Advertisement

Journal of Neurology

, Volume 256, Issue 8, pp 1205–1214 | Cite as

Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases

  • Felix GeserEmail author
  • Maria Martinez-Lage
  • Linda K. Kwong
  • Virginia M.-Y. Lee
  • John Q. Trojanowski
Review

Abstract

Ever since the significance of pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) for human disease has been recognized in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), a number of publications have emerged reporting on this pathology in a variety of neurodegenerative diseases. Given the heterogeneous and, in part, conflicting nature of the recent findings, we here review pathological TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. To this end, we propose a classification scheme in which pathological TDP-43 is the major disease defining pathology in one group, or is present in addition to other neurodegenerative hallmark pathologies in a second category. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders akin to α-synucleinopathies and tauopathies, with the concept of ALS and FTLD-U to be widened to a broad clinico-pathological multisystem disease, i.e., TDP-43 proteinopathy.

Keywords

Amyotrophic lateral sclerosis (ALS) Frontotemporal dementia TDP-43 proteinopathy 

Notes

Acknowledgments

The authors would like to thank T. Schuck and J. Robinson for their expert technical assistance and our collaborators within and beyond the Center for Neurodegenerative Disease Research (CNDR) who contributed to the studies reviewed here from CNDR. Further, they thank their patients and families who made this research possible. This work was funded by the National Institutes of Health (AG10124, AG17586).

References

  1. 1.
    Abhyankar MM, Urekar C, Reddi PP (2007) A novel CpG-free vertebrate insulator silences the testis-specific SP-10 gene in somatic tissues: role for TDP-43 in insulator function. J Biol Chem 282:36143–36154. doi: 10.1074/jbc.M705811200 PubMedCrossRefGoogle Scholar
  2. 2.
    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 61:435–445. doi: 10.1002/ana.21154 PubMedCrossRefGoogle 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 351:602–611. doi: 10.1016/j.bbrc.2006.10.093 PubMedCrossRefGoogle Scholar
  4. 4.
    Arai T, Mackenzie IR, Hasegawa M, Nonoka T, Niizato K, Tsuchiya K, Iritani S, Onaya M, Akiyama H (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117:125–136Google Scholar
  5. 5.
    Armstrong RA, Lantos PL, Cairns NJ (2005) Overlap between neurodegenerative disorders. Neuropathology 25:111–124. doi: 10.1111/j.1440-1789.2005.00605.x PubMedCrossRefGoogle Scholar
  6. 6.
    Ayala YM, Misteli T, Baralle FE (2008) TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression. Proc Natl Acad Sci USA 105:3785–3789. doi: 10.1073/pnas.0800546105 PubMedCrossRefGoogle Scholar
  7. 7.
    Ayala YM, Zago P, D’Ambrogio A, Xu YF, Petrucelli L, Buratti E, Baralle FE (2008) Structural determinants of the cellular localization and shuttling of TDP-43. J Cell Sci 121:3778–3785. doi: 10.1242/jcs.038950 PubMedCrossRefGoogle Scholar
  8. 8.
    Baker M, Mackenzie IR, 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, Berger Z, 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. doi: 10.1038/nature05016 PubMedCrossRefGoogle Scholar
  9. 9.
    Banks GT, Kuta A, Isaacs AM, Fisher EM (2008) TDP-43 is a culprit in human neurodegeneration, and not just an innocent bystander. Mamm Genome 19:299–305. doi: 10.1007/s00335-008-9117-x PubMedCrossRefGoogle Scholar
  10. 10.
    Bigio EH (2008) TAR DNA-binding protein-43 in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimer disease. Acta Neuropathol 116:135–140. doi: 10.1007/s00401-008-0405-z PubMedCrossRefGoogle Scholar
  11. 11.
    Bigio EH (2008) Update on recent molecular and genetic advances in frontotemporal lobar degeneration. J Neuropathol Exp Neurol 67:635–648PubMedCrossRefGoogle Scholar
  12. 12.
    Bose JK, Wang IF, Hung L, Tarn WY, Shen CK (2008) TDP-43 overexpression enhances exon 7 inclusion during the survival of motor neuron pre-mRNA splicing. J Biol Chem 283:28852–28859. doi: 10.1074/jbc.M805376200 PubMedCrossRefGoogle Scholar
  13. 13.
    Brandmeir NJ, Geser F, Kwong LK, Zimmerman E, Qian J, Lee VM, Trojanowski JQ (2008) Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease. Acta Neuropathol 115:123–131. doi: 10.1007/s00401-007-0315-5 PubMedCrossRefGoogle Scholar
  14. 14.
    Brownell B, Oppenheimer DR, Hughes JT (1970) The central nervous system in motor neurone disease. J Neurol Neurosurg Psychiatry 33:338–357. doi: 10.1136/jnnp.33.3.338 PubMedCrossRefGoogle Scholar
  15. 15.
    Buratti E, Baralle FE (2008) Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci 13:867–878. doi: 10.2741/2727 PubMedCrossRefGoogle Scholar
  16. 16.
    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 74:1322–1325. doi: 10.1086/420978 PubMedCrossRefGoogle Scholar
  17. 17.
    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 20:1774–1784. doi: 10.1093/emboj/20.7.1774 PubMedCrossRefGoogle Scholar
  18. 18.
    Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, White CLIII, 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 DM (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22. doi: 10.1007/s00401-007-0237-2 PubMedCrossRefGoogle Scholar
  19. 19.
    Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ, Foong C, White CLIII, Schneider JA, Kretzschmar HA, Carter D, Taylor-Reinwald L, Paulsmeyer K, Strider J, Gitcho M, Goate AM, Morris JC, Mishra M, Kwong LK, Stieber A, Xu Y, Forman MS, Trojanowski JQ, Lee VM, Mackenzie IR (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240. doi: 10.2353/ajpath.2007.070182 PubMedCrossRefGoogle Scholar
  20. 20.
    Chen-Plotkin AS, Geser F, Plotkin JB, Clark CM, Kwong LK, Yuan W, Grossman M, Van Deerlin VM, Trojanowski JQ, Lee VM (2008) Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration. Hum Mol Genet 17:1349–1362. doi: 10.1093/hmg/ddn023 PubMedCrossRefGoogle Scholar
  21. 21.
    Cruts M, Gijselinck I, van der ZJ, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den BM, Cuijt 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. doi: 10.1038/nature05017
  22. 22.
    Daoud H, Valdmanis PN, Kabashi E, Dion P, Dupre N, Camu W, Meininger V, Rouleau GA (2008) Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis. J Med Genet 46:112–114Google Scholar
  23. 23.
    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 113:521–533. doi: 10.1007/s00401-006-0189-y PubMedCrossRefGoogle Scholar
  24. 24.
    Dickson DW (2008) TDP-43 immunoreactivity in neurodegenerative disorders: disease versus mechanism specificity. Acta Neuropathol 115:147–149. doi: 10.1007/s00401-007-0323-5 PubMedCrossRefGoogle Scholar
  25. 25.
    Dickson DW, Josephs KA, Amador-Ortiz C (2007) TDP-43 in differential diagnosis of motor neuron disorders. Acta Neuropathol 114:71–79. doi: 10.1007/s00401-007-0234-5 PubMedCrossRefGoogle Scholar
  26. 26.
    Elman LB, McCluskey L, Grossman M (2008) Motor neuron disease and frontotemporal lobar degeneration: a tale of two disorders linked to TDP-43. Neurosignals 16:85–90. doi: 10.1159/000109762 PubMedCrossRefGoogle Scholar
  27. 27.
    Farrer MJ, Hulihan MM, Kachergus JM, Dachsel JC, Stoessl AJ, Grantier LL, Calne S, Calne DB, Lechevalier B, Chapon F, Tsuboi Y, Yamada T, Gutmann L, Elibol B, Bhatia KP, Wider C, Vilarino-Guell C, Ross OA, Brown LA, Castanedes-Casey M, Dickson DW, Wszolek ZK (2009) DCTN1 mutations in Perry syndrome. Nat Genet 41:163–165Google Scholar
  28. 28.
    Foulds P, McAuley E, Gibbons L, Davidson Y, Pickering-Brown SM, Neary D, Snowden JS, Allsop D, Mann DM (2008) TDP-43 protein in plasma may index TDP-43 brain pathology in Alzheimer’s disease and frontotemporal lobar degeneration. Acta Neuropathol 116:141–146. doi: 10.1007/s00401-008-0389-8 PubMedCrossRefGoogle Scholar
  29. 29.
    Freeman SH, Spires-Jones T, Hyman BT, Growdon JH, Frosch MP (2008) TAR-DNA binding protein 43 in Pick disease. J Neuropathol Exp Neurol 67:62–67. doi: 10.1097/nen.0b013e3181609361 PubMedCrossRefGoogle Scholar
  30. 30.
    Fujishiro H, Uchikado H, Arai T, Hasegawa M, Akiyama H, Yokota O, Tsuchiya K, Togo T, Iseki E, Hirayasu Y (2008) Accumulation of phosphorylated TDP-43 in brains of patients with argyrophilic grain disease. Acta Neuropathol 117:151–158Google Scholar
  31. 31.
    Fujita K, Ito H, Nakano S, Kinoshita Y, Wate R, Kusaka H (2008) Immunohistochemical identification of messenger RNA-related proteins in basophilic inclusions of adult-onset atypical motor neuron disease. Acta Neuropathol 116:439–445. doi: 10.1007/s00401-008-0415-x PubMedCrossRefGoogle Scholar
  32. 32.
    Geser F, Martinez-Lage M, Robinson J, Uryu K, Neumann M, Brandmeir NJ, Xie SX, Kwong L, Elman L, McCluskey L, Clark CM, Malunda J, Miller B, Zimmerman E, Qian J, Van Deerlin VM, Grossman M, Lee VM-Y, Trojanowski JQ (2009) The clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch Neurol (in press)Google Scholar
  33. 33.
    Geser F, Brandmeir NJ, Kwong LK, Martinez-Lage M, Elman L, McCluskey L, Xie SX, Lee VM, Trojanowski JQ (2008) Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis. Arch Neurol 65:636–641. doi: 10.1001/archneur.65.5.636 PubMedCrossRefGoogle Scholar
  34. 34.
    Geser F, Winton MJ, Kwong LK, Xu Y, Xie SX, Igaz LM, Garruto RM, Perl DP, Galasko D, Lee VM, Trojanowski JQ (2007) Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol (Berl) 115:133–145Google Scholar
  35. 35.
    Gijselinck I, Sleegers K, Engelborghs S, Robberecht W, Martin JJ, Vandenberghe R, Sciot R, Dermaut B, Goossens D, van der ZJ, De Pooter T, Del Favero J, Santens P, De Jonghe P, De Deyn PP, Van Broeckhoven C, Cruts M (2007) Neuronal inclusion protein TDP-43 has no primary genetic role in FTD and ALS. Neurobiol Aging. [Epub ahead of print] Google Scholar
  36. 36.
    Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White CLIII, Bigio EH, Caselli R, Baker M, Al Lozi MT, Morris JC, Pestronk A, Rademakers R, Goate AM, Cairns NJ (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63:535–538. doi: 10.1002/ana.21344 PubMedCrossRefGoogle Scholar
  37. 37.
    Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (2004) The microprocessor complex mediates the genesis of microRNAs. Nature 432:235–240. doi: 10.1038/nature03120 PubMedCrossRefGoogle Scholar
  38. 38.
    Grossman M, Wood EM, Moore P, Neumann M, Kwong L, Forman MS, Clark CM, McCluskey LF, Miller BL, Lee VM, Trojanowski JQ (2007) TDP-43 pathologic lesions and clinical phenotype in frontotemporal lobar degeneration with ubiquitin-positive inclusions. Arch Neurol 64:1449–1454. doi: 10.1001/archneur.64.10.1449 PubMedCrossRefGoogle Scholar
  39. 39.
    Guerreiro RJ, Schymick JC, Crews C, Singleton A, Hardy J, Traynor BJ (2008) TDP-43 is not a common cause of sporadic amyotrophic lateral sclerosis. PLoS ONE 3:e2450. doi: 10.1371/journal.pone.0002450 PubMedCrossRefGoogle Scholar
  40. 40.
    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 130:1386–1394. doi: 10.1093/brain/awm065 PubMedCrossRefGoogle Scholar
  41. 41.
    Hasegawa M, Arai T, Nonaka T, Kametani F, Yoshida M, Hashizume Y, Beach TG, Buratti E, Baralle F, Morita M, Nakano I, Oda T, Tsuchiya K, Akiyama H (2008) Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 64:60–70. doi: 10.1002/ana.21425 PubMedCrossRefGoogle Scholar
  42. 42.
    Hatanpaa KJ, Bigio EH, Cairns NJ, Womack KB, Weintraub S, Morris JC, Foong C, Xiao G, Hladik C, Mantanona TY, White CLIII (2008) TAR DNA-binding protein 43 immunohistochemistry reveals extensive neuritic pathology in FTLD-U: a midwest-southwest consortium for FTLD study. J Neuropathol Exp Neurol 67:271–279. doi: 10.1097/NEN.0b013e31816a12a6 PubMedCrossRefGoogle Scholar
  43. 43.
    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) Appearance pattern of TDP-43 in Japanese frontotemporal lobar degeneration with ubiquitin-positive inclusions. Neurosci Lett 419:213–218. doi: 10.1016/j.neulet.2007.04.051 PubMedCrossRefGoogle Scholar
  44. 44.
    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 1184:284–294. doi: 10.1016/j.brainres.2007.09.048 PubMedCrossRefGoogle Scholar
  45. 45.
    Hu WT, Josephs KA, Knopman DS, Boeve BF, Dickson DW, Petersen RC, Parisi JE (2008) Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease. Acta Neuropathol 116:215–220. doi: 10.1007/s00401-008-0400-4 PubMedCrossRefGoogle Scholar
  46. 46.
    Igaz LM, Kwong LK, Xu Y, Truax AC, Uryu K, Neumann M, Clark CM, Elman LB, Miller BL, Grossman M, McCluskey LF, Trojanowski JQ, Lee VM (2008) Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am J Pathol 173:182–194. doi: 10.2353/ajpath.2008.080003 PubMedCrossRefGoogle Scholar
  47. 47.
    Inukai Y, Nonaka T, Arai T, Yoshida M, Hashizume Y, Beach TG, Buratti E, Baralle FE, Akiyama H, Hisanaga S, Hasegawa M (2008) Abnormal phosphorylation of Ser409/410 of TDP-43 in FTLD-U and ALS. FEBS Lett 582:2899–2904. doi: 10.1016/j.febslet.2008.07.027 PubMedCrossRefGoogle Scholar
  48. 48.
    Isaacs AM, Powell C, Webb TE, Linehan JM, Collinge J, Brandner S (2008) Lack of TAR-DNA binding protein-43 (TDP-43) pathology in human prion diseases. Neuropathol Appl Neurobiol 34:446–456. doi: 10.1111/j.1365-2990.2008.00963.x PubMedCrossRefGoogle Scholar
  49. 49.
    Josephs KA, Dickson DW (2007) Frontotemporal lobar degeneration with upper motor neuron disease/primary lateral sclerosis. Neurology 69:1800–1801. doi: 10.1212/01.wnl.0000277270.99272.7e PubMedCrossRefGoogle Scholar
  50. 50.
    Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande VC, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, Pradat PF, Camu W, Meininger V, Dupre N, Rouleau GA (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574. doi: 10.1038/ng.132 PubMedCrossRefGoogle Scholar
  51. 51.
    Kasai T, Tokuda T, Ishigami N, Sasayama H, Foulds P, Mitchell DJ, Mann DM, Allsop D, Nakagawa M (2009) Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neuropathol 117:55–62. doi: 10.1007/s00401-008-0456-1 PubMedCrossRefGoogle Scholar
  52. 52.
    Kuhnlein P, Sperfeld AD, Vanmassenhove B, Van D, V, Lee VM, Trojanowski JQ, Kretzschmar HA, Ludolph AC, Neumann M (2008) Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations. Arch Neurol 65:1185–1189. doi: 10.1001/archneur.65.9.1185
  53. 53.
    Kusters B, van Hoeve BJ, Schelhaas HJ, Ter Laak H, van Engelen BG, Lammens M (2009) TDP-43 accumulation is common in myopathies with rimmed vacuoles. Acta Neuropathol 117:209–211. doi: 10.1007/s00401-008-0471-2 PubMedCrossRefGoogle Scholar
  54. 54.
    Kwong LK, Neumann M, Sampathu DM, Lee VM, Trojanowski JQ (2007) TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease. Acta Neuropathol 114:63–70. doi: 10.1007/s00401-007-0226-5 PubMedCrossRefGoogle Scholar
  55. 55.
    Kwong LK, Uryu K, Trojanowski JQ, Lee VM (2008) TDP-43 proteinopathies: neurodegenerative protein misfolding diseases without amyloidosis. Neurosignals 16:41–51. doi: 10.1159/000109758 PubMedCrossRefGoogle Scholar
  56. 56.
    Lee EB, Lee VM, Trojanowski JQ, Neumann M (2008) TDP-43 immunoreactivity in anoxic, ischemic and neoplastic lesions of the central nervous system. Acta Neuropathol 115:305–311. doi: 10.1007/s00401-007-0331-5 PubMedCrossRefGoogle Scholar
  57. 57.
    Lin WL, Dickson DW (2008) Ultrastructural localization of TDP-43 in filamentous neuronal inclusions in various neurodegenerative diseases. Acta Neuropathol 116:205–213. doi: 10.1007/s00401-008-0408-9 PubMedCrossRefGoogle Scholar
  58. 58.
    Liscic RM, Grinberg LT, Zidar J, Gitcho MA, Cairns NJ (2008) ALS and FTLD: two faces of TDP-43 proteinopathy. Eur J Neurol 15:772–780. doi: 10.1111/j.1468-1331.2008.02195.x PubMedCrossRefGoogle Scholar
  59. 59.
    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 112:539–549. doi: 10.1007/s00401-006-0138-9 PubMedCrossRefGoogle Scholar
  60. 60.
    Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Ravits J, Stewart H, Eisen A, McClusky L, Kretzschmar HA, Monoranu CM, Highley JR, Kirby J, Siddique T, Shaw PJ, Lee VM-Y, Trojanowski JQ (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61:427–434. doi: 10.1002/ana.21147 PubMedCrossRefGoogle Scholar
  61. 61.
    Mackenzie IR, 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. doi: 10.1097/01.jnen.0000174335.27708.0a PubMedCrossRefGoogle Scholar
  62. 62.
    Mackenzie IR, Foti D, Woulfe J, Hurwitz TA (2008) Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions. Brain 131:1282–1293. doi: 10.1093/brain/awn061 PubMedCrossRefGoogle Scholar
  63. 63.
    Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJ, Kumar-Singh S, Akiyama H, Baborie A, Spina S, Dickson DW, Trojanowski JQ, Mann DM (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117:15–18. doi: 10.1007/s00401-008-0460-5 PubMedCrossRefGoogle Scholar
  64. 64.
    Mackenzie IR, Rademakers R (2008) The role of transactive response DNA-binding protein-43 in amyotrophic lateral sclerosis and frontotemporal dementia. Curr Opin Neurol 21:693–700. doi: 10.1097/WCO.0b013e3283168d1d PubMedCrossRefGoogle Scholar
  65. 65.
    Mateen FJ, Josephs KA (2008) TDP-43 is not present in brain tissue of patients with schizophrenia. Schizophr Res 108:297–298Google Scholar
  66. 66.
    McCluskey LF, Elman LB, Martinez-Lage M, Van D, V, Yuan W, Clay D, Siderowf A, Trojanowski JQ (2009) Amyotrophic lateral sclerosis-plus syndrome with TAR DNA-binding protein-43 pathology. Arch Neurol 66:121–124. doi: 10.1001/archneur.66.1.121
  67. 67.
    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 33:6000–6010. doi: 10.1093/nar/gki897 PubMedCrossRefGoogle Scholar
  68. 68.
    Mishra M, Paunesku T, Woloschak GE, Siddique T, Zhu LJ, Lin S, Greco K, Bigio EH (2007) Gene expression analysis of frontotemporal lobar degeneration of the motor neuron disease type with ubiquitinated inclusions. Acta Neuropathol 114:81–94. doi: 10.1007/s00401-007-0240-7 PubMedCrossRefGoogle Scholar
  69. 69.
    Mori F, Tanji K, Zhang HX, Nishihira Y, Tan CF, Takahashi H, Wakabayashi K (2008) Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia. Acta Neuropathol 116:193–203. doi: 10.1007/s00401-008-0396-9 PubMedCrossRefGoogle Scholar
  70. 70.
    Nakamura M, Ito H, Wate R, Nakano S, Hirano A, Kusaka H (2008) Phosphorylated Smad2/3 immunoreactivity in sporadic and familial amyotrophic lateral sclerosis and its mouse model. Acta Neuropathol 115:327–334. doi: 10.1007/s00401-007-0337-z PubMedCrossRefGoogle Scholar
  71. 71.
    Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Duda JE, 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 VM, Trojanowski JQ (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114:221–229. doi: 10.1007/s00401-007-0261-2 PubMedCrossRefGoogle Scholar
  72. 72.
    Neumann M, Kwong LK, Lee EB, Kremmer E, Flatley A, Xu Y, Forman MS, Troost D, Kretzschmar HA, Trojanowski JQ, Lee VM (2009) Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 117:137–149Google Scholar
  73. 73.
    Neumann M, Kwong LK, Sampathu DM, Trojanowski JQ, Lee VM (2007) TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: protein misfolding diseases without amyloidosis. Arch Neurol 64:1388–1394. doi: 10.1001/archneur.64.10.1388 PubMedCrossRefGoogle Scholar
  74. 74.
    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 66:152–157. doi: 10.1097/nen.0b013e31803020b9 PubMedCrossRefGoogle Scholar
  75. 75.
    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 314:130–133. doi: 10.1126/science.1134108 PubMedCrossRefGoogle Scholar
  76. 76.
    Nishihira Y, Tan CF, Hoshi Y, Iwanaga K, Yamada M, Kawachi I, Tsujihata M, Hozumi I, Morita T, Onodera O, Nishizawa M, Kakita A, Takahashi H (2009) Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology. Acta Neuropathol 117:45–53. doi: 10.1007/s00401-008-0443-6 PubMedCrossRefGoogle Scholar
  77. 77.
    Nishihira Y, Tan CF, Onodera O, Toyoshima Y, Yamada M, Morita T, Nishizawa M, Kakita A, Takahashi H (2008) Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions. Acta Neuropathol 116:169–182. doi: 10.1007/s00401-008-0385-z PubMedCrossRefGoogle Scholar
  78. 78.
    Nishihira Y, Tan CF, Toyoshima Y, Yonemochi Y, Kondo H, Nakajima T, Takahashi H (2009) Sporadic amyotrophic lateral sclerosis: widespread multisystem degeneration with TDP-43 pathology in a patient after long-term survival on a respirator. Neuropathology. [Epub ahead of print]Google Scholar
  79. 79.
    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
  80. 80.
    Pamphlett R, Kum JS (2008) TDP-43 inclusions do not protect motor neurons from sporadic ALS. Acta Neuropathol 116:221–222. doi: 10.1007/s00401-008-0392-0 PubMedCrossRefGoogle Scholar
  81. 81.
    Robertson J, Sanelli T, Xiao S, Yang W, Horne P, Hammond R, Pioro EP, Strong MJ (2007) Lack of TDP-43 abnormalities in mutant SOD1 transgenic mice shows disparity with ALS. Neurosci Lett 420:128–132. doi: 10.1016/j.neulet.2007.03.066 PubMedCrossRefGoogle Scholar
  82. 82.
    Roeber S, Mackenzie IR, Kretzschmar HA, Neumann M (2008) TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD. Acta Neuropathol 116:147–157. doi: 10.1007/s00401-008-0395-x PubMedCrossRefGoogle Scholar
  83. 83.
    Rollinson S, Snowden JS, Neary D, Morrison KE, Mann DM, Pickering-Brown SM (2007) TDP-43 gene analysis in frontotemporal lobar degeneration. Neurosci Lett 419:1–4. doi: 10.1016/j.neulet.2007.03.044 PubMedCrossRefGoogle Scholar
  84. 84.
    Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ, Kuntz K, Crook RJ, Sreedharan J, Vance C, Sorenson E, Lippa C, Bigio EH, Geschwind DH, Knopman DS, Mitsumoto H, Petersen RC, Cashman NR, Hutton M, Shaw CE, Boylan KB, Boeve B, Graff-Radford NR, Wszolek ZK, Caselli RJ, Dickson DW, Mackenzie IR, Petrucelli L, Rademakers R (2008) Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet 4:e1000193. doi: 10.1371/journal.pgen.1000193
  85. 85.
    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 169:1343–1352. doi: 10.2353/ajpath.2006.060438 PubMedCrossRefGoogle Scholar
  86. 86.
    Sanelli T, Xiao S, Horne P, Bilbao J, Zinman L, Robertson J (2007) Evidence that TDP-43 is not the major ubiquitinated target within the pathological inclusions of amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 66:1147–1153. doi: 10.1097/nen.0b013e31815c5edd PubMedCrossRefGoogle Scholar
  87. 87.
    Schumacher A, Friedrich P, Diehl-Schmid J, Ibach B, Perneczky R, Eisele T, Vukovich R, Foerstl H, Riemenschneider M (2009) No association of TDP-43 with sporadic frontotemporal dementia. Neurobiol Aging 30:157–159. doi: 10.1016/j.neurobiolaging.2007.05.022 PubMedCrossRefGoogle Scholar
  88. 88.
    Schwab C, Arai T, Hasegawa M, Yu S, McGeer PL (2008) Colocalization of transactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington disease. J Neuropathol Exp Neurol 67:1159–1165. doi: 10.1097/NEN.0b013e31818e8951 PubMedCrossRefGoogle Scholar
  89. 89.
    Skibinski G, Parkinson NJ, Brown JM, Chakrabarti L, Lloyd SL, Hummerich H, Nielsen JE, Hodges JR, Spillantini MG, Thusgaard T, Brandner S, Brun A, Rossor MN, Gade A, Johannsen P, Sorensen SA, Gydesen S, Fisher EM, Collinge J (2005) Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet 37:806–808. doi: 10.1038/ng1609 PubMedCrossRefGoogle Scholar
  90. 90.
    Sleegers K, Brouwers N, Maurer-Stroh S, van Es MA, Van Damme P, van Vught PW, van der ZJ, Serneels S, De Pooter T, Van den BM, Cruts M, Schymkowitz J, De Jonghe P, Rousseau F, van den Berg LH, Robberecht W, Van Broeckhoven C (2008) Progranulin genetic variability contributes to amyotrophic lateral sclerosis. Neurology 71:253–259. doi: 10.1212/01.wnl.0000289191.54852.75
  91. 91.
    Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al Chalabi A, Miller CC, Nicholson G, Shaw CE (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672. doi: 10.1126/science.1154584 PubMedCrossRefGoogle Scholar
  92. 92.
    Steinacker P, Hendrich C, Sperfeld AD, Jesse S, von Arnim CA, Lehnert S, Pabst A, Uttner I, Tumani H, Lee VM, Trojanowski JQ, Kretzschmar HA, Ludolph A, Neumann M, Otto M (2008) TDP-43 in cerebrospinal fluid of patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol 65:1481–1487. doi: 10.1001/archneur.65.11.1481 PubMedCrossRefGoogle Scholar
  93. 93.
    Strong MJ (2008) The syndromes of frontotemporal dysfunction in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 9:323–338. doi: 10.1080/17482960802372371 PubMedCrossRefGoogle Scholar
  94. 94.
    Strong MJ, Grace G, Lomen-Hoerth C, Woolley-Levine S, Goldstein LH, Murphy J, Shoesmith C, Rosenfeld J, Leigh P, Bruijn L, Ince P, Figlewicz D (2009) Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. Amyotroph Lateral Scler (in press)Google Scholar
  95. 95.
    Strong MJ, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C, Shoesmith C (2007) TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci 35:320–327. doi: 10.1016/j.mcn.2007.03.007 PubMedCrossRefGoogle Scholar
  96. 96.
    Sumi H, Kato S, Mochimaru Y, Fujimura H, Etoh M, Sakoda S (2009) Nuclear TAR DNA binding protein 43 expression in spinal cord neurons correlates with the clinical course in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 68:37–47. doi: 10.1097/NEN.0b013e3181919cb5 PubMedCrossRefGoogle Scholar
  97. 97.
    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) 113:535–542Google Scholar
  98. 98.
    Temiz P, Weihl CC, Pestronk A (2008) Inflammatory myopathies with mitochondrial pathology and protein aggregates. J Neurol Sci 278:25–29Google Scholar
  99. 99.
    Thorpe JR, Tang H, Atherton J, Cairns NJ (2008) Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy. J Neural Transm 115:1661–1671. doi: 10.1007/s00702-008-0137-1 PubMedCrossRefGoogle Scholar
  100. 100.
    Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M, Miller BL, Kretzschmar HA, Lee VM, Trojanowski JQ, Neumann M (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67:555–564. doi: 10.1097/NEN.0b013e31817713b5 PubMedCrossRefGoogle Scholar
  101. 101.
    Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, Clay D, Wood EM, Chen-Plotkin AS, Martinez-Lage M, Steinbart E, McCluskey L, Grossman M, Neumann M, Wu IL, Yang WS, Kalb R, Galasko DR, Montine TJ, Trojanowski JQ, Lee VM, Schellenberg GD, Yu CE (2008) TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 7:409–416. doi: 10.1016/S1474-4422(08)70071-1 PubMedCrossRefGoogle Scholar
  102. 102.
    Wang HY, Wang IF, Bose J, Shen CK (2004) Structural diversity and functional implications of the eukaryotic TDP gene family. Genomics 83:130–139. doi: 10.1016/S0888-7543(03)00214-3 PubMedCrossRefGoogle Scholar
  103. 103.
    Wang IF, Reddy NM, Shen CK (2002) Higher order arrangement of the eukaryotic nuclear bodies. Proc Natl Acad Sci USA 99:13583–13588. doi: 10.1073/pnas.212483099 PubMedCrossRefGoogle Scholar
  104. 104.
    Wang IF, Wu LS, Chang HY, Shen CK (2008) TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor. J Neurochem 105:797–806. doi: 10.1111/j.1471-4159.2007.05190.x PubMedCrossRefGoogle Scholar
  105. 105.
    Wang IF, Wu LS, Shen CK (2008) TDP-43: an emerging new player in neurodegenerative diseases. Trends Mol Med 14:479–485. doi: 10.1016/j.molmed.2008.09.001 PubMedCrossRefGoogle Scholar
  106. 106.
    Weihl CC, Temiz P, Miller SE, Watts G, Smith C, Forman M, Hanson PI, Kimonis V, Pestronk A (2008) TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia. J Neurol Neurosurg Psychiatry 79:1186–1189. doi: 10.1136/jnnp.2007.131334 PubMedCrossRefGoogle Scholar
  107. 107.
    Wider C, Dickson DW, Stoessl AJ, Tsuboi Y, Chapon F, Gutmann L, Lechevalier B, Calne DB, Personett DA, Hulihan M, Kachergus J, Rademakers R, Baker MC, Grantier LL, Sujith OK, Brown L, Calne S, Farrer MJ, Wszolek ZK (2008) Pallidonigral TDP-43 pathology in Perry syndrome. Parkinsonism Relat Disord. [Epub ahead of print]Google Scholar
  108. 108.
    Yokoseki A, Shiga A, Tan CF, Tagawa A, Kaneko H, Koyama A, Eguchi H, Tsujino A, Ikeuchi T, Kakita A, Okamoto K, Nishizawa M, Takahashi H, Onodera O (2008) TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 63:538–542. doi: 10.1002/ana.21392 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Felix Geser
    • 1
    Email author
  • Maria Martinez-Lage
    • 1
  • Linda K. Kwong
    • 1
  • Virginia M.-Y. Lee
    • 1
  • John Q. Trojanowski
    • 1
  1. 1.Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

Personalised recommendations