Acta Neuropathologica

, Volume 124, Issue 5, pp 705–716 | Cite as

Transportin 1 accumulates specifically with FET proteins but no other transportin cargos in FTLD-FUS and is absent in FUS inclusions in ALS with FUS mutations

  • Manuela Neumann
  • Chiara F. Valori
  • Olaf Ansorge
  • Hans A. Kretzschmar
  • David G. Munoz
  • Hirofumi Kusaka
  • Osamu Yokota
  • Kenji Ishihara
  • Lee-Cyn Ang
  • Juan M. Bilbao
  • Ian R. A. Mackenzie
Original Paper


Accumulation of the DNA/RNA binding protein fused in sarcoma (FUS) as inclusions in neurons and glia is the pathological hallmark of amyotrophic lateral sclerosis patients with mutations in FUS (ALS-FUS) as well as in several subtypes of frontotemporal lobar degeneration (FTLD-FUS), which are not associated with FUS mutations. Despite some overlap in the phenotype and neuropathology of FTLD-FUS and ALS-FUS, significant differences of potential pathomechanistic relevance were recently identified in the protein composition of inclusions in these conditions. While ALS-FUS showed only accumulation of FUS, inclusions in FTLD-FUS revealed co-accumulation of all members of the FET protein family, that include FUS, Ewing’s sarcoma (EWS) and TATA-binding protein-associated factor 15 (TAF15) suggesting a more complex disturbance of transportin-mediated nuclear import of proteins in FTLD-FUS compared to ALS-FUS. To gain more insight into the mechanisms of inclusion body formation, we investigated the role of Transportin 1 (Trn1) as well as 13 additional cargo proteins of Transportin in the spectrum of FUS-opathies by immunohistochemistry and biochemically. FUS-positive inclusions in six ALS-FUS cases including four different mutations did not label for Trn1. In sharp contrast, the FET-positive pathology in all FTLD-FUS subtypes was also strongly labeled for Trn1 and often associated with a reduction in the normal nuclear staining of Trn1 in inclusion bearing cells, while no biochemical changes of Trn1 were detectable in FTLD-FUS. Notably, despite the dramatic changes in the subcellular distribution of Trn1 in FTLD-FUS, alterations of its cargo proteins were restricted to FET proteins and no changes in the normal physiological staining of 13 additional Trn1 targets, such as hnRNPA1, PAPBN1 and Sam68, were observed in FTLD-FUS. These data imply a specific dysfunction in the interaction between Trn1 and FET proteins in the inclusion body formation in FTLD-FUS. Moreover, the absence of Trn1 in ALS-FUS provides further evidence that ALS-FUS and FTLD-FUS have different underlying pathomechanisms.


Transportin FUS TAF15 EWS Amyotrophic lateral sclerosis Frontotemporal dementia 



We thank Margaret Luk and Jay Tracy for their excellent technical assistance. This work was supported by grants from the Swiss National Science Foundation (31003A-132864, MN); the Synapsis Foundation (MN); the Canadian Institutes of Health Research (74580 and 179009, IM), the Pacific Alzheimer’s Research Foundation (C06-01, IM); and the NIHR Oxford Biomedical Research Centre (OA).

Supplementary material

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Supplementary material 1 (PDF 1101 kb)


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Manuela Neumann
    • 1
    • 2
    • 3
  • Chiara F. Valori
    • 1
  • Olaf Ansorge
    • 4
  • Hans A. Kretzschmar
    • 5
  • David G. Munoz
    • 6
  • Hirofumi Kusaka
    • 7
  • Osamu Yokota
    • 8
  • Kenji Ishihara
    • 9
  • Lee-Cyn Ang
    • 10
  • Juan M. Bilbao
    • 11
  • Ian R. A. Mackenzie
    • 12
  1. 1.Institute of NeuropathologyUniversity Hospital ZurichZurichSwitzerland
  2. 2.Department of NeuropathologyUniversity of TübingenTübingenGermany
  3. 3.DZNE, German Center for Neurodegenerative DiseasesTübingenGermany
  4. 4.Department of NeuropathologyJohn Radcliffe HospitalOxfordUK
  5. 5.Center for Neuropathology and Prion ResearchLudwig-Maximilians-UniversityMunichGermany
  6. 6.Department of Laboratory Medicine and Pathobiology, Li Ka Shing Knowledge Institute, St. Michael’s HospitalUniversity of TorontoTorontoCanada
  7. 7.Department of NeurologyKansai Medical UniversityOsakaJapan
  8. 8.Department of NeuropsychiatryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  9. 9.Department of NeurologyShowa University School of MedicineTokyoJapan
  10. 10.Department of PathologyLondon Health Sciences CentreLondonCanada
  11. 11.Department of PathologySunnybrook Health Sciences CentreTorontoCanada
  12. 12.Department of Pathology, Vancouver General HospitalUniversity of British ColumbiaVancouverCanada

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