Acta Neuropathologica

, Volume 115, Issue 3, pp 305–311 | Cite as

TDP-43 immunoreactivity in anoxic, ischemic and neoplastic lesions of the central nervous system

  • Edward B. Lee
  • Virginia M.-Y. Lee
  • John Q. Trojanowski
  • Manuela Neumann
Original Paper

Abstract

TDP-43 proteinopathies are a newly categorized group of neurodegenerative diseases characterized by progressive cognitive and motor impairments associated with the abnormal accumulation and mislocalization of the nuclear TAR–DNA-binding protein-43 (TDP-43) in neurons and glia. Little is known about the expression and distribution of TDP-43 in normal and pathologic states. To determine whether TDP-43 inclusions arise in response to metabolic insults such as anoxia or ischemia, a panel of anoxic, ischemic and neoplastic lesions was examined for TDP-43 expression by immunohistochemistry. These lesions did not exhibit TDP-43 inclusions like those seen in neurodegenerative frontotemporal dementia and motor neuron disease. However, TDP-43 was found in Rosenthal fibers and eosinophilic granular bodies associated with low-grade tumors and reactive brain tissue. Furthermore, cytoplasmic TDP-43 was seen in M-phase tumor cells, but not in mitotic spindles. These findings expand our knowledge of the distribution and localization of TDP-43, and indicate that the TDP-43 inclusions seen in frontotemporal dementias and motor neuron diseases are specific to a neurodegenerative process.

Keywords

TDP-43 Ischemia Anoxia Rosenthal fiber Eosinophilic granular body Mitosis Hippocampal sclerosis 

Notes

Acknowledgments

Supported by an intradepartmental grant from the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania (to EBL) and a grant by the Federal Ministry of Education and Research (BMBF: “Degenerative dementias: Target identification, validation and translation into treatment strategies (01GI0704)” to MN).

References

  1. 1.
    Acharya KK, Govind CK, Shore AN, Stoler MH, Reddi PP (2006) cis-requirement for the maintenance of round spermatid-specific transcription. Dev Biol 295:781–790PubMedCrossRefGoogle Scholar
  2. 2.
    Amador-Ortiz C, Lin WIL, 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 61:435–445PubMedCrossRefGoogle Scholar
  3. 3.
    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 351:602–611PubMedCrossRefGoogle Scholar
  4. 4.
    Ayala YM, Pantano S, D’Ambrogio A, Buratti E, Brindisi A, Marchetti C, Romano M, Baralle FE (2005) Human, Drosophila, and C. elegans TDP43 nucleic acid binding properties and splicing regulatory function. J Mol Biol 348:575–588PubMedCrossRefGoogle Scholar
  5. 5.
    Brenner M, Johnson AN, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A (2001) Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 27:117–120PubMedCrossRefGoogle Scholar
  6. 6.
    Buratti E, Dork 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
  7. 7.
    Buratti E, Brindisi A, Pagani F, Baralle FE (2004) Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance. Am J Hum Genet 74:1322–1325PubMedCrossRefGoogle Scholar
  8. 8.
    Davidson Y, Kelley T, Mackenzie IR, Pickering-Brown S, Du Plessis D, Neary D, Snowden JS, Mann DM (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol (Berl) 113:521–533CrossRefGoogle Scholar
  9. 9.
    Dickson DW, Josephs KA, Amador-Ortiz C (2007) TDP-43 in differential diagnosis of motor neuron disorders. Acta Neuropathol (Berl) 114:71–79CrossRefGoogle Scholar
  10. 10.
    Forman MS, Trojanowski, Lee VMY (2007) TDP-43: a novel neurodegenerative proteinopathy. Curr Opin Neurobiol. doi: 10.1016/j.conb.2007.08.005
  11. 11.
    Geser F, Winton MJ, Kwong LK, Xu Y, Xie SX, Igaz LM, Garruto RM, Perl DP, Galasko D, Lee VMY, Trojanowski JQ (2008) Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol 115:133–145PubMedCrossRefGoogle Scholar
  12. 12.
    Grossman M, Wood EM, Moore P, Neumann M, Kwong L, Forman MS, Clark CM, McCluskey LF, Miller BL, Lee VMY, Trojanowski JQ (2007) TDP-43 pathologic lesions and clinical phenotype in frontotemporal lobar degeneration with ubiquitin-positive inclusions. Arch Neurol 64:1449–1454PubMedCrossRefGoogle Scholar
  13. 13.
    Hasegawa M, Arai T, Akiyama H, Nonaka T, Mori H, Hashimoto T, Yamazaki M, Oyanagi K (2007) TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. Brain 130:1386–1394PubMedCrossRefGoogle Scholar
  14. 14.
    Higashi S, Iseki E, Yamamoto R, Minegishi M, Hino H, Fujisawa K, Togo T, Katsuse O, Uchikado H, Furukawa Y, Kosaka K, Arai H (2007) Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res. doi: 10.1016/j.brainres.2007.09.048
  15. 15.
    Iwaki T, Iwaki A, Tateishi J, Sakaki Y, Goldman JE (1993) Alpha B-crystallin and 27-kD heat shock protein are regulated by stress conditions in the central nervous system and accumulate in Rosenthal fibers. Am J Pathol 143:487–495PubMedGoogle Scholar
  16. 16.
    Kwong LK, Neumann M, Sampathu DM, Lee VMY, Trojanowski JQ (2007) TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease. Acta Neuropathol (Berl) 114:63–70CrossRefGoogle Scholar
  17. 17.
    Lowe J, Blanchard A, Morrell K, Lennox G, Reynolds L, Billett 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 fibers in cerebellar astrocytomas, cytoplasmic bodies in muscle, and Mallory bodies in alcoholic liver disease. J Pathol 155:9–15PubMedCrossRefGoogle Scholar
  18. 18.
    Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Rayits J, Stewart H, Eisen A, McClusky L, Kretzschmar HA, Monoranu CM, Highley JR, Kirby J, Siddique T, Shaw PJ, Lee VMY, Trojanowski JQ (2007) Pathologic TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61:427–434PubMedCrossRefGoogle Scholar
  19. 19.
    Mathern GW, Adelson PD, Cahan LD, Leite JP (2002) Hippocampal neuron damage in human epilepsy: Meyer’s hypothesis revisited. Prog Brain Res 135:237–251PubMedGoogle Scholar
  20. 20.
    Meldrum BS (1997) First Alfred Meyer memorial lecture. epileptic brain damage a consequence and a cause of seizures. Neuropathol Appl Neurobiol 23:185–201PubMedCrossRefGoogle Scholar
  21. 21.
    Mercado PA, Ayala YM, Romano M, Buratti E, Baralle FE (2005) Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene. Nucleic Acids Res 33:6000–6010PubMedCrossRefGoogle Scholar
  22. 22.
    Murayama S, Bouldin TW, Suzuki K (1992) Immunocytochemical and ultrastructural studies of eosinophilic granular bodies in astrocytic tumors. Acta Neuropathol (Berl) 83:408–414CrossRefGoogle Scholar
  23. 23.
    Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Arnold SE, Siderowf A, Grossman M, Leverenz JB, Woltjer R, Lopez OL, Hamilton R, Tsuang DW, Galasko D, Masliah E, Kaye J, Clark CM, Montine TJ, Lee VMY, Trojanowski JQ (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114:221–229PubMedCrossRefGoogle Scholar
  24. 24.
    Neumann M, Kwong LK, Sampathu DM, Trojanowski JQ, Lee VMY (2007) TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: protein misfolding diseases without amyloidoses. Arch Neurol 64:1388–1394PubMedCrossRefGoogle Scholar
  25. 25.
    Neumann M, Kwong LK, Truax AC, Vanmassenhove B, Kretzschmar HA, Van Deerlin VM, Clark CM, Grossman M, Miller BL, Trojanowski JQ, Lee VMY (2007) TDP-43 positive white matter pathology in frontotemporal lobar degeneration with ubiquitin-positive inclusions. J Neuropathol Exp Neurol 66:177–183PubMedGoogle Scholar
  26. 26.
    Neumann M, Mackenzie IR, Cairns NJ, Boyer PJ, Markesbery WR, Smith CD, Taylor JP, Kretzschmar HA, Kimonis VE, Forman MS (2007) TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP mutations. J Neuropathol Exp Neurol 66:152–157PubMedCrossRefGoogle Scholar
  27. 27.
    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VMY (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRefGoogle Scholar
  28. 28.
    Ou SH, Wu F, Harrich D, Garcia-Martinez LF, Gaynor RB (1995) Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 69:3584–3596PubMedGoogle Scholar
  29. 29.
    Tan CF, Eguchi H, Tagawa A, Onodera O, Iwasaki T, Tsujino A, Nishizawa M, Kakita A, Takahashi H (2007) TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol 113:535–542PubMedCrossRefGoogle Scholar
  30. 30.
    Tomokane N, Iwaki T, Tateishi J, Iwaki A, Goldman JE (1991) Rosenthal fibers share epitopes with alpha Β-crystallin, glial fibrillary acidic protein, and ubiquitin, but not with vimentin. Immunoelectron microscopy with colloidal gold. Am J Pathol 138:875–885PubMedGoogle Scholar
  31. 31.
    Volpe JJ (ed) (2001) Neurology of the newborn. W.B. Saunders, Philadelphia, pp 217–396Google Scholar
  32. 32.
    Wang IF, Reddy NM, Shen CK (2002) Higher order arrangement of the eukaryotic nuclear bodies. Proc Natl Acad Sci USA 99:13585–13588Google Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Edward B. Lee
    • 1
  • Virginia M.-Y. Lee
    • 1
  • John Q. Trojanowski
    • 1
  • Manuela Neumann
    • 2
  1. 1.Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease ResearchUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Center for Neuropathology and Prion ResearchLudwig-Maximilians University MunichMunichGermany

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