a stroke rat model. J. Neurosci. 25, 8967–8977 (2005).

  44. 44.

    et al. The cellular prion protein modulates phagocytosis and inflammatory response. J. Leukoc. Biol. 77, 238–246 (2005).

  45. 45.

    , , & Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal. Proc. Natl Acad. Sci. USA 103, 2184–2189 (2006).

  46. 46.

    , , , & Prion protein (PrPC) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis. Proc. Natl Acad. Sci. USA 103, 3416–3421 (2006).

  47. 47.

    et al. Altered behavioural response to acute stress in mice lacking cellular prion protein. Behav. Brain Res. 162, 173–181 (2005).

  48. 48.

    , , , & Mice deficient for prion protein exhibit normal neuronal excitability and synaptic transmission in the hippocampus. Proc. Natl Acad. Sci. USA 93, 2403–2407 (1996).

  49. 49.

    et al. Brain copper content and cuproenzyme activity do not vary with prion protein expression level. J. Biol. Chem. 275, 7455–7458 (2000).

  50. 50.

    , & Role of microglia and host prion protein in neurotoxicity of a prion protein fragment. Nature 380, 345–347 (1996).

  51. 51.

    , & Neurotoxicity of prion peptide 106-126 not confirmed. FEBS Lett. 458, 65–68 (1999).

  52. 52.

    , & Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science 298, 1781–1785 (2002).

  53. 53.

    et al. Mutant PrP is delayed in its exit from the endoplasmic reticulum, but neither wild-type nor mutant PrP undergoes retrotranslocation prior to proteasomal degradation. J. Biol. Chem. 278, 21732–21743 (2003).

  54. 54.

    et al. Cellular prion protein promotes Brucella infection into macrophages. J. Exp. Med. 198, 5–17 (2003).

  55. 55.

    et al. Absence of evidence for the participation of the macrophage cellular prion protein in infection with Brucella suis. Infect. Immun. 73, 6229–6236 (2005).

  56. 56.

    et al. Prion protein interaction with glycosaminoglycan occurs with the formation of oligomeric complexes stabilized by Cu(II) bridges. J. Mol. Biol. 319, 527–540 (2002).

  57. 57.

    et al. Potent antiscrapie activities of degenerate phosphorothioate oligonucleotides. Antimicrob. Agents Chemother. 50, 1034–1044 (2006).

  58. 58.

    & A Trans-dominant negative 37kDa/67kDa laminin receptor mutant impairs PrPSc propagation in scrapie-infected neuronal cells. J. Mol. Biol. 358, 57–66 (2006).

  59. 59.

    et al. Bovine prion is endocytosed by human enterocytes via the 37 kDa/67 kDa laminin receptor. Am. J. Pathol. 167, 1033–1042 (2005).

  60. 60.

    et al. Identification of interaction domains of the prion protein with its 37-kDa/67-kDa laminin receptor. EMBO J. 20, 5876–5886 (2001).

  61. 61.

    et al. Knock-down of the 37-kDa/67-kDa laminin receptor in mouse brain by transgenic expression of specific antisense LRP RNA. Transgenic Res. 13, 81–85 (2004).

  62. 62.

    et al. Cellular prion protein acquires resistance to proteolytic degradation following copper ion binding. Biol. Chem. 385, 739–747 (2004).

  63. 63.

    , & Copper converts the cellular prion protein into a protease-resistant species that is distinct from the scrapie isoform. J. Biol. Chem. 276, 11432–11438 (2001).

  64. 64.

    , , , & Copper binding to PrPC may inhibit prion disease propagation. Brain Res. 993, 192–200 (2003).

  65. 65.

    , , & Misfolding of the prion protein at the plasma membrane induces endocytosis, intracellular retention and degradation. Traffic. 5, 426–436 (2004).

  66. 66.

    et al. Copper chelation delays the onset of prion disease. J. Biol. Chem. 278, 46199–46202 (2003).

  67. 67.

    et al. Reversibility of scrapie inactivation is enhanced by copper. J. Biol. Chem. 273, 25545–25547 (1998).

  68. 68.

    , & Ionic strength and transition metals control PrPSc protease resistance and conversion-inducing activity. J. Biol. Chem. 279, 40788–40794 (2004).

  69. 69.

    , , , & Copper (II) ions potently inhibit purified PrPres amplification. J. Neurochem. 96, 1409–1415 (2006).

  70. 70.

    , , & Copper(II) inhibits in vitro conversion of prion protein into amyloid fibrils. Biochemistry 44, 6776–6787 (2005).

  71. 71.

    et al. Cellular heparan sulfate participates in the metabolism of prions. J. Biol. Chem. 278, 40041–40049 (2003).

  72. 72.

    et al. Uptake and neuritic transport of scrapie prion protein coincident with infection of neuronal cells. J. Neurosci. 25, 5207–5216 (2005).

  73. 73.

    , , , & Conversion of raft associated prion protein to the protease-resistant state requires insertion of PrP-res (PrPSc) into contiguous membranes. EMBO J. 21, 1031–1040 (2002).

  74. 74.

    et al. Cellular prion protein binds laminin and mediates neuritogenesis. Brain Res. Mol. Brain Res. 76, 85–92 (2000).

  75. 75.

    , , , & Prion protein as trans-interacting partner for neurons is involved in neurite outgrowth and neuronal survival. Mol. Cell. Neurosci. 22, 227–233 (2003).

  76. 76.

    et al. Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science 303, 1514–1516 (2004).

  77. 77.

    , , & Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis. J. Cell Sci. 118, 5141–5153 (2005).

  78. 78.

    et al. NADPH oxidase and extracellular regulated kinases 1/2 are targets of prion protein signaling in neuronal and nonneuronal cells. Proc. Natl Acad. Sci. USA 100, 13326–13331 (2003).

  79. 79.

    et al. Cellular isoform of the scrapie agent protein participates in lymphocyte activation. Cell 61, 185–192 (1990).

  80. 80.

    et al. Overexpression of cellular prion protein induces an antioxidant environment altering T cell development in the thymus. J. Immunol. 176, 3490–3497 (2006).

  81. 81.

    & Prion protein expression in human leukocyte differentiation. Blood 91, 1556–1561 (1998).

  82. 82.

    & The scrapie-associated form of PrP is made from a cell surface precursor that is both protease- and phospholipase-sensitive. J. Biol. Chem. 266, 18217–18223 (1991).

  83. 83.

    , & Evidence for synthesis of scrapie prion protein in the endocytic pathway. J. Biol. Chem. 267, 16188–16199 (1992).

  84. 84.

    , & The highways and byways of prion protein trafficking. Trends Cell Biol. 15, 102–111 (2005).

  85. 85.

    , , & N-terminal truncation of the scrapie-associated form of PrP by lysosomal protease(s): implications regarding the site of conversion of PrP to the protease-resistant state. J. Virol. 65, 6597–6603 (1991).

  86. 86.

    et al. S-nitrosylated protein–disulphide isomerase links protein misfolding to neurodegeneration. Nature 441, 513–517 (2006).

  87. 87.

    et al. Cells release prions in association with exosomes. Proc. Natl Acad. Sci. USA 101, 9683–9688 (2004).

  88. 88.

    et al. A porphyrin increases survival time of mice after intracerebral prion infection. Antimicrob. Agents Chemother. 50, 759–761 (2006).

  89. 89.

    et al. Inhibition of protease-resistant prion protein formation in a transformed deer cell line infected with chronic wasting disease. J. Virol. 80, 596–604 (2006).

  90. 90.

    & Prion diseases — close to effective therapy? Nature Rev. Drug Discov. 3, 874–884 (2004).

  91. 91.

    et al. Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models. J. Virol. 78, 4999–5006 (2004).

  92. 92.

    et al. Prions and spongiform encephalopathy (TSE) chemotherapeutics: a common mechanism for anti-TSE compounds? Acc. Chem. Res. 39, 646–653 (2006).

  93. 93.

    , , , & Binding of the protease-sensitive form of PrP (prion protein) to sulfated glycosaminoglycan and Congo red. J. Virol. 68, 2135–2141 (1994).

  94. 94.

    , , & Identification of the heparan sulfate binding sites in the cellular prion protein. J. Biol. Chem. 277, 18421–18430 (2002).

  95. 95.

    , , & Sulfated glycans stimulate endocytosis of the cellular isoform of the prion protein, PrPC, in cultured cells. J. Biol. Chem. 270, 30221–30229 (1995).

  96. 96.

    et al. Prion proteins with insertion mutations have altered N-terminal conformation and increased ligand binding activity and are more susceptible to oxidative attack. J. Biol. Chem. 281, 10698–10705 (2006).

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Acknowledgements

We gratefully acknowledge the helpful comments of W. Caughey, U. Dittmer, B. Chesebro, S. Priola, V. Sim, D. Kocisko, K. Sun Lee and J. Silveira. This work was supported by the Intramural Program of NIAID, NIH.

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  1. National Institute of Allergy and Infectious Disease, National Institutes of Health, Rocky Mountain Laboratories, 903 South 4th Street, Hamilton, Montana 59840, USA.

    • Byron Caughey
    •  & Gerald S. Baron

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The authors declare no competing financial interests.

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Correspondence to Byron Caughey or Gerald S. Baron.

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