Acta Neuropathologica

, Volume 121, Issue 2, pp 207–218 | Cite as

Distinct pathological subtypes of FTLD-FUS

  • Ian R. A. MackenzieEmail author
  • David G. Munoz
  • Hirofumi Kusaka
  • Osamu Yokota
  • Kenji Ishihara
  • Sigrun Roeber
  • Hans A. Kretzschmar
  • Nigel J. Cairns
  • Manuela Neumann
Original Paper


Most cases of frontotemporal lobar degeneration (FTLD) are characterized by abnormal intracellular accumulation of either tau or TDP-43 protein. However, in ~10% of cases, composed of a heterogenous collection of uncommon disorders, the molecular basis remains to be uncertain. We recently discovered that the pathological changes in several tau/TDP-43-negative FTLD subtypes are immunoreactive (ir) for the fused in sarcoma (FUS) protein. In this study, we directly compared the pattern of FUS-ir pathology in cases of atypical FTLD-U (aFTLD-U, N = 10), neuronal intermediate filament inclusion disease (NIFID, N = 5) and basophilic inclusion body disease (BIBD, N = 8), to determine whether these are discrete entities or represent a pathological continuum. All cases had FUS-ir pathology in the cerebral neocortex, hippocampus and a similar wide range of subcortical regions. Although there was significant overlap, each group showed specific differences that distinguished them from the others. Cases of aFTLD-U consistently had less pathology in subcortical regions. In addition, the neuronal inclusions in aFTLD-U usually had a uniform, round shape, whereas NIFID and BIBD were characterized by a variety of inclusion morphologies. In all cases of aFTLD-U and NIFID, vermiform neuronal intranuclear inclusions (NII) were readily identified in the hippocampus and neocortex. In contrast, only two cases of BIBD had very rare NII in a single subcortical region. These findings support aFTLD-U, NIFID and BIBD as representing closely related, but distinct entities that share a common molecular pathogenesis. Although cases with overlapping pathology may exist, we recommend retaining the terms aFTLD-U, NIFID and BIBD for specific FTLD-FUS subtypes.


Frontotemporal dementia Frontotemporal lobar degeneration Fused in sarcoma Atypical frontotemporal lobar degeneration with ubiquitinated inclusions Neuronal intermediate filament inclusion disease Basophilic inclusion body disease 



We thank Margaret Luk and Mareike Schroff for their excellent technical assistance. This work was supported by grants from Canadian Institutes of Health Research (grant number 74580, IM); the Pacific Alzheimer Research Foundation (IM); the German Federal Ministry of Education and Research (grant number 01GI0704, MN); the Stavros-Niarchos Foundation (MN); the Synapsis Foundation (MN); and the German Brain Bank “BrainNet” (HK).


  1. 1.
    Andersson MK, Stahlberg A, Arvidsson Y et al (2008) The multifunctional FUS, EWS, and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response. BMC Cell Biol 9:37CrossRefPubMedGoogle Scholar
  2. 2.
    Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611CrossRefPubMedGoogle Scholar
  3. 3.
    Baumer D, Hilton D, Paine AML et al (2010) Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations. Neurology 75:611–618CrossRefPubMedGoogle Scholar
  4. 4.
    Behring B, Beuche W, Kretzschmar HA (1998) Progressive dementia with parkinsonism in corticobasal degeneration and brainstem degeneration with neuronal inclusions. Neurology 51:285–288PubMedGoogle Scholar
  5. 5.
    Bigio EH, Lipton AM, White CL, Dickson DW, Hirano A (2003) Frontotemporal and motor neurone degeneration with neurofilament inclusion bodies: additional evidence for overlap between FTD and ALS. Neuropathol Appl Neurobiol 29:239–253CrossRefPubMedGoogle Scholar
  6. 6.
    Blair IP, Williams KL, Warrich ST et al (2010) FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis. J Neurol Neurosurg Psychiatry 81:639–645CrossRefPubMedGoogle Scholar
  7. 7.
    Cairns NJ, Grossman M, Arnold SE et al (2004) Clinical and neuropathological variation in neuronal intermediate filament inclusion disease. Neurology 63:1376–1384PubMedGoogle Scholar
  8. 8.
    Cairns NJ, Perry RH, Jaros E et al (2003) Patients with a novel neurofilamentopathy: dementia with neurofilament inclusions. Neurosci Lett 341:177–180CrossRefPubMedGoogle Scholar
  9. 9.
    Cairns NJ, Zhukareva V, Uryu K et al (2004) α-Internexin is present in the pathological inclusions of neuronal intermediate filament inclusion disease. Am J Pathol 164:2153–2161PubMedGoogle Scholar
  10. 10.
    Davidson Y, Kelley T, Mackenzie IRA et al (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol 113:521–533CrossRefPubMedGoogle Scholar
  11. 11.
    Fujii R, Okabe S, Urushido T et al (2005) The RNA binding protein TLS is translocated to dendritic spines by mGluR5 activation and regulates spine morphology. Curr Biol 15:587–593CrossRefPubMedGoogle Scholar
  12. 12.
    Fujii R, Takumi T (2005) TLS facilitates transport of mRNA encoding an actin-stabilizing protein to dendritic spines. J Cell Sci 118:5755–5765CrossRefPubMedGoogle Scholar
  13. 13.
    Fujita Y, Fujita S, Takatama M, Ikeda M, Okamoto K (2010) Numerous FUS-positive inclusions in an elderly woman with motor neuron disease. Neuropathology. doi: 10.1111/j.1440-1789.2010.01146.x
  14. 14.
    Groen EJN, van ES MA, van Vught PWJ et al (2010) FUS mutations in familial amyotrophic lateral sclerosis in the Netherlands. Arch Neurol 67:224–230CrossRefPubMedGoogle Scholar
  15. 15.
    Hamada K, Fukazawa T, Yanagihara T et al (1995) Dementia with ALS features and diffuse Pick body-like inclusions (atypical Pick’s disease?). Clin Neuropathol 14:1–6PubMedGoogle Scholar
  16. 16.
    Hewitt C, Kirby J, Highley R et al (2010) Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 67:455–461CrossRefPubMedGoogle Scholar
  17. 17.
    Huang EJ, Zhang J, Geser F et al (2010) Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions. Brain Pathol 20:1069–1076CrossRefPubMedGoogle Scholar
  18. 18.
    Ishihara K, Araki S, Ihori N et al (2006) An autopsy case of frontotemporal dementia with severe dysarthria and motor neuron disease showing numerous basophilic inclusions. Neuopathology 26:447–454CrossRefGoogle Scholar
  19. 19.
    Josephs KA, Holton JL, Rossor MN et al (2003) Neurofilament inclusion body disease: a new proteinopathy? Brain 126:2291–2303CrossRefPubMedGoogle Scholar
  20. 20.
    Josephs KA, Holton JL, Rossor MN et al (2004) Frontotemporal lobar degeneration and ubiquitin immunohistochemistry. Neuropathol Appl Neurobiol 30:369–373CrossRefPubMedGoogle Scholar
  21. 21.
    Josephs KA, Lin WL, Ahmed Z, Stroh DA, Graff-Radford NR, Dickson DW (2008) Frontotemporal lobar degeneration with ubiquitin-positive, but TDP-43-negative inclusions. Acta Neuropathol 116:159–167CrossRefPubMedGoogle Scholar
  22. 22.
    Josephs KA, Uchikado H, McComb RD et al (2005) Extending the clinicopathological spectrum of neurofilament inclusion disease. Acta Neuropathol 109:427–432CrossRefPubMedGoogle Scholar
  23. 23.
    Kobayashi Z, Tsuchiya K, Arai T et al (2010) Occurence of basophilic inclusions and FUS-immunoreactive neuronal and glial inclusions in a case of familial amyotrophic lateral sclerosis. J Neurol Sci 293:6–11CrossRefPubMedGoogle Scholar
  24. 24.
    Kusaka H, Matsumoto S, Imai T (1990) An adult-onset case of sporadic motor neuron disease with basophilic inclusions. Acta Neuropathol 80:660–665CrossRefPubMedGoogle Scholar
  25. 25.
    Kusaka H, Matsumoto S, Imai T (1993) Adult-onset motor neuron disease with basophilic intraneuronal inclusion bodies. Clin Neuopathol 12:215–218Google Scholar
  26. 26.
    Kwiatkowski TJ, Bosco DA, LeClerc AL et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208CrossRefPubMedGoogle Scholar
  27. 27.
    Lagier-Tourenne C, Cleveland DW (2009) Rethinking ALS: the FUS about TDP-43. Cell 136:1001–1004CrossRefPubMedGoogle Scholar
  28. 28.
    Loy CT, McCusker E, Kril JJ et al (2010) Very early-onset frontotemporal dementia with no family history predicts underlying fused in sarcoma pathology. Brain. doi: 10.1093/brain/awq186
  29. 29.
    Mackenzie IR, Feldman H (2004) Neurofilament inclusion body disease with early onset frontotemporal dementia and primary lateral sclerosis. Clin Neuropathol 23:183–193PubMedGoogle Scholar
  30. 30.
    Mackenzie IRA, Foti D, Woulfe J, Hurwitz TA (2008) Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions. Brain 131:1282–1293CrossRefPubMedGoogle Scholar
  31. 31.
    Mackenzie IR, Neumann M, Bigio EH et al (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117:15–18CrossRefPubMedGoogle Scholar
  32. 32.
    Mackenzie IRA, Neumann M, Bigio EH et al (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4CrossRefPubMedGoogle Scholar
  33. 33.
    Mackenzie IRA, Rademakers R, Neumann M (2010) TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 9:995–1007CrossRefPubMedGoogle Scholar
  34. 34.
    Mackenzie IRA, Shi J, Shaw CL et al (2006) Dementia lacking distinctive histology (DLDH) revisited. Acta Neuropathol 112:551–559CrossRefPubMedGoogle Scholar
  35. 35.
    Matsuoka T, Fujii N, Kondo A et al (2010) An autopsied case of sporadic adult-onset amyotrophic lateral sclerosis with FUS-positive basophilic inclusions. Neuropathology. doi: 10.1111/j.1440-1789.2010.01129.x
  36. 36.
    Molina-Porcel L, Llado A, Rey MJ et al (2008) Clinical and pathological heterogeneity of neuronal intermediate filament inclusion disease. Arch Neurol 65:272–275CrossRefPubMedGoogle Scholar
  37. 37.
    Munoz-Garcia D, Ludwin SK (1984) Classic and generalized variants of Pick’s disease: a clinicopathological, ultrastructural, and immunocytochemical comparative study. Ann Neurol 16:467–480CrossRefPubMedGoogle Scholar
  38. 38.
    Munoz DG, Neumann M, Kusaka H et al (2009) FUS pathology in basophilic inclusion body disease. Acta Neuropathol 118:617–627CrossRefPubMedGoogle Scholar
  39. 39.
    Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IRA (2009) Frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931CrossRefPubMedGoogle Scholar
  40. 40.
    Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie IRA (2009) Abundant FUS pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118:605–616CrossRefPubMedGoogle Scholar
  41. 41.
    Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133CrossRefPubMedGoogle Scholar
  42. 42.
    Neumann M, Tolnay M, Mackenzie IRA (2009) The molecular basis of frontotemporal dementia. Exp Rev Mol Med 11:e23CrossRefGoogle Scholar
  43. 43.
    Rademakers R, Stewart H, DeJesus-Hernandez M et al (2010) FUS gene mutations in familial and sporadic amyotrophic lateral sclerosis. Muscle Nerve 42:170–176CrossRefPubMedGoogle Scholar
  44. 44.
    Riggi N, Cironi L, Suva ML, Stamenkovic I (2007) Sarcomas: genetics, signalling, and cellular origins. Part I: The fellowship of TET. J Pathol 213:4–20CrossRefPubMedGoogle Scholar
  45. 45.
    Robertson J, Bilbao J, Zinman L et al (2010) A novel double mutation in FUS gene causing sporadic ALS. Neurobiol Aging. doi: 10.1016/j.neurobiolaging.2010.05.015
  46. 46.
    Roeber S, Bazner H, Hennerici M, Porstmann R, Kretzschmar HA (2006) Neurodegeneration with features of NIFID and ALS-extended clinical and neuropathological spectrum. Brain Pathol 16:228–234CrossRefPubMedGoogle Scholar
  47. 47.
    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 116:147–157CrossRefPubMedGoogle Scholar
  48. 48.
    Rohrer JD, Lashley T, Holton J et al (2010) The clinical and neuroanatomical phenotype of FUS associated frontotemporal lobar degeneration. J Neurol Neursurg Psychiatry. doi: 10.1136/jnnp.2010.214437
  49. 49.
    Seelar H, Klijnsma KY, de Koning I et al (2010) Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration. J Neurol 257:747–753CrossRefGoogle Scholar
  50. 50.
    Suzuki N, Aoki M, Warita H et al (2010) FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusions. J Hum Genet 55:252–254CrossRefPubMedGoogle Scholar
  51. 51.
    Tateishi T, Hokonohara T, Yamasaki R et al (2010) Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation. Acta Neuropathol 119:255–364CrossRefGoogle Scholar
  52. 52.
    Ticozzi N, Silani V, LeClerc AL et al (2009) Analysis of FUS gene mutation in familial amyotrophic lateral sclerosis within an Italian cohort. Neurology 73:1180–1185CrossRefPubMedGoogle Scholar
  53. 53.
    Tsuchiya K, Matsunaga T, Aoki M et al (2001) Familial amyotrophic lateral sclerosis with posterior column degeneration and basophilic inclusion bodies: a clinical, genetic and pathological study. Clin Neuropathol 20:53–59PubMedGoogle Scholar
  54. 54.
    Uchikado H, Shaw G, Wang DS, Dickson DW (2005) Screening for neurofilament inclusion disease using alpha-internexin immunohistochemistry. Neurology 64:1658–1659CrossRefPubMedGoogle Scholar
  55. 55.
    Urwin H, Josephs KA, Rohrer JD et al (2010) FUS pathology defines the majority of tau-and TDP-43-negative frontotemporal lobar degeneration. Acta Neuropathol 120:33–41CrossRefPubMedGoogle Scholar
  56. 56.
    Vance C, Rogelj B, Hortobagyi T et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211CrossRefPubMedGoogle Scholar
  57. 57.
    Van Langenhove T, van der Zee J, Sleegers K et al (2010) Genetic contribution of FUS to frontotemporal lobar degeneration. Neurology 74:366–371CrossRefPubMedGoogle Scholar
  58. 58.
    Yamamoto-Watanabe Y, Watanabe M, Okamoto K et al (2010) A Japanese ALS6 family with mutation R521C in the FUS/TLS gene: a clinical, pathological and genetic report. J Neurol Sci 296:59–63CrossRefPubMedGoogle Scholar
  59. 59.
    Yan J, Deng HX, Siddique N et al (2010) Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology 75:807–814CrossRefPubMedGoogle Scholar
  60. 60.
    Yang S, Warraich ST, Nicholson GA, Blair IP (2010) Fused in sarcoma/translocated in liposarcoma: a multifunctional DNA/RNA binding protein. Int J Biochem Cell Biol 42:1408–1411CrossRefPubMedGoogle Scholar
  61. 61.
    Yokota O, Tsuchiya K, Terada S et al (2008) Basophilic inclusion body disease and neuronal intermediate filament inclusion disease: a comparative clinicopathological study. Acta Neuropathol 115:561–575CrossRefPubMedGoogle Scholar
  62. 62.
    Zinszner H, Sok J, Immanuel D, Yin Y, Ron D (1997) TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling. J Cell Sci 110:1741–1750PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Ian R. A. Mackenzie
    • 1
    Email author
  • David G. Munoz
    • 2
  • Hirofumi Kusaka
    • 3
  • Osamu Yokota
    • 4
  • Kenji Ishihara
    • 5
  • Sigrun Roeber
    • 6
  • Hans A. Kretzschmar
    • 6
  • Nigel J. Cairns
    • 7
  • Manuela Neumann
    • 8
  1. 1.Department of PathologyVancouver General Hospital, University of British ColumbiaVancouverCanada
  2. 2.Department of Laboratory Medicine and PathobiologySt., Michael’s Hospital, University of TorontoTorontoCanada
  3. 3.Department of NeurologyKansai Medical UniversityOsakaJapan
  4. 4.Department of NeuropsychiatryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  5. 5.Department of NeurologyShowa University School of MedicineTokyoJapan
  6. 6.Center for Neuropathology and Prion ResearchLudwig-Maximilians UniversityMunichGermany
  7. 7.Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisUSA
  8. 8.Institute of NeuropathologyUniversity Hospital ZurichZurichSwitzerland

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