Acta Neuropathologica

, Volume 110, Issue 3, pp 232–238 | Cite as

Redox metals and oxidative abnormalities in human prion diseases

  • Robert B. Petersen
  • Sandra L. Siedlak
  • Hyoung-gon Lee
  • Yong-Sun Kim
  • Akihiko Nunomura
  • Fabrizio Tagliavini
  • Bernardino Ghetti
  • Patrick Cras
  • Paula I. Moreira
  • Rudy J. Castellani
  • Marin Guentchev
  • Herbert Budka
  • James W. Ironside
  • Pierluigi Gambetti
  • Mark A. Smith
  • George Perry
Regular Paper


Prion diseases are characterized by the accumulation of diffuse and aggregated plaques of protease-resistant prion protein (PrP) in the brains of affected individuals and animals. Whereas prion diseases in animals appear to be almost exclusively transmitted by infection, human prion diseases most often occur sporadically and, to a lesser extent, by inheritance or infection. In the sporadic cases (sporadic Creutzfeld-Jakob disease, sCJD), PrP-containing plaques are infrequent, whereas in transmitted (variant CJD) and inherited (Gerstmann-Straussler-Scheinker Syndrome) cases, plaques are a usual feature. In the current study, representative cases from each of the classes of human prion disease were analyzed for the presence of markers of oxidative damage that have been found in other neurodegenerative diseases. Interestingly, we found that the pattern of deposition of PrP, amyloid-β, and redox active metals was distinct for the various prion diseases. Whereas 8-hydroxyguanosine has been shown to be increased in sCJD, and inducible NOS is increased in scrapie-infected mice, well-studied markers of oxidative damage that accumulate in the lesions of other neurodegenerative diseases (such as Alzheimer’s disease, progressive supranuclear palsy, and Parkinson’s disease), such as heme oxygenase-1 and lipid peroxidation, were not found around PrP deposits or in vulnerable neurons. These findings suggest an important distinction in prion-related oxidative stress, indicating that different neurodegenerative pathways are involved in different prion diseases.


Creutzfeld-Jakob disease Gerstmann-Straussler-Scheinker syndrome Oxidative damage Prion Redox metals 


  1. 1.
    Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, Bohlen A von, Schulz-Schaeffer W, Giese A, Westaway D, Kretzschmar H (1997) The cellular prion protein binds copper in vivo. Nature 390:684–687PubMedGoogle Scholar
  2. 2.
    Budka H, Aguzzi A, Brown P, Brucher JM, Bugiani O, Gullotta F, Haltia M, Hauw JJ, Ironside JW, Jellinger K (1995) Neuropathological diagnostic criteria for Creutzfeldt-Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases). Brain Pathol 5:459–466PubMedGoogle Scholar
  3. 3.
    Bugiani O, Giaccone G, Verga L, Pollo B, Frangione B, Farlow MR, Tagliavini F, Ghetti B (1993) Beta PP participates in PrP-amyloid plaques of Gerstmann-Straussler-Scheinker disease, Indiana kindred. J Neuropathol Exp Neurol 52:64–70PubMedGoogle Scholar
  4. 4.
    Castellani RJ, Harris PL, Sayre LM, Fujii J, Taniguchi N, Vitek MP, Founds H, Atwood CS, Perry G, Smith MA (2001) Active glycation in neurofibrillary pathology of Alzheimer disease: N(epsilon)-(carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med 31:175–180CrossRefPubMedGoogle Scholar
  5. 5.
    Castellani RJ, Perry G, Smith MA (2004) Prion disease and Alzheimer’s disease: pathogenic overlap. Acta Neurobiol Exp (Wars) 64:11–17Google Scholar
  6. 6.
    DeArmond SJ (2000) Cerebral amyloidosis in prion diseases. Amyloid 7:3–6PubMedGoogle Scholar
  7. 7.
    Fernaeus S, Halldin J, Bedecs K, Land T (2005) Changed iron regulation in scrapie-infected neuroblastoma cells. Brain Res Mol Brain Res 133:266–273CrossRefPubMedGoogle Scholar
  8. 8.
    Ferrer I (1999) Nuclear DNA fragmentation in Creutzfeldt-Jakob disease: does a mere positive in situ nuclear end-labeling indicate apoptosis? Acta Neuropathol 97:5–12PubMedGoogle Scholar
  9. 9.
    Gambetti P, Kong Q, Zou W, Parchi P, Chen SG (2003) Sporadic and familial CJD: classification and characterisation. Br Med Bull 66:213–239CrossRefPubMedGoogle Scholar
  10. 10.
    Ghetti B, Tagliavini F, Masters CL, Beyreuther K, Giaccone G, Verga L, Farlow MR, Conneally PM, Dlouhy SR, Azzarelli B (1989) Gerstmann-Straussler-Scheinker disease. II. Neurofibrillary tangles and plaques with PrP-amyloid coexist in an affected family. Neurology 39:1453-1461PubMedGoogle Scholar
  11. 11.
    Ghetti B, Tagliavini F, Takao M, Bugiani O, Piccardo P (2003) Hereditary prion protein amyloidoses. Clin Lab Med 23:65–85, viiiCrossRefPubMedGoogle Scholar
  12. 12.
    Guentchev M, Wanschitz J, Voigtlander T, Flicker H, Budka H (1999) Selective neuronal vulnerability in human prion diseases. Fatal familial insomnia differs from other types of prion diseases. Am J Pathol 155:1453–1457PubMedGoogle Scholar
  13. 13.
    Guentchev M, Voigtlander T, Haberler C, Groschup MH, Budka H (2000) Evidence for oxidative stress in experimental prion disease. Neurobiol Dis 7:270–273PubMedGoogle Scholar
  14. 14.
    Guentchev M, Siedlak SL, Jarius C, Tagliavini F, Castellani RJ, Perry G, Smith MA, Budka H (2002) Oxidative damage to nucleic acids in human prion disease. Neurobiol Dis 9:275–281CrossRefPubMedGoogle Scholar
  15. 15.
    Hall D, Edskes H (2004) Silent prions lying in wait: a two-hit model of prion/amyloid formation and infection. J Mol Biol 336:775–786CrossRefPubMedGoogle Scholar
  16. 16.
    Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023PubMedGoogle Scholar
  17. 17.
    Honda K, Smith MA, Zhu X, Baus D, Merrick WC, Tartakoff AM, Hattier T, Harris PL, Siedlak SL, Fujioka H, Liu Q, Moreira PI, Miller FP, Nunomura A, Shimohama S, Perry G (2005) Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron. J Biol Chem [Mar 14; Epub ahead of print]Google Scholar
  18. 18.
    Ironside JW (2000) Pathology of variant Creutzfeldt-Jakob disease. Arch Virol Suppl (16):143–151Google Scholar
  19. 19.
    Kascsak RJ, Rubenstein R, Merz PA, Tonna-DeMasi M, Fersko R, Carp RI, Wisniewski HM, Diringer H (1987) Mouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins. J Virol 61:3688–3693PubMedGoogle Scholar
  20. 20.
    Klatzo I, Gajdusek DC, Zigas V (1959) Pathology of Kuru. Lab Invest 8:799–847PubMedGoogle Scholar
  21. 21.
    Kubler E, Oesch B, Raeber AJ (2003) Diagnosis of prion diseases. Br Med Bull 66:267–279CrossRefPubMedGoogle Scholar
  22. 22.
    Lucas M, Izquierdo G, Munoz C, Solano F (1997) Internucleosomal breakdown of the DNA of brain cortex in human spongiform encephalopathy. Neurochem Int 31:241–244CrossRefPubMedGoogle Scholar
  23. 23.
    Mishra RS, Basu S, Gu Y, Luo X, Zou WQ, Mishra R, Li R, Chen SG, Gambetti P, Fujioka H, Singh N (2004) Protease-resistant human prion protein and ferritin are cotransported across Caco-2 epithelial cells: implications for species barrier in prion uptake from the intestine. J Neurosci 24:11280–11290CrossRefPubMedGoogle Scholar
  24. 24.
    Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, Smith MA (1999) RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J Neurosci 19:1959–1964PubMedGoogle Scholar
  25. 25.
    Nunomura A, Perry G, Pappolla MA, Friedland RP, Hirai K, Chiba S, Smith MA (2000) Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome. J Neuropathol Exp Neurol 59:1011–1017PubMedGoogle Scholar
  26. 26.
    Perry G, Sayre LM, Atwood CS, Castellani RJ, Cash AD, Rottkamp CA, Smith MA (2002) The role of iron and copper in the aetiology of neurodegenerative disorders: therapeutic implications. CNS Drugs 16:339–352PubMedGoogle Scholar
  27. 27.
    Piccardo P, Ghetti B, Dickson DW, Vinters HV, Giaccone G, Bugiani O, Tagliavini F, Young K, Dlouhy SR, Seiler C, et al (1995) Gerstmann-Straussler-Scheinker disease (PRNP P102L): amyloid deposits are best recognized by antibodies directed to epitopes in PrP region 90–165. J Neuropathol Exp Neurol 54:790–801PubMedGoogle Scholar
  28. 28.
    Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383CrossRefPubMedGoogle Scholar
  29. 29.
    Rachidi W, Vilette D, Guiraud P, Arlotto M, Riondel J, Laude H, Lehmann S, Favier A (2003) Expression of prion protein increases cellular copper binding and antioxidant enzyme activities but not copper delivery. J Biol Chem 278:9064–9072CrossRefPubMedGoogle Scholar
  30. 30.
    Roucou X, Gains M, LeBlanc AC (2004) Neuroprotective functions of prion protein. J Neurosci Res 75:153–161CrossRefPubMedGoogle Scholar
  31. 31.
    Sayre LM, Zelasko DA, Harris PL, Perry G, Salomon RG, Smith MA (1997) 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease. J Neurochem 68:2092–2097PubMedGoogle Scholar
  32. 32.
    Sayre LM, Perry G, Smith MA (1999) In situ methods for detection and localization of markers of oxidative stress: application in neurodegenerative disorders. Methods Enzymol 309:133–152PubMedGoogle Scholar
  33. 33.
    Sayre LM, Perry G, Atwood CS, Smith MA (2000) The role of metals in neurodegenerative diseases. Cell Mol Biol (Noisy-le-grand) 46:731–741Google Scholar
  34. 34.
    Sigurdsson EM, Brown DR, Alim MA, Scholtzova H, Carp R, Meeker HC, Prelli F, Frangione B, Wisniewski T (2003) Copper chelation delays the onset of prion disease. J Biol Chem 278:46199–46202CrossRefPubMedGoogle Scholar
  35. 35.
    Smith MA, Kutty RK, Richey PL, Yan SD, Stern D, Chader GJ, Wiggert B, Petersen RB, Perry G (1994) Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer’s disease. Am J Pathol 145:42–47PubMedGoogle Scholar
  36. 36.
    Smith MA, Harris PL, Sayre LM, Perry G (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA 94:9866–9868CrossRefPubMedGoogle Scholar
  37. 37.
    Thackray AM, Knight R, Haswell SJ, Bujdoso R, Brown DR (2002) Metal imbalance and compromised antioxidant function are early changes in prion disease. Biochem J 362:253–258PubMedGoogle Scholar
  38. 38.
    Wong BS, Chen SG, Colucci M, Xie Z, Pan T, Liu T, Li R, Gambetti P, Sy MS, Brown DR (2001) Aberrant metal binding by prion protein in human prion disease. J Neurochem 78:1400–1408CrossRefPubMedGoogle Scholar
  39. 39.
    Wong BS, Liu T, Li R, Pan T, Petersen RB, Smith MA, Gambetti P, Perry G, Manson JC, Brown DR, Sy MS (2001) Increased levels of oxidative stress markers detected in the brains of mice devoid of prion protein. J Neurochem 76:565–572CrossRefPubMedGoogle Scholar
  40. 40.
    Wong BS, Liu T, Paisley D, Li R, Pan T, Chen SG, Perry G, Petersen RB, Smith MA, Melton DW, Gambetti P, Brown DR, Sy MS (2001) Induction of HO-1 and NOS in doppel-expressing mice devoid of PrP: implications for doppel function. Mol Cell Neurosci 17:768–775PubMedGoogle Scholar
  41. 41.
    Zhu X, Castellani RJ, Takeda A, Nunomura A, Atwood CS, Perry G, Smith MA (2001) Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the ‘two hit’ hypothesis. Mech Ageing Dev 123:39–46CrossRefPubMedGoogle Scholar
  42. 42.
    Zhu X, Raina AK, Perry G, Smith MA (2004) Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol 3:219–226CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Robert B. Petersen
    • 1
  • Sandra L. Siedlak
    • 1
  • Hyoung-gon Lee
    • 1
  • Yong-Sun Kim
    • 2
  • Akihiko Nunomura
    • 3
  • Fabrizio Tagliavini
    • 4
  • Bernardino Ghetti
    • 5
  • Patrick Cras
    • 6
  • Paula I. Moreira
    • 7
  • Rudy J. Castellani
    • 8
  • Marin Guentchev
    • 9
  • Herbert Budka
    • 9
  • James W. Ironside
    • 10
  • Pierluigi Gambetti
    • 1
  • Mark A. Smith
    • 1
  • George Perry
    • 1
  1. 1.Institute of PathologyCase Western Reserve UniversityClevelandUSA
  2. 2.College of MedicineHallym UniversityGangwon-doKorea
  3. 3.Department of Psychiatry and NeurologyAsahikawa Medical CollegeAsahikawaJapan
  4. 4.Istituto Neurologico Carlo BestaMilanoItaly
  5. 5.Department of PathologyIndiana University School of MedicineIndianapolisUSA
  6. 6.Universiteits PleiniBorn Bunge FoundationWilrijkBelgium
  7. 7.Center for Neuroscience and Cell Biology of CoimbraUniversity of CoimbraCoimbraPortugal
  8. 8.NeuropathologyMichigan State UniversityEast LansingUSA
  9. 9.Institute of NeurologyMedical University of Vienna and Austrian Reference Center for Human Prion DiseaseViennaAustria
  10. 10.Centre for NeuroscienceThe University of EdinburghEdinburghScotland

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