Skip to main content

Advertisement

Log in

TDP-43 in ubiquitinated inclusions in the inferior olives in frontotemporal lobar degeneration and in other neurodegenerative diseases: a degenerative process distinct from normal ageing

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Ubiquitin immunoreactive (UBQ-ir) inclusions were present to variable extents in the inferior olivary nucleus (ION) in 37/48 (77%) patients with frontotemporal lobar degeneration (FTLD), in 10/11 (91%) patients with motor neurone disease (MND), in 5/5 (100%) patients with Alzheimer’s disease (AD), 5/7 (71%) patients with dementia with Lewy bodies, 13/19 (68%) patients with Parkinson’s disease, 11/11(100%) patients with Progressive Supranuclear Palsy, 2/6 (33%) patients with Multisystem Atrophy, 1/3 (33%) patients with Huntington’s disease and in 14/14 (100%) normal elderly control subjects. In FTLD, UBQ-ir inclusions were present in 26/32 (81%) patients with FTLD-U, in 10/15 (67%) patients with tauopathy, and in the single patient with Dementia Lacking Distinctive Histology. In 13 FTLD-U patients, and in a single AD and in 2 MND patients, the UBQ-ir inclusions had a rounded, spicular or skein-type appearance, and these were also TDP-43 immunoreactive (TDP-43-ir). In all other affected patients in all diagnostic groups, and in control subjects, the UBQ-ir neuronal cytoplasmic inclusions (NCI) were of a conglomerated type, resembling a cluster of large granules or globules, but were never TDP-43-ir. In 3 of the 13 FTLD-U patients with spicular NCI, conglomerated NCI were also present but in separate cells. Double-labelling immunohistochemistry, and confocal microscopy, for UBQ and TDP-43 confirmed that only the spicular UBQ-ir inclusions in patients with FTLD-U, AD and MND contained TDP-43, though in these patients there were occasional TDP-43 immunoreactive inclusions that were not UBQ-ir. Nuclear TDP-43 immunoreactivity was absent in ION in FTLD-U, AD or MND when TDP-43 cytoplasmic inclusions were present, but remained in neurones with UBQ-ir, TDP-43 negative inclusions. The target protein within the UBQ-ir, TDP-43-negative inclusions remains unknown, but present studies indicate that this is not tau, neurofilament or internexin proteins. These TDP-43 negative, UBQ-ir inclusions appear to be more related to ageing than neurodegeneration, and are without apparent diagnostic significance. The pathophysiological mechanism leading to their formation, and any consequences their presence may have on nerve cell function, remain unknown.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Amador-Ortiz C, Lin W-L, Ahmed Z, Personett D, Davies P, Duara R, Graff-Radford NR, Hutton ML, Dickson DW (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445

    Article  PubMed  CAS  Google Scholar 

  2. Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611

    Article  PubMed  CAS  Google Scholar 

  3. Baker M, Mackenzie IRA, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M (2006) Mutations in Progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919

    Article  PubMed  CAS  Google Scholar 

  4. Barden H (1970) Relationship of Golgi thiamine pyrophosphatase and lysosomal acid phosphatase to neuromelanin and lipofuscin in cerebral neurones of ageing rhesus monkeys. J Neuropathol Exp Neurol 29:225–240

    Article  PubMed  CAS  Google Scholar 

  5. Boeve BF, Baker M, Dickson DW, Parisi JE, Giannini C, Jsephs KA, Hutton M, Pickering-Brown SM, Rademakers R, Tang-Wai D, Jack CR, Kantarci K, Shiung MM, Golde T, Smith GE, Geda YE, Knopman DS, Petersen RC (2006) Frontotemporal dementia and Parkinsonism associated with the IVS1 + 1G → A mutation in progranulin: a clinicopathologic study. Brain 129:3103–3114

    Article  PubMed  Google Scholar 

  6. Brooks B, Miller R, Swash M, Munsat T (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293–299

    Article  PubMed  CAS  Google Scholar 

  7. Brun A, Englund E, Gustafson L, Passant U, Mann DMA, Neary D, Snowden JS (1994) Clinical, neuropsychological and neuropathological criteria for fronto-temporal dementia. J Neurol Neurosurg Psychiatry 57:416–418

    Article  Google Scholar 

  8. Cairns NJ, Bigio EH, Mackenzie IRA, Neumann M, Lee VM, Hatanpaa KJ, White CL III, Schneider JA, Grinberg LT, Halliday G, Duyckaerts C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Murayama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DMA (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22

    Article  PubMed  Google Scholar 

  9. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin J-J, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cujit I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924

    Article  PubMed  CAS  Google Scholar 

  10. Davidson Y, Kelley T, Mackenzie IR, Pickering-Brown SM, Du Plessis D, Neary D, Snowden JS, Mann DMA (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol 113:521–533

    Article  PubMed  CAS  Google Scholar 

  11. Dickson DW, Josephs KA, Amador-Ortiz C (2007) TDP-43 in the differential diagnosis of motor neuron disorders. Acta Neuropathol 114:71–79

    Article  PubMed  CAS  Google Scholar 

  12. Dickson DW, Wertin A, Kress Y, Ksiezak-Reding H, Yen S-H (1990) Ubiquitin immunoreactive structures in normal human brains. Lab Invest 63:87–99

    PubMed  CAS  Google Scholar 

  13. Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van Deerlin V, M-Y LeeV, Miller BL, Trojanowski JQ, Grossman M (2006) Frontotemporal dementia: clinicopathological correlations. Ann Neurol 59:952–962

    Article  PubMed  Google Scholar 

  14. Ii K, Ito H, Tanaka K, Hirano A (1997) Immunocytochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly. J Neuropathol Exp Neurol 56:125–131

    Article  PubMed  CAS  Google Scholar 

  15. Josephs KA, Holton JL, Rossor MN, Godbolt AK, Osawa T, Strand K, Khan N, Al-Sarraj S, Revesz T (2004) Frontotemporal lobar degeneration and ubiquitin immunohistochemistry. Neuropathol Appl Neurobiol 30:369–373

    Article  PubMed  CAS  Google Scholar 

  16. Josephs KA, Petersen RC, Knopman DS, Boeve BF, Whitwell JL, Duffy JR, Parisi JE, Dickson DW (2006) Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology 66:41–48

    Article  PubMed  CAS  Google Scholar 

  17. Kato S, Hirano A, Suenaga T, Yen S-H (1990) Ubiquitinated eosinophilic granules in the inferior olivary nucleus. Neuropathol Appl Neurobiol 16:135–139

    Article  PubMed  CAS  Google Scholar 

  18. Katsuse O, Dickson DW (2005) Ubiquitin immunohistochemistry of frontotemporal lobar degeneration differentiates cases with and without motor neurone disease. Alzheimer Dis Assoc Disord 19(suppl 1):S37–S43

    Article  PubMed  CAS  Google Scholar 

  19. Lasn H, Winblad B, Bogdanovic N (2001) The number of neurons in the inferior olivary nucleus in Alzheimer’s disease and normal ageing: a stereological study using the optical fractionator. J Alzheimer’s Disease 3:159–168

    Google Scholar 

  20. 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

    Article  PubMed  CAS  Google Scholar 

  21. Lipton AM, White CL III, Bigio EH (2004) Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration. Acta Neuropathol 108:379–385

    Article  PubMed  Google Scholar 

  22. Litvan I, Hauw JJ, Bartko JJ, Lantos PL, Daniel SE, Horoupian DS, McKee A, Dickson D, Bancher C, Tabaton M, Jellinger K, Anderson DW (1996) Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropath Exp Neurol 55:97–105

    Article  PubMed  CAS  Google Scholar 

  23. Lowe JS, Lennox G, Jefferson D, Morrell K, McQuire D, Gray T, Landon M, Doherty FJ, Mayer RJ (1988) A filamentous inclusion body within anterior horn neurones in motor neurone disease detected by immunocytochemical localisation of ubiquitin. Neurosci Lett 94:203–210

    Article  PubMed  CAS  Google Scholar 

  24. Mackenzie IRA, Feldman H (2003) The relationship between extramotor ubiquitin-immunoreactive neuronal inclusions and dementia in motor neurone disease. Acta Neuropathol 105:98–102

    PubMed  CAS  Google Scholar 

  25. Mackenzie IRA, Feldman HH (2005) Ubiquitin immunohistochemistry suggests classic Motor Neuron Disease, Motor Neuron Disease with dementia and Frontotemporal dementia of the Motor Neuron Disease type represent a clinicopathologic spectrum. J Neuropathol Exp Neurol 64:730–739

    Article  PubMed  Google Scholar 

  26. Mackenzie IRA, Baborie A, Pickering-Brown SM, Du Plessis D, Jaros E, Perry RH, Neary D, Snowden JS, Mann DMA (2006) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration. Acta Neuropathol 112:539–549

    Article  PubMed  Google Scholar 

  27. Mackenzie IRA, Baker M, Pickering-Brown S, Hsiung G-Y, Lindholm C, Dwosh E, Gass J, Cannon A, Rademakers R, Hutton M, Feldman H (2006) The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 129:3081–3090

    Article  PubMed  Google Scholar 

  28. Mackenzie IRA, Shi J, Shaw CL, Du Pleassis D, Neary D, Snowden D, Mann DMA (2006) dementia lacking distinctive histology (DLDH) revisited. Acta Neuropathol 112:551–559

    Article  PubMed  Google Scholar 

  29. Mackenzie IRA, Neumann M, Bigio E, Cairns NJ, Alafuzoff I, Krill J, Kovacs GG, Ghetti B, Halliday G, Holm IR, Ince PG, Kamphourst W, Revesz T, Rozemuller AJM, Kumar-Singh S, Akiyama H, Baborie A, Spina S, Dickson DW, Trojanowski JQ, Mann DMA (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117:15–18

    Article  PubMed  Google Scholar 

  30. Mann DMA, Sinclair KGA (1978) The quantitative assessment of lipofuscin pigment, cytoplasmic RNA and nucleolar volume in senile dementia. Neuropathol Appl Neurobiol 4:129–135

    Article  PubMed  CAS  Google Scholar 

  31. Mann DMA, Yates PO (1974) Ageing in the human nervous system. I The lipofuscin content of nerve cells. Brain 97:481–488

    Article  PubMed  CAS  Google Scholar 

  32. Mann DMA, Yates PO, Stamp JE (1978) Relationship of lipofuscin pigment to ageing in the human nervous system. J Neurol Sci 35:83–93

    Article  Google Scholar 

  33. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson JA, Ince PG, Bergeron C, Burns A, Miller BL, Lovestone S, Collerton D, Jansen EN, Ballard C, de Vos RA, Wilcock GK, Jellinger KA, Perry RH (1996) Consensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47:1113–1124

    PubMed  CAS  Google Scholar 

  34. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, Belle G, Berg L (1991) The consortium to establish a registry for Alzheimer’s disease. Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486

    PubMed  CAS  Google Scholar 

  35. Moatamed F (1966) Cell frequencies in the human inferior olivary nuclear complex. J Comp Neurol 128:109–116

    Article  PubMed  CAS  Google Scholar 

  36. Monagle RD, Brody H (1974) Effects of age upon the main nucleus of the inferior olive in humans. J Comp Neurol 155:61–66

    Article  PubMed  CAS  Google Scholar 

  37. Mott RT, Dickson DW, Trojanowski JQ, Zhukareva V, Lee VM, Forman M, Van Deerlin V, Ervin JF, Wang DS, Schmechel DE, Hulette CM (2005) Neuropathologic, biochemical, and molecular characterization of the frontotemporal dementias. J Neuropathol Exp Neurol 64:420–428

    PubMed  CAS  Google Scholar 

  38. Mukherjee O, Pastor P, Cairns NJ, Chakraverty S, Kauwe JSK, Shears S, Behrens MJ, Budde J, Hinrichs AL, Norton J, Levich D, Taylor-Reinwald L, Gitcho M, Tu P-H, Grinberg LT, Liscic RM, Armendariz J, Morris JC, Goate AM (2006) HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol 60:314–322

    Article  PubMed  CAS  Google Scholar 

  39. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 51:1546–1554

    PubMed  CAS  Google Scholar 

  40. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuk T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar H, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133

    Article  PubMed  CAS  Google Scholar 

  41. Pickering-Brown SM, Baker M, Gass J, Boeve BF, Loy CT, Brooks WS, Mackenzie IR, Martins RN, Kwok JB, Halliday GM, Kril JJ, Schofield PR, Mann DM, Hutton M (2006) Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain 129:3124–3126

    Article  PubMed  Google Scholar 

  42. Sandoz P, Meier-Ruge W (1977) Age-related loss of nerve cells from the human inferior olives and unchanged volume of its grey matter. IRCS Med Sci 5:376

    Google Scholar 

  43. Shi J, Shaw CL, Richardson AMT, Bailey K, Tian J, Varma AR, Neary D, Snowden JS, Mann DMA (2005) Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation. Acta Neuropathol 110:501–512

    Article  PubMed  Google Scholar 

  44. Snowden JS, Pickering-Brown SM, Mackenzie IR, Richardson AMT, Varma A, Neary D, Mann DMA (2006) Progranulin gene mutations associated with frontotemporal dementia and progressive aphasia. Brain 129:3091–3102

    Article  PubMed  CAS  Google Scholar 

  45. Taniguchi S, McDonagh AM, Pickering-Brown SM, Umeda Y, Iwatsubo T, Hasegawa M, Mann DMA (2004) The neuropathology of frontotemporal lobar degeneration with respect to the cytological and biochemical characteristics of tau protein. Neuropathol Appl Neurobiol 30:1–18

    Article  PubMed  CAS  Google Scholar 

  46. Trojanowski JQ, Revesz T, Neuropathology Working Group on MS (2007) Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol Appl Neurobiol 33:615–620

    Article  PubMed  CAS  Google Scholar 

  47. Woulfe J, Kertesz A, Munoz D (2001) Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions. Acta Neuropathol 102:94–102

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Dr. Bandopadhyaya is funded by the Parkinson’s Disease Society of UK. The work of the Manchester Brain Bank is supported by the Alzheimers Research Trust and Alzheimers Society through the Brains for Dementia Research Initiative. We thank The UK Parkinson’s Disease Society Tissue Bank for providing tissue samples.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David M. A. Mann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Davidson, Y., Amin, H., Kelley, T. et al. TDP-43 in ubiquitinated inclusions in the inferior olives in frontotemporal lobar degeneration and in other neurodegenerative diseases: a degenerative process distinct from normal ageing. Acta Neuropathol 118, 359–369 (2009). https://doi.org/10.1007/s00401-009-0526-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-009-0526-z

Keywords

Navigation