Acta Neuropathologica

, 118:605 | Cite as

Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease

  • Manuela Neumann
  • Sigrun Roeber
  • Hans A. Kretzschmar
  • Rosa Rademakers
  • Matt Baker
  • Ian R. A. Mackenzie
Original Paper


Neuronal intermediate filament inclusion disease (NIFID) is an uncommon neurodegenerative condition that typically presents as early-onset, sporadic frontotemporal dementia (FTD), associated with a pyramidal and/or extrapyramidal movement disorder. The neuropathology is characterized by frontotemporal lobar degeneration with neuronal inclusions that are immunoreactive for all class IV intermediate filaments (IF), light, medium and heavy neurofilament subunits and α-internexin. However, not all the inclusions in NIFID are IF-positive and the primary molecular defect remains uncertain. Mutations in the gene encoding the fused in sarcoma (FUS) protein have recently been identified as a cause of familial amyotrophic lateral sclerosis (ALS). Because of the recognized clinical, genetic and pathological overlap between FTD and ALS, we investigated the possible role of FUS in NIFID. We found abnormal intracellular accumulation of FUS to be a consistent feature of our NIFID cases (n = 5). More neuronal inclusions were labeled using FUS immunohistochemistry than for IF. Several types of inclusions were consistently FUS-positive but IF-negative, including neuronal intranuclear inclusions and glial cytoplasmic inclusions. Double-label immunofluorescence confirmed that many cells had only FUS-positive inclusions and that all cells with IF-positive inclusions also contained pathological FUS. No mutation in the FUS gene was identified in a single case with DNA available. These findings suggest that FUS may play an important role in the pathogenesis of NIFID.


Frontotemporal dementia Frontotemporal lobar degeneration Neuronal intermediate filament disease Fused in sarcoma Translocated in liposarcoma 



We thank Margaret Luk, Mareike Schroff and Mirjam Lutz 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 Deutsche Forschungsgemeinschaft (SFB 596, MN); the Stavros-Niarchos Foundation (MN); the Synapsis Foundation (MN); the German Brain Bank “BrainNet” (HK) and the National Institute of Health (grant number P50 AG16574, RR).


  1. 1.
    Al Chalabi A, Miller CC (2003) Neurofilaments and neurological disease. Bioessays 25:346–355CrossRefPubMedGoogle Scholar
  2. 2.
    Aman P, Panagopoulos I, Lassen C et al (1996) Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS. Genomics 37:1–8CrossRefPubMedGoogle Scholar
  3. 3.
    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
  4. 4.
    Baechtold H, Kuroda M, Sok J, Ron D, Lopez BS, Akhmedov AT (1999) Human 75-kDa DNA-pairing protein is identical to the pro-oncoprotein TLD/FUS and is able to promote D-loop formation. J Biol Chem 274:34337–34342CrossRefPubMedGoogle Scholar
  5. 5.
    Bertrand P, Akhmedov AT, Delacote F, Durrbach A, Lopez BS (1999) Human POMp75 is identified as the pro-oncoprotein TLS/FUS: both POMp75 and POMp100 DNA homologous pairing activities are associated with cell proliferation. Oncogene 18:4515–4521CrossRefPubMedGoogle Scholar
  6. 6.
    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
  7. 7.
    Cairns NJ, Bigio EH, Mackenzie IRA et al (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22CrossRefPubMedGoogle Scholar
  8. 8.
    Cairns NJ, Grossman M, Arnold SE et al (2004) Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease. Neurology 63:1376–1384PubMedGoogle Scholar
  9. 9.
    Cairns NJ, Perry RH, Jaros E et al (2003) Patients with a novel neurofilamentopathy: dementia with neurofilament inclusions. Neurosci Lett 341:177–180CrossRefPubMedGoogle Scholar
  10. 10.
    Cairns NJ, Uryu K, Bigio EH et al (2004) α-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases. Acta Neuropathol (Berl) 108:213–223CrossRefGoogle Scholar
  11. 11.
    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
  12. 12.
    Crozat A, Aman P, Mandahl N, Ron D (1993) Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 363:640–644CrossRefPubMedGoogle Scholar
  13. 13.
    Doi H, Okamura K, Bauer PO et al (2008) RNA-binding protein TLS is a major nuclear aggregate-interacting protein in Huntingtin exon 1 with expanded polyglutamine-expressing cells. J Biol Chem 283:6489–6500CrossRefPubMedGoogle Scholar
  14. 14.
    Duyckaerts C, Mokhtari K, Fontaine B et al (2003) Maladie de Pick généralisée: une démence mal nommée caractérisée par des inclusions neurofilamentaires. Rev Neurol 159:219Google Scholar
  15. 15.
    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
  16. 16.
    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
  17. 17.
    Gearing M, Castellano AA, Hunter SB et al (2003) Unusual neuropathological findings in a case of primary lateral sclerosis. J Neuropathol Exp Neurol 62:555Google Scholar
  18. 18.
    Josephs KA, Holton JL, Rossor MN et al (2003) Neurofilament inclusion body disease: a new proteinopathy? Brain 126:2291–2303CrossRefPubMedGoogle Scholar
  19. 19.
    Josephs KA, Uchikado H, McComb RD et al (2005) Extending the clinicopathological spectrum of neurofilament inclusion disease. Acta Neuropathol 109:427–432CrossRefPubMedGoogle Scholar
  20. 20.
    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
  21. 21.
    Lagier-Tourenne C, Cleveland DW (2009) Rethinking ALS: the FUS about TDP-43. Cell 136:1001–1004CrossRefPubMedGoogle Scholar
  22. 22.
    Law WJ, Cann KL, Hicks GG (2006) TLS, EWS, and TAF15: a model for transcriptional integration of gene expression. Brief Funct Genomic Proteomic 5:8–14CrossRefPubMedGoogle Scholar
  23. 23.
    Liu Q, Xie F, Siedlak SL et al (2004) Neurofilament proteins in neurodegenerative diseases. Cell Mol Life Sci 61:3057–3075CrossRefPubMedGoogle Scholar
  24. 24.
    Mackenzie IR, Feldman H (2004) Neurofilament inclusion body disease with early onset frontotemporal dementia and primary lateral sclerosis. Clin Neuropathol 23:183–193PubMedGoogle Scholar
  25. 25.
    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
  26. 26.
    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
  27. 27.
    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
  28. 28.
    Momeni P, Cairns NJ, Perry RH et al (2006) Mutation analysis of patients with neuronal intermediate filament inclusion disease (NIFID). Neurobiol Aging 27:778.e1–778.e6CrossRefGoogle Scholar
  29. 29.
    Mosaheb S, Thorpe JR, Hashemzadeh-Bonehi L, Bigio EH, Gearing M, Cairns NJ (2005) Neuronal intranuclear inclusions are ultrastructurally and immunologically distinct from cytoplasmic inclusions of neuronal intermediate filament inclusion disease. Acta Neuropathol 110:360–368CrossRefPubMedGoogle Scholar
  30. 30.
    Neary D, Snowden JS, Gustafson L et al (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554PubMedGoogle Scholar
  31. 31.
    Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IRA (2009) Frontotemporal lobar degeneration with FUS pathology. Brain. doi: 10.1093/brain/awp214
  32. 32.
    Perrotti D, Bonatti S, Trotta R et al (1998) TLS/FUS, a pro-oncogene involved in multiple chromosomal translocations, is a novel regulator of BCR/ABL-mediated leukemogenesis. EMBO J 17:4442–4455CrossRefPubMedGoogle Scholar
  33. 33.
    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
  34. 34.
    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
  35. 35.
    Trojanowski JQ, Dickson D (2001) Update on the neuropathological diagnosis of frontotemporal dementia. J Neuropathol Exp Neurol 60:1123–1126PubMedGoogle Scholar
  36. 36.
    Uchikado H, Li A, Lin WL, Dickson DW (2006) Heterogeneous inclusions in neurofilament inclusion disease. Neuropathol 26:417–421CrossRefGoogle Scholar
  37. 37.
    Uchikado H, Shaw G, Wang DS, Dickson DW (2005) Screening for neurofilament inclusion disease using alpha-internexin immunohistochemistry. Neurology 64:1658–1659CrossRefPubMedGoogle Scholar
  38. 38.
    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
  39. 39.
    Yang L, Embree LJ, Tsai S, Hickstein DD (1998) Oncoprotein TLS interacts with serine-arginine proteins involved in RNA splicing. J Biol Chem 273:27761–27764CrossRefPubMedGoogle Scholar
  40. 40.
    Yokoo H, Oyama T, Hirato J, Sasaki A, Nakazato Y (1994) A case of Pick’s disease with unusual neuronal inclusions. Acta Neuropathol 88:267–272CrossRefPubMedGoogle Scholar
  41. 41.
    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
  42. 42.
    Zinszner H, Sok J, Immanuel D, Ron D (1997) TLD (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling. J Cell Sci 110:1741–1750PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Manuela Neumann
    • 1
  • Sigrun Roeber
    • 2
  • Hans A. Kretzschmar
    • 2
  • Rosa Rademakers
    • 3
  • Matt Baker
    • 3
  • Ian R. A. Mackenzie
    • 4
  1. 1.Institute of NeuropathologyUniversity Hospital of ZürichZurichSwitzerland
  2. 2.Center for Neuropathology and Prion ResearchLudwig-Maximilians UniversityMunichGermany
  3. 3.Department of NeuroscienceMayo Clinic College of MedicineJacksonvilleUSA
  4. 4.Department of Pathology and Laboratory Medicine, Vancouver General HospitalVancouverCanada

Personalised recommendations