Acta Neuropathologica

, Volume 114, Issue 3, pp 221–229

Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases

  • Hanae Nakashima-Yasuda
  • Kunihiro Uryu
  • John Robinson
  • Sharon X. Xie
  • Howard Hurtig
  • John E. Duda
  • Steven E. Arnold
  • Andrew Siderowf
  • Murray Grossman
  • James B. Leverenz
  • Randy Woltjer
  • Oscar L. Lopez
  • Ronald Hamilton
  • Debby W. Tsuang
  • Douglas Galasko
  • Eliezer Masliah
  • Jeffrey Kaye
  • Christopher M. Clark
  • Thomas J. Montine
  • Virginia M. -Y. Lee
  • John Q. Trojanowski
Original Paper

Abstract

Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson’s disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer’s disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.

Keywords

Frontotemporal lobar degeneration TDP-43 Dementia with Lewy bodies Parkinson’s disease 

References

  1. 1.
    Amador-Ortiz C, Lin WL, 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
  2. 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 351:602–611PubMedCrossRefGoogle Scholar
  3. 3.
    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
  4. 4.
    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
  5. 5.
    Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ, Foong C, White CL III, Schneider JA, Kretzschmar HA, Carter D, Paulsmeyer K, Strider J, Gitcho M, Goate AM, Morris JC, Mishra M, Kwong LK, Stieber A, Xu Y, Forman MS, Trojanowski JQ, Lee VM-Y, Mackenzie IR (2007) TDP-43 in Familial and Sporadic Frontotemporal Lobar Degeneration with Ubiquitin Inclusions. Am J Pathol 171:227–240PubMedCrossRefGoogle Scholar
  6. 6.
    Davidson Y, Kelley T, Mackenzie IR, Pickering-Brown S, Du PD, 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
  7. 7.
    Duda JE, Giasson BI, Mabon ME, Lee VM-Y, Trojanowski JQ (2002) Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases. Ann Neurol 52:205–210PubMedCrossRefGoogle Scholar
  8. 8.
    Forman MS, Trojanowski JQ, Lee VM-Y (2004) Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med 10:1055–1063PubMedCrossRefGoogle Scholar
  9. 9.
    Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van DV, Lee VM-Y, Miller BL, Trojanowski JQ, Grossman M (2006) Frontotemporal dementia: clinicopathological correlations. Ann Neurol 59:952–962PubMedCrossRefGoogle Scholar
  10. 10.
    Gelb DJ, Oliver E, Gilman S (1999) Diagnostic criteria for Parkinson disease. Arch Neurol 56:33–39PubMedCrossRefGoogle Scholar
  11. 11.
    Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM-Y (2003) Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300:636–640PubMedCrossRefGoogle Scholar
  12. 12.
    Gidalevitz T, Ben Zvi A, Ho KH, Brignull HR, Morimoto RI (2006) Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311:1471–1474PubMedCrossRefGoogle 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.
    Horiguchi T, Uryu K, Giasson BI, Ischiropoulos H, LightFoot R, Bellmann C, Richter-Landsberg C, Lee VM-Y, Trojanowski JQ (2003) Nitration of tau protein is linked to neurodegeneration in tauopathies. Am J Pathol 163:1021–1031PubMedGoogle Scholar
  15. 15.
    Lee VM-Y, Giasson BI, Trojanowski JQ (2004) More than just two peas in a pod: common amyloidogenic properties of tau and alpha-synuclein in neurodegenerative diseases. Trends Neurosci 27:129–134PubMedCrossRefGoogle Scholar
  16. 16.
    Leverenz JB, Yu CE, Montine TJ, Steinbart E, Bekris LM, Zabetian C, Kwong LK, Lee VM-Y, Schellenberg GD, Bird TD (2007) A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology. Brain 130:1360–1374PubMedCrossRefGoogle Scholar
  17. 17.
    Mackenzie IR, Baborie A, Pickering-Brown S, Du PD, Jaros E, Perry RH, Neary D, Snowden JS, Mann DM (2006) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol (Berl) 112:539–549CrossRefGoogle Scholar
  18. 18.
    Mackenzie IR, Baker M, Pickering-Brown S, Hsiung GY, Lindholm C, Dwosh E, Gass J, Cannon A, Rademakers R, Hutton M, Feldman HH (2006) The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 129:3081–3090PubMedCrossRefGoogle Scholar
  19. 19.
    McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM-Y, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium. Neurology 65:1863–1872PubMedCrossRefGoogle Scholar
  20. 20.
    McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ (2001) Clinical and pathological diagnosis of frontotemporal dementia: report of the work group on frontotemporal dementia and Pick’s disease. Arch Neurol 58:1803–1809PubMedCrossRefGoogle 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.
    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 VM-Y (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRefGoogle Scholar
  23. 23.
    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 gene mutations. J Neuropathol Exp Neurol 66:152–157PubMedCrossRefGoogle Scholar
  24. 24.
    Romijn HJ, van Uum JFM, Breedijk I, Emmering J, Radu I, Pool CW (1999) Double immunolabeling of neuropeptides in the human hypothalamus as analyzed by confocal laser scanning fluorescence microscopy. J Histochem Cytochem 47:229–236PubMedGoogle Scholar
  25. 25.
    Sampathu DM, Neumann M, Kwong LK, Chou TT, Micsenyi M, Truax A, Bruce J, Grossman M, Trojanowski JQ, Lee VM-Y (2006) Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am J Pathol 169:1343–1352PubMedCrossRefGoogle Scholar
  26. 26.
    Seelaar H, Jurgen SH, Azmani A, Kusters B, Rosso S, Majoor-Krakauer D, de Rijik MC, Rizzu P, Brummelhuis MT, van Doorn PA, Kamphorst W, Willemsen R, van Swieten JC (2007) TDP-43 pathology in familial frontotemporal dementia and motor neuron disease without Progranulin mutations. Brain 130:1375–1385PubMedCrossRefGoogle Scholar
  27. 27.
    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 (Berl) 113:535–542CrossRefGoogle Scholar
  28. 28.
    The National Institute of Aging, Reagan Institute Working Group (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
  29. 29.
    Trojanowski JQ, Mattson MP (2003) Overview of protein aggregation in single, double, and triple neurodegenerative brain amyloidoses. Neuromolecular Med 4:1–6PubMedCrossRefGoogle Scholar
  30. 30.
    Uryu K, Richter-Landsberg C, Welch W, Sun E, Goldbaum O, Norris EH, Pham CT, Yazawa I, Hilburger K, Micsenyi M, Giasson BI, Bonini NM, Lee VM-Y, Trojanowski JQ (2006) Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies. Am J Pathol 168:947–961PubMedCrossRefGoogle Scholar
  31. 31.
    Yokota O, Tsuchiya K, Oda T, Ishihara T, de Silva R, Lees AJ, Arai T, Uchihara T, Ishizu H, Kuroda S, Akiyama H (2006) Amyotrophic lateral sclerosis with dementia: an autopsy case showing many Bunina bodies, tau-positive neuronal and astrocytic plaque-like pathologies, and pallido-nigral degeneration. Acta Neuropathol 112:633–645PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Hanae Nakashima-Yasuda
    • 1
  • Kunihiro Uryu
    • 1
  • John Robinson
    • 1
  • Sharon X. Xie
    • 4
  • Howard Hurtig
    • 3
  • John E. Duda
    • 3
    • 6
  • Steven E. Arnold
    • 5
  • Andrew Siderowf
    • 3
  • Murray Grossman
    • 3
  • James B. Leverenz
    • 7
    • 8
    • 10
    • 11
  • Randy Woltjer
    • 9
  • Oscar L. Lopez
    • 12
  • Ronald Hamilton
    • 13
  • Debby W. Tsuang
    • 7
    • 11
  • Douglas Galasko
    • 14
  • Eliezer Masliah
    • 14
    • 15
  • Jeffrey Kaye
    • 16
  • Christopher M. Clark
    • 3
  • Thomas J. Montine
    • 9
  • Virginia M. -Y. Lee
    • 1
  • John Q. Trojanowski
    • 1
    • 2
  1. 1.Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease ResearchUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Institute on AgingUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  3. 3.Department of NeurologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  4. 4.Department of Biostatistics and EpidemiologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  5. 5.Department of PsychiatryUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  6. 6.Parkinson’s Disease Research, Education and Clinical CenterPhiladelphia VAMCPhiladelphiaUSA
  7. 7.Department of Psychiatry and Behavioral SciencesUniversity of WashingtonSeattleUSA
  8. 8.Department of NeurologyUniversity of WashingtonSeattleUSA
  9. 9.Department of PathologyUniversity of WashingtonSeattleUSA
  10. 10.Mental Illness Research, Education, and Clinical CenterVA Puget Sound Health Care SystemSeattleUSA
  11. 11.Parkinson’s Disease Research, Education, and Clinical CenterVA Puget Sound Health Care SystemSeattleUSA
  12. 12.Department of NeurologyUniversity of PittsburghPittsburghUSA
  13. 13.Department of PathologyUniversity of PittsburghPittsburghUSA
  14. 14.Department of NeuroscienceUniversity of California-San DiegoSan DiegoUSA
  15. 15.Department of PathologyUniversity of California-San DiegoSan DiegoUSA
  16. 16.Department of NeurologyOregon Health & Sciences UniversityPortlandUSA

Personalised recommendations