Skip to main content
SpringerLink
Log in

New aspects of the pathology of neurodegenerative disorders as revealed by ubiquitin antibodies

  • Regular Papers
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Summary

Ubiquitin has previously been identified as a component of neuronal inclusions in neurodegenerative disorders. In this investigation, we examined tissue from cases of Alzheimer's disease (AD), Pick's discase, Parkinson's disease (PD), and progressive supranuclear palsy (PSP) to identify previously unrecognized ubiquitinated structures and to assess the evolution of neuronal inclusions. In AD, approximately 60% of neurofibrillary tangles (NFTs) that were stained with an anti-paired helical filaments (PHF) serum were identified by the ubiquitin antibodies. Extracellular NFTs were not labelled with anti-PHF but were unlabelled or weakly labelled with anti-ubiquitin antibodies. In Pick's disease, most Pick bodies were strongly labelled by the ubiquitin antibodies, and in addition some hippocampal CA1 neurones contained granular or strand-like ubiquitin-immunoreactive (IR) inclusions associated with more typical Pick bodies. Typical Lewy bodies in PD cases showed an unlabelled central core with an outer ring intensely labelled by ubiquitin antibodies. Pale bodies in pigmented substantia nigra neurones appeared as large well-defined, rounded structures without an identifiable core or peripheral zone. Some pale bodies were unlabelled by ubiquitin antibodies, but others showed labelling of variable intensity. Pale bodies which were labelled by ubiquitin antibodies tended also to be labelled by BF10, a monoclonal antibody against phosphorylated neurofilaments. We suggest that pale bodies in PD may represent stages in the formation of Lewy bodies. In addition, we observed numerous spindle-shaped ubiquitin-IR swellings of dendrites of pigmented substantia nigra neurones. In contrast to inclusions of AD and Pick's disease, the PHF-positive fibrillary neuronal inclusions of PSP were either unlabelled or only weakly labelled by ubiquitin antibodies. No ubiquitinated structures were seen in neurones from corresponding areas in aged controls. Identification of ubiquitinated proteins in neurodegenerative disorders may provide insights into molecular events associated with cell death.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Anderton BH, Breinberg D, Downes MJ, Green PJ, Tomlinson BE, Ulrich J, Wood JN, Kahn J (1982) Monoclonal antibodies show that neurofibrillary tangles and neurofilaments share antigenic determinants. Nature 298: 84–86

    Google Scholar 

  2. Bancher C, Lassmann H, Budka H, Grundke-Iqbal I, Iqbal K, Wiche G, Seitelberger F (1987) Neurofibrillary tangles in Alzheimer's disease and progressive supranuclear palsy: antigenic similarities and differences. Acta Neuropathol (Berl) 74: 39–46

    Google Scholar 

  3. 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 formation of neurofibrillary tangles in Alzheimer's disease. Brain Res 477: 90–99

    Google Scholar 

  4. Bancher C, Lassmann H, Budka H, Jellinger K, Grundke-Iqbal I, Iqbal K, Wiche G, Seitelberger F, Wisniewski HM (1989) An antigenic profile of Lewy bodies: immunocytochemical indication for protein phosphorylation and ubiquitination. J Neuropathol Exp Neurol 48: 81–93

    Google Scholar 

  5. Braak H, Braak E, Iqbal IG, Iqbal K (1986) Occurrence of neuropil threads in the senile human brain and in Alzheimer's disease: a third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques. Neurosci Lett 65: 351–355

    Google Scholar 

  6. Brion J-P, Couck AM, Passareiro E, Flament-Durand J (1985) Neurofibrillary tangles of Alzheimer's disease: an immunohistochemical study. J Submicrosc Cytol 17: 89–96

    Google Scholar 

  7. Brion J-P, Passareiro H, Nunex J, Flament-Durand J (1985) Mise en evidence immunologique de la proteine tau au niveau des lesions de degenerescence neurofibrillaires de la maladie d'Alzheimer. Arch Biol 95: 229–235

    Google Scholar 

  8. Brion J-P, Power D, Hue D, Anderton BH, Flament-Durand J (1989) Heterogeneity of ubiquitin immunoreactivity in neurofibrillary tangles of Alzheimer's disease. Neurochem Int (in press)

  9. Chou S (1988) Motorneuron inclusions in ALS are heavily ubiquitinated. J Neuropathol Exp Neurol 47: 334 [Abstr]

    Google Scholar 

  10. Cole GM, Timiras PS (1987) Ubiquitin-protein conjugates in Alzheimer's disease lesions. Neurosci Lett 79: 207–212

    Google Scholar 

  11. Cork LC, Sternberger NH, Sternberger LA, Casanova MF, Struble RG, Price DL (1986) Phosphorylated neurofilament antigens in neurofibrillary tangles in Alzheimer's disease. J Neuropathol Exp Neurol 45: 56–64

    Google Scholar 

  12. Delacourte A, Defossez A (1986) Alzheimer's disease: tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments. J Neurol Sci 76: 173–186

    Google Scholar 

  13. Dickson DW, Yen SH, Susuki KI, Davies P, Garcia JH, Hirano A (1986) Ballooned neurones in select neurodegenerative disease contain phosphorylated neurofilament epitopes. Acta Neuropathol (Berl) 71: 216–223

    Google Scholar 

  14. Dickson DW, Ksiezak-Reding H, Davies P, Yen SH (1987) A monoclonal antibody that recognises a phosphorylated epitope in Alzheimer neurofibrillary tangles, neurofilaments and tau proteins immunostains granulovacuolar degeneration. Acta Neuropathol (Berl) 73: 254–258

    Google Scholar 

  15. Galloway PG, Grundke-Iqbal I, Iqbal K, Perry G (1988) Lewy bodies contain epitopes both shared and distinct from Alzheimer neurofibrillary tangles. J Neuropathol Exp Neurol 47: 654–663

    Google Scholar 

  16. Gambetti P, Sheckett G, Ghetti B, Hirano A Dahl D (1983) Neurofibrillary change in human brain: an immunocytochemical study with neurofilament antiserum. J Neuropathol Exp Neurol 42: 69–79

    Google Scholar 

  17. Gibb WRG, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J Neurol Neurosurg Psychiatry 51: 745–752

    Google Scholar 

  18. Goldman JE (1988) Cytoskeletal abnormalities in Parkinson's disease. Adv Behav Biol 34: 191–197

    Google Scholar 

  19. Goldman JE, Yen S-H, Chiu FC, Peress N (1983) Lewy bodies of Parinson's disease contain NF antigens. Science 221: 1082–1084

    Google Scholar 

  20. Greenfield JG, Bosanquet FD (1953) The brain stem lesions in Parkinsonism. J Neurol Neurosurg Psychiatry 16: 213–226

    Google Scholar 

  21. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM (1986) Microtubule-associated protein tau. J Biol Chem 261: 6084–6089

    Google Scholar 

  22. Grundke-Iqbal I, Iqbal K, Tung Y-C, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83: 4913–4917

    Google Scholar 

  23. Hassler R (1983) Zur Pathologie der Paralysis agitans und des postenzephalitischen Parkinsonismus. J Psychol Neurol 48: 387–476

    Google Scholar 

  24. Haugh MC, Probst A, Ulrich J, Kahn J, Anderton BH (1986) Alzheimer neurofibrillary tangles contain phosphorylated and hidden neurofilament epitopes. J Neurol Neurosurg Psychiatry 49: 1213–1220

    Google Scholar 

  25. Hershko A, Ciechanover A (1986) The ubiquitin pathway for the degradation of intracellular proteins. Prog Nucleic Acid Res Mol Biol 33: 19–56

    Google Scholar 

  26. Ihara Y, Nukina N, Miura R, Ogawara M (1986) Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J Biochem 99: 1807–1810

    Google Scholar 

  27. Joachim CL, Morris JH, Selkoe DJ, Kosik KS (1987) Tau epitopes are incorporated into a range of lesions in Alzheimer's disease. J Neuropathol Exp Neurol 46: 611–622

    Google Scholar 

  28. Kahn J, Anderton BH, Probst A, Ulrich J, Esiri M (1985) Immunohistological study of granulovacuolar degeneration using monoclonal antibodies to neurofilaments. J Neurol Neurosurg Psychiatry 48: 924–926

    Google Scholar 

  29. Kosik KS, Duffy LK, Dowling MM, Abraham C, McCluskey A, Selkoe DJ (1984) Microtubule-associated incorporation of certain epitopes into Alzheimer neurofibrillary tangles. Proc Natl Acad Sci USA 81: 7941–7945

    Google Scholar 

  30. Kosik KS, Joachim CI, Selkoe DJ (1986) Microtubule-associated protein tau is a major antigenic component of paired helical filaments in Alzheimer's disease. Proc Natl Acad Sci USA 83: 4044–4048

    Google Scholar 

  31. Kowall NW, Kosik KS (1987) Axonal description and aberrant localisation of tau protein characterise the neuropil pathology of Alzheimer's disease. Ann Neurol 22: 659–664

    Google Scholar 

  32. Kuzuhura S, Mori H, Izumiyama N, Yoshimura M, Ihara Y (1988) Lewy bodies are ubiquitinated. Acta Neuropathol (Berl) 75: 345–353

    Google Scholar 

  33. Leigh PN, Anderton BH, Dodson A, Gallo J-M, Swash M, Power DM (1988) Ubiquitin deposits in anterior horn cells in motor neurone disease. Neurosci Lett 93: 197–203

    Google Scholar 

  34. Lennox G, Lowe J, Morrell K, Landon M, Mayer RJ (1988) Ubiquitin is a component of neurofibrillary tangles in a variety of neurodegenerative disease. Neurosci Lett 94: 211–217

    Google Scholar 

  35. Lennox G, Lowe J, Morrell K, Landon M, Mayer RJ (1989) Anti-ubiquitin immunocytochemistry is more sensitive than conventional techniques in the detection of diffuse Lewy body disease. J Neurol Neurosurg Psychiatry 52: 67–71

    Google Scholar 

  36. Lowe J, Blanchard A, Morrell K, Lennox G, Reynolds L, Billet M, Landon M, Mayer RJ (1988) Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson's disease, Pick's disease, and Alzheimer's disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and Mallory bodies in Alcoholic liver disease. J Pathol 155: 9–15

    Google Scholar 

  37. Lowe J, Lennox G, Jefferson D, Morrell K, MyQuire D, Gray T, Landon M, Mayer RJ (1988) A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochemical localisation of ubiquitin-protein conjugates. Neurosci Lett 94: 203–210

    Google Scholar 

  38. Love S, Saitoh T, Quijada S, Cole GM, Terry RD (1988) Alz-50, ubiquitin and tau immunoreactivity of neurofibrillary tangles, Pick bodies and Lewy bodies. J Neuropathol Exp Neurol 47: 393–405

    Google Scholar 

  39. Mann DM, Marcyniuk B, Yates PO, Neary D, Snowden JS (1988) The progression of the pathological changes of Alzheimer's disease in frontal and temporal neocortex examined both at biopsy and at autopsy. Neuropathol Appl Neurobiol 14: 177–195

    Google Scholar 

  40. Manetto V, Perry G, Tabaton M, Mulvihill P, Fried V, Smith H, Gambetti P, Autilio-Gambetti L (1988) Ubiquitin is associated with abnormal cytoplasmic filaments characteristic of neurodegenerative disease. Proc Natl Acad Sci USA 85: 4501–4505

    Google Scholar 

  41. Miller CCJ, Brion J-P, Calvert R, Chin TK, Eagles PAM, Downes MJ, Flament-Durand J, Haugh M, Kahn J, Probst A, Ulrich J, Anderton BH (1986) Alzheimer's paired helical filaments share epitopes with neurofilament side arms. EMBO J 5: 269–276

    Google Scholar 

  42. Mori H, Kondo J, Ihara Y (1987) Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science 235: 1641–1644

    Google Scholar 

  43. Munoz-Garcia D, Ludwin SK (1984) Classic and generalised variants of Pick's disease: a clinicopathological ultrastructural and immunocytochemical comparative study. Ann Neurol 16: 467–480

    Google Scholar 

  44. Nukina N, Ihara Y (1986) One of the antigenic determinants of paired helical filaments is related to tau protein. J Biochem 99: 1541–1544

    Google Scholar 

  45. Pappolla MA, Shank DL, Alzofon J, Dudley AW (1988) Colloid (hyaline) inclusion bodies in the central nervous system: their presence in the substantia nigra is diagnostic of Parkinson's disease. Hum Pathol 19: 27–31

    Google Scholar 

  46. Perry G, Friedman R, Kang DH, Manetto V, Autilio-Gambetti L, Gambetti P (1987) Antibodies to the neuronal cytoskeleton are elicited by Alzheimer paired helical filament fractions. Brain Res 420: 233–242

    Google Scholar 

  47. Perry G, Friedman R, Shaw G, Chau V (1987) Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of alzheimer disease brains. Proc Natl Acad Sci USA 84: 3033–3036

    Google Scholar 

  48. Pollock NJ, Mirra SS Binder LI, Hansen LA, Wood JG (1986) Filamentous aggregates in Pick's disease, progressive supranuclear palsy, and Alzheimer's disease share antigenic determinants with microtubule-associated protein, tau. Lancet II: 1211

    Google Scholar 

  49. Price DL, Altschuler J, Struble RG, Casanova MF, Cork LC, Murphy DB (1986) Sequestration of tubulin in neurons in Alzheimer's disease. Brain Res 385: 305–310

    Google Scholar 

  50. Probst A, Ulrich J, Heitz PU (1982) Senile dementia of Alzheimer type: astroglial reaction to extracellular neurofibrillary tangles in the hippocampus. An immunocytochemical and electron study. Acta Neuropathol (Berl) 57: 75–79

    Google Scholar 

  51. Probst A, Anderton BH, Ulrich J, Kohler R, Kahn J, Heitx PU (1983) Pick's disease: an immunocytochemical study of neuronal changes. Acta Neuropathol (Berl) 60: 175–182

    Google Scholar 

  52. Probst A, Langui D, Lautenschläger C, Ulrich J, Brion J-P, Anderton BH (1988) Progressive supranuclear palsy: neuropil threads in addition to neurofibrillary tangles. Acta Neuropathol 77: 61–68

    Google Scholar 

  53. Rechsteiner M (1987) Ubiquitin-mediated pathways for intracellular proteolysis. Ann Rev Cell Biol 3: 1–30

    Google Scholar 

  54. Roy S, Wolman L (1969) Ultrastructural observations in Parkinsonism. J Pathol 99: 39–44

    Google Scholar 

  55. Schmidt ML, Gur RE, Gur RC, Trojanowski JQ (1988) Intraneuronal and extracellular neurofibrillary tangles exhibit mutually exclusive cytoskeletal antigens. Ann Neurol 23: 184–189

    Google Scholar 

  56. Steele JC, Richardson JC, Olzewski J (1964) Progressive Supranuclear Palsy. Arch Neurol 10: 333–359

    Google Scholar 

  57. Ulrich J, Haugh M, Anderton BH, Probst A, Lautenschlager C, His B (1987) Alzheimer dementia and Pick bodies are associated with identical phosphorylated neurofilament epitopes. Acta Neuropathol (Berl) 73: 240–246

    Google Scholar 

  58. Wood JG, Mirra SS, Pollock NJ, Binder NJ, Binder LI (1986) Neurofibrillary tangles of Alzheimer's disease share antigenic determinants with the axonal microtubule-associated protein tau. Proc Natl Acad Sci USA 83: 4040–4043

    Google Scholar 

  59. Yamaguchi H, Morimatsu M, Hirai S, Takahashi K (1987) Alzheimer's neurofibrillary tangles are penetrated by astrological processes and appear eosinophilic in their final stages. Acta Neuropathol (Berl) 72: 214–217

    Google Scholar 

  60. Yen SH, Dickson DW, Crowe A, Butler M, Shelanski ML (1987) Alzheimer's neurofibrillary tangles contain epitopes and epitopes in common with the heat-stable microtubule-associated proteins tau and MAP 2. Am J Pathol 126: 81–91

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Immunology St, George's Hospital Medical School, Cranmer Terrace, SW17 0RE, London, Great Britain

    P. N. Leigh, G. E. Dale, D. P. Power, A. Dodson & B. H. Anderton

  2. Department of Neurology, St. George's Hospital Medical School, Cranmer Terrace, SW17 0RE, London, Great Britain

    P. N. Leigh, G. E. Dale, D. P. Power, A. Dodson & B. H. Anderton

  3. Institut für Pathologie, Universität Basel, Schonbeinstrasse 40, CH-4003, Basel, Switzerland

    A. Probst

  4. Department d'Anatomie Pathologique et de Microscopie Electronique, Universite Libre de Bruxelles, Bruxelles, Belgium

    J. -P. Brion

Authors
  1. P. N. Leigh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Probst
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. E. Dale
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. P. Power
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. -P. Brion
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Dodson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B. H. Anderton
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported by the Medical Research Council, The Wellcome Trust, and Medical Research Committee of St George's Hospital Medical School, and the Parkinson's Disease Society of Great Britain

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leigh, P.N., Probst, A., Dale, G.E. et al. New aspects of the pathology of neurodegenerative disorders as revealed by ubiquitin antibodies. Acta Neuropathol 79, 61–72 (1989). https://doi.org/10.1007/BF00308959

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00308959

Key words

Search

Navigation