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 (original) (raw)

Abstract

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.

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Acknowledgments

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).

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Authors and Affiliations

  1. Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland
    Manuela Neumann & Chiara F. Valori
  2. Department of Neuropathology, University of Tübingen, Calwerstr. 3, 72076, Tübingen, Germany
    Manuela Neumann
  3. DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany
    Manuela Neumann
  4. Department of Neuropathology, John Radcliffe Hospital, Oxford, UK
    Olaf Ansorge
  5. Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany
    Hans A. Kretzschmar
  6. Department of Laboratory Medicine and Pathobiology, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Canada
    David G. Munoz
  7. Department of Neurology, Kansai Medical University, Osaka, Japan
    Hirofumi Kusaka
  8. Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
    Osamu Yokota
  9. Department of Neurology, Showa University School of Medicine, Tokyo, Japan
    Kenji Ishihara
  10. Department of Pathology, London Health Sciences Centre, London, ON, Canada
    Lee-Cyn Ang
  11. Department of Pathology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
    Juan M. Bilbao
  12. Department of Pathology, Vancouver General Hospital, University of British Columbia, Vancouver, Canada
    Ian R. A. Mackenzie

Authors

  1. Manuela Neumann
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  2. Chiara F. Valori
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  3. Olaf Ansorge
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  4. Hans A. Kretzschmar
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  5. David G. Munoz
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  6. Hirofumi Kusaka
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  7. Osamu Yokota
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  8. Kenji Ishihara
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  9. Lee-Cyn Ang
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  10. Juan M. Bilbao
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  11. Ian R. A. Mackenzie
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Correspondence toManuela Neumann.

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Neumann, M., Valori, C.F., Ansorge, O. et al. 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.Acta Neuropathol 124, 705–716 (2012). https://doi.org/10.1007/s00401-012-1020-6

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