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Protein-Based Neuropathology and Molecular Classification of Human Neurodegenerative Diseases

  • Gabor G. Kovacs
  • Herbert Budka
Chapter
Part of the Focus on Structural Biology book series (FOSB, volume 7)

Abstract

Neurodegenerative diseases are characterized by death and progressive loss of neurons in distinct areas of the central nervous system. Classification is based on clinical presentation, anatomical regions affected, inclusion bearing cell-types and conformationally altered proteins involved in the process. In this chapter, the current molecular pathological classification of neurodegenerative diseases is reviewed by summarizing the proteins relevant for neurodegenerative diseases and their morphological types as extra- and intracellular deposits.

Keywords

Amyotrophic Lateral Sclerosis Multiple System Atrophy Prion Disease Progressive Supranuclear Palsy Frontotemporal Lobar Degeneration 
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.
    Bredesen DE, Rao RV, Mehlen P (2006) Cell death in the nervous system. Nature 443:796–802PubMedCrossRefGoogle Scholar
  2. 2.
    Wishart TM, Parson SH,Gillingwater TH (2006) Synaptic vulnerability in neurodegenerative disease. J Neuropathol Exp Neurol 65:733–739PubMedCrossRefGoogle Scholar
  3. 3.
    Sayre LM, Perry G, Smith MA (2008) Oxidative stress and neurotoxicity. Chem Res Toxicol 21:172–188PubMedCrossRefGoogle Scholar
  4. 4.
    Mayer RJ, Tipler C, Arnold J, Laszlo L, Al-Khedhairy A, Lowe J, Landon M (1996) Endosome-lysosomes, ubiquitin and neurodegeneration. Adv Exp Med Biol 389:261–269PubMedGoogle Scholar
  5. 5.
    Fink AL (1998) Protein aggregation: folding aggregates, inclusion bodies and amyloid. Fold Des 3:R9–R23PubMedCrossRefGoogle Scholar
  6. 6.
    Dobson CM (2003) Protein folding and misfolding. Nature 426:884–890PubMedCrossRefGoogle Scholar
  7. 7.
    Dickson DW (2005) Required techniques and useful molecular markers in the neuropathologic diagnosis of neurodegenerative diseases. Acta Neuropathol (Berl) 109:14–24CrossRefGoogle Scholar
  8. 8.
    Lee VMY, Goedert M, Trojanowski J (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159PubMedCrossRefGoogle Scholar
  9. 9.
    Goedert M, Klug A, Crowther RA (2006) Tau protein, the paired helical filament and Alzheimer’s disease. J Alzheimers Dis 9:195–207PubMedGoogle Scholar
  10. 10.
    de Silva R, Lashley T, Strand C, Shiarli AM, Shi J, Tian J, Bailey KL, Davies P, Bigio EH, Arima K et al. (2006) An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies. Acta Neuropathol (Berl) 111:329–340CrossRefGoogle Scholar
  11. 11.
    Goedert M, Jakes R (2005) Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta 1739:240–250PubMedGoogle Scholar
  12. 12.
    Dickson DW, Rademakers R, Hutton ML (2007) Progressive supranuclear palsy: pathology and genetics. Brain Pathol 17:74–82PubMedCrossRefGoogle Scholar
  13. 13.
    Masters CL, Beyruether K (2003) Molecular pathogenesis of Alzheimer’s disease. In: Dickson D (ed) Neurodegeneration: The molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 69–73Google Scholar
  14. 14.
    Zetterberg H, Ruetschi U, Portelius E, Brinkmalm G, Andreasson U, Blennow K, Brinkmalm A (2008) Clinical proteomics in neurodegenerative disorders. Acta Neurol Scand 118: 1–11PubMedCrossRefGoogle Scholar
  15. 15.
    Bertram L, Tanzi R (2003) Genetics of Alzheimer’s disease. In: Dickson D (ed) Neurodegeneration: The molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 40–46Google Scholar
  16. 16.
    Chai CK (2007) The genetics of Alzheimer’s disease. Am J Alzheimers Dis Other Demen 22:37–41PubMedCrossRefGoogle Scholar
  17. 17.
    Chandra S, Fornai F, Kwon HB, Yazdani U, Atasoy D, Liu X, Hammer RE, Battaglia G, German DC, Castillo PE et al. (2004) Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci U S A 101:14966–14971PubMedCrossRefGoogle Scholar
  18. 18.
    Clayton DF, George JM (1998) The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci 21:249–254PubMedCrossRefGoogle Scholar
  19. 19.
    Sidhu A, Wersinger C, Vernier P (2004) alpha-Synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson’s disease. FEBS Lett 565: 1–5PubMedCrossRefGoogle Scholar
  20. 20.
    Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R et al. (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 22:8797–8807PubMedGoogle Scholar
  21. 21.
    Sidhu A, Wersinger C, Vernier P (2004) Does alpha-synuclein modulate dopaminergic synaptic content and tone at the synapse? FASEB J 18:637–647PubMedCrossRefGoogle Scholar
  22. 22.
    Wersinger C, Sidhu A (2003) Attenuation of dopamine transporter activity by alpha-synuclein. Neurosci Lett 340:189–192PubMedCrossRefGoogle Scholar
  23. 23.
    Wersinger C, Sidhu A (2005) Disruption of the interaction of alpha-synuclein with microtubules enhances cell surface recruitment of the dopamine transporter. Biochemistry 44:13612–13624PubMedCrossRefGoogle Scholar
  24. 24.
    Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2: 492–501PubMedCrossRefGoogle Scholar
  25. 25.
    Dickson DW (2001) Alpha-synuclein and the Lewy body disorders. Curr Opin Neurol 14:423–432PubMedCrossRefGoogle Scholar
  26. 26.
    Neumann M, Muller V, Kretzschmar HA, Haass C, Kahle PJ (2004) Regional distribution of proteinase K-resistant alpha-synuclein correlates with Lewy body disease stage. J Neuropathol Exp Neurol 63:1225–1235PubMedGoogle Scholar
  27. 27.
    Campbell BC, McLean CA, Culvenor JG, Gai WP, Blumbergs PC, Jakala P, Beyreuther K, Masters CL, Li QX (2001) The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson’s disease. J Neurochem 76:87–96PubMedCrossRefGoogle Scholar
  28. 28.
    Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047PubMedCrossRefGoogle Scholar
  29. 29.
    Gwinn-Hardy K, Singleton AA (2002) Familial Lewy body diseases. J Geriatr Psychiatry Neurol 15:217–223PubMedGoogle Scholar
  30. 30.
    Gasser T (2007) Update on the genetics of Parkinson’s disease. Mov Disord 22(Suppl 17):S343–S350CrossRefGoogle Scholar
  31. 31.
    Prusiner SB (1998) Prions. Proc Natl Acad Sci U S A 95:13363–13383PubMedCrossRefGoogle Scholar
  32. 32.
    Legname G, Baskakov IV, Nguyen HO, Riesner D, Cohen FE, DeArmond SJ, Prusiner SB (2004) Synthetic mammalian prions. Science 305:673–676PubMedCrossRefGoogle Scholar
  33. 33.
    Safar J, Wille H, Itri V, Groth D, Serban H, Torchia M, Cohen FE, Prusiner SB (1998) Eight prion strains have PrP(Sc) molecules with different conformations. Nat Med 4:1157–1165PubMedCrossRefGoogle Scholar
  34. 34.
    Caughey B, Baron GS (2006) Prions and their partners in crime. Nature 443:803–810PubMedCrossRefGoogle Scholar
  35. 35.
    Kovacs GG, Kalev O, Gelpi E, Haberler C, Wanschitz J, Strohschneider M, Molnár MJ, László L, Budka H (2004) The prion protein in human neuromuscular diseases. J Pathol 204:241–247PubMedCrossRefGoogle Scholar
  36. 36.
    Aguzzi A, Heikenwalder M (2006) Pathogenesis of prion diseases: current status and future outlook. Nat Rev Microbiol 4:765–775PubMedCrossRefGoogle Scholar
  37. 37.
    Kovacs GG, Trabattoni G, Hainfellner JA, Ironside JW, Knight RS, Budka H (2002) Mutations of the prion protein gene phenotypic spectrum. J Neurol 249:1567–1582PubMedCrossRefGoogle Scholar
  38. 38.
    Hill AF, Joiner S, Wadsworth JD, Sidle KC, Bell JE, Budka H, Ironside JW, Collinge J (2003) Molecular classification of sporadic Creutzfeldt-Jakob disease. . Brain 126:1333–1346PubMedCrossRefGoogle Scholar
  39. 39.
    Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I, Budka H, Kopp N, Piccardo P et al. (1999) Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46:224–233PubMedCrossRefGoogle Scholar
  40. 40.
    Ayala YM, Pagani F, Baralle FE (2006) TDP43 depletion rescues aberrant CFTR exon 9 skipping. FEBS Lett 580:1339–1344PubMedCrossRefGoogle Scholar
  41. 41.
    Buratti E, Dörk T, Zuccato E, Pagani F, Romano M, Baralle FE (2001) Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J 20:1774–1784PubMedCrossRefGoogle Scholar
  42. 42.
    Wang IF, Reddy NM, Shen CK (2002) Higher order arrangement of the eukaryotic nuclear bodies. Proc Natl Acad Sci U S A 99:13583–13588PubMedCrossRefGoogle Scholar
  43. 43.
    Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E et al. (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672PubMedCrossRefGoogle Scholar
  44. 44.
    Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White CL III, Bigio EH, Caselli R et al. (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63:535–538PubMedCrossRefGoogle Scholar
  45. 45.
    Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, White CL III, Schneider JA, Grinberg LT, Halliday G et al. (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol (Berl) 114:5–22CrossRefGoogle Scholar
  46. 46.
    Cairns NJ, Uryu K, Bigio EH, Mackenzie IR, Gearing M, Duyckaerts C, Yokoo H, Nakazato Y, Jaros E, Perry RH et al. (2004) alpha-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases. Acta Neuropathol (Berl) 108:213–223CrossRefGoogle Scholar
  47. 47.
    Cairns NJ, Lee VM, Trojanowski JQ (2004) The cytoskeleton in neurodegenerative diseases. J Pathol 204:438–449PubMedCrossRefGoogle Scholar
  48. 48.
    Yokota O, Tsuchiya K, Terada S, Ishizu H, Uchikado H, Ikeda M, Oyanagi K, Nakano I, Murayama S, Kuroda S et al. (2008) Basophilic inclusion body disease and neuronal intermediate filament inclusion disease: a comparative clinicopathological study. Acta Neuropathol (Berl) 115:561–575CrossRefGoogle Scholar
  49. 49.
    Orr HT, Zoghbi HY (2007) Trinucleotide repeat disorders. Annu Rev Neurosci 30:575–621PubMedCrossRefGoogle Scholar
  50. 50.
    Takao M, Benson MD, Murrell JR, Yazaki M, Piccardo P, Unverzagt FW, Davis RL, Holohan PD, Lawrence DA, Richardson R et al. (2000) Neuroserpin mutation S52R causes neuroserpin accumulation in neurons and is associated with progressive myoclonus epilepsy. J Neuropathol Exp Neurol 59:1070–1086PubMedGoogle Scholar
  51. 51.
    Schrimpf SP, Bleiker AJ, Brecevic L, Kozlov SV, Berger P, Osterwalder T, Krueger SR, Schinzel A, Sonderegger P (1997) Human neuroserpin (PI12): cDNA cloning and chromosomal localization to 3q26. Genomics 40:55–62PubMedCrossRefGoogle Scholar
  52. 52.
    Davis RL, Holohan PD, Shrimpton AE, Tatum AH, Daucher J, Collins GH, Todd R, Bradshaw C, Kent P, Feiglin D et al. (1999) Familial encephalopathy with neuroserpin inclusion bodies. Am J Pathol 155:1901–1913PubMedGoogle Scholar
  53. 53.
    Davis RL, Shrimpton AE, Holohan PD, Bradshaw C, Feiglin D, Collins GH, Sonderegger P, Kinter J, Becker LM, Lacbawan F et al. (1999) Familial dementia caused by polymerization of mutant neuroserpin. Nature 401:376–379PubMedGoogle Scholar
  54. 54.
    Vidal R, Delisle MB, Ghetti B (2004) Neurodegeneration caused by proteins with an aberrant carboxyl-terminus. J Neuropathol Exp Neurol 63:787–800PubMedGoogle Scholar
  55. 55.
    Vidal R, Ghiso J, Frangione B (2000) New familial forms of cerebral amyloid and dementia. Mol Psychiatry 5:575–576PubMedCrossRefGoogle Scholar
  56. 56.
    Kovacs GG, Gelpi E, Lehotzky A, Höftberger R, Erdei A, Budka H, Ovádi J (2007) The brain-specific protein TPPP/p25 in pathological protein deposits of neurodegenerative diseases. Acta Neuropathol (Berl) 113:153–161CrossRefGoogle Scholar
  57. 57.
    Kovacs GG, László L, Kovács J, Jensen PH, Lindersson E, Botond G, Molnár T, Perczel A, Hudecz F, Mező G et al. (2004) Natively unfolded tubulin polymerization promoting protein TPPP/p25 is a common marker of alpha-synucleinopathies. Neurobiol Dis 17:155–162PubMedCrossRefGoogle Scholar
  58. 58.
    Kovacs GG, László L (2001) The message of ubiquitin immunohistochemistry in conformational neurodegenerative diseases. In: Solomon B, Taraboulos A, Katchalski-Katzir E (eds) Conformational diseases – A compendium. Bialik Institute, Jerusalem, pp 249–258.Google Scholar
  59. 59.
    Wooten MW, Hu X, Babu JR, Seibenhener ML, Geetha T, Paine MG, Wooten MC (2006) Signaling, polyubiquitination, trafficking, and inclusions: Sequestosome 1/p62’s role in neurodegenerative disease. J Biomed Biotechnol 2006:62079PubMedGoogle Scholar
  60. 60.
    Kuusisto E, Kauppinen T, Alafuzoff I (2008) Use of p62/SQSTM1 antibodies for neuropathological diagnosis. Neuropathol Appl Neurobiol 34:169–180PubMedCrossRefGoogle Scholar
  61. 61.
    Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche G, Seitelberger F, Grundke-Iqbal I, Iqbal K, Wisniewski HM (1989) Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res 477:90–99PubMedCrossRefGoogle Scholar
  62. 62.
    Kuusisto E, Parkkinen L, Alafuzoff I (2003) Morphogenesis of Lewy bodies: dissimilar incorporation of alpha-synuclein, ubiquitin, and p62. J Neuropathol Exp Neurol 62:1241–1253PubMedGoogle Scholar
  63. 63.
    Mackenzie IR, Foti D, Woulfe J, Hurwitz TA (2008) Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions. Brain 131:1282–1293PubMedCrossRefGoogle Scholar
  64. 64.
    Pickering-Brown SM (2007) The complex aetiology of frontotemporal lobar degeneration. Exp Neurol 206:1–10PubMedCrossRefGoogle Scholar
  65. 65.
    Neurodegeneration: Duyckaerts C, Dickson DW (2003) Neuropathology of Alzheimer’s disease. In: Dickson D (ed) Neurodegeneration: The molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 47–65Google Scholar
  66. 66.
    Kovacs GG, Head MW, Hegyi I, Bunn TJ, Flicker H, Hainfellner JA, McCardle L, László L, Jarius C, Ironside JW et al. (2002) Immunohistochemistry for the prion protein: comparison of different monoclonal antibodies in human prion disease subtypes. Brain Pathol 12:1–11PubMedGoogle Scholar
  67. 67.
    Kovacs GG, Preusser M, Strohschneider M, Budka H (2005) Subcellular localization of disease-associated prion protein in the human brain. Am J Pathol 166:287–294PubMedGoogle Scholar
  68. 68.
    Koperek O, Kovacs GG, Ritchie D, Ironside JW, Budka H, Wick G (2002) Disease-associated prion protein in vessel walls. Am J Pathol 161:1979–1984PubMedGoogle Scholar
  69. 69.
    Kovacs GG, Head MW, Bunn T, Laszlo L, Will RG, Ironside JW (2000) Clinicopathological phenotype of codon 129 valine homozygote sporadic Creutzfeldt-Jakob disease. Neuropathol Appl Neurobiol 26:463–472PubMedCrossRefGoogle Scholar
  70. 70.
    Probst A, Herzig MC, Mistl C, Ipsen S, Tolnay M (2001) Perisomatic granules (non-plaque dystrophic dendrites) of hippocampal CA1 neurons in Alzheimer’s disease and Pick’s disease: a lesion distinct from granulovacuolar degeneration. Acta Neuropathol (Berl) 102:636–644Google Scholar
  71. 71.
    Tolnay M, Clavaguera F (2004) Argyrophilic grain disease: a late-onset dementia with distinctive features among tauopathies. Neuropathology 24:269–283PubMedCrossRefGoogle Scholar
  72. 72.
    Kovacs GG, Pittman A, Revesz T, Luk C, Lees A, Kiss E, Tariska P, Laszlo L, Molnár K, Molnar MJ et al. (2008) MAPT S305I mutation: implications for argyrophilic grain disease. Acta Neuropathol (Berl). 116:103–118CrossRefGoogle Scholar
  73. 73.
    Saito Y, Ruberu NN, Sawabe M, Arai T, Tanaka N, Kakuta Y, Yamanouchi H, Murayama S (2004) Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol 63:911–918PubMedGoogle Scholar
  74. 74.
    Arima K, Nakamura M, Sunohara N, Nishio T, Ogawa M, Hirai S, Kawai M, Ikeda K (1999) Immunohistochemical and ultrastructural characterization of neuritic clusters around ghost tangles in the hippocampal formation in progressive supranuclear palsy brains. Acta Neuropathol (Berl) 97:565–576CrossRefGoogle Scholar
  75. 75.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 82:239–259CrossRefGoogle Scholar
  76. 76.
    Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486PubMedGoogle Scholar
  77. 77.
    Group W (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging 18:S1–S2CrossRefGoogle Scholar
  78. 78.
    Pocchiari M, Puopolo M, Croes EA, Budka H, Gelpi E, Collins S, Lewis V, Sutcliffe T, Guilivi A, Delasnerie-Laupretre N et al. (2004) Predictors of survival in sporadic Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies. Brain 127:2348–2359PubMedCrossRefGoogle Scholar
  79. 79.
    Dickson DW (1999) Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J Neurol 246 Suppl 2:II6–II15PubMedCrossRefGoogle Scholar
  80. 80.
    Ferrer I, Santpere G, van Leeuwen FW (2008) Argyrophilic grain disease. Brain 131:1416–1432PubMedCrossRefGoogle Scholar
  81. 81.
    Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMedCrossRefGoogle Scholar
  82. 82.
    McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK et al. (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872PubMedCrossRefGoogle Scholar
  83. 83.
    Terada S, Ishizu H, Yokota O, Tsuchiya K, Nakashima H, Ishihara T, Fujita D, Ueda K, Ikeda K, Kuroda S (2003) Glial involvement in diffuse Lewy body disease. Acta Neuropathol (Berl) 105:163–169Google Scholar
  84. 84.
    Piao YS, Wakabayashi K, Hayashi S, Yoshimoto M, Takahashi H (2000) Aggregation of alpha-synuclein/NACP in the neuronal and glial cells in diffuse Lewy body disease: a survey of six patients. Clin Neuropathol 19:163–169PubMedGoogle Scholar
  85. 85.
    Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94:79–100PubMedCrossRefGoogle Scholar
  86. 86.
    Baker KG, Huang Y, McCann H, Gai WP, Jensen PH, Halliday GM (2006) P25alpha immunoreactive but alpha-synuclein immunonegative neuronal inclusions in multiple system atrophy. Acta Neuropathol (Berl) 111:193–19CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Gabor G. Kovacs
    • 1
  • Herbert Budka
  1. 1.Institute of NeurologyMedical University of ViennaAKH 4JAustria

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