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Transportin1: a marker of FTLD-FUS

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Abstract

The term frontotemporal lobar degeneration (FTLD) describes a group of disorders that are subdivided by the presence of one of a number of pathological proteins identified in the inclusion bodies observed post-mortem. The FUS variant is defined by the presence of the fused in sarcoma protein (FUS) in the pathological inclusions. However, similar to other FTLDs, the disease pathogenesis of FTLD-FUS remains largely poorly understood. Here we present data that the protein transportin1 (TRN1) is abundant in the FUS-positive inclusions. TRN1, the protein product of the TNP01 gene, is responsible for shuttling proteins containing an M9 nuclear localisation signal between the nuclear and cytoplasmic compartments. RNA interacting proteins, including FUS, have been implicated as targets of TRN1. Using TRN1 immunohistochemistry and Western blotting in this study, we investigated 13 cases of FTLD-FUS including 6 cases with neuronal intermediate filament inclusion disease (NIFID) and 7 atypical frontotemporal lobar degeneration with ubiquitinated inclusion (aFTLD-U) cases. The data from our immunohistochemical studies show that FUS-immunoreactive inclusions are also strongly labelled with the anti-TRN1 antibody and double-label immunofluorescence studies indicate good co-localisation between the FUS and TRN1 pathologies. Our biochemical investigations demonstrate that urea-soluble TRN1 is present in aFTLD-U and NIFID, but not in normal control brains. These findings implicate abnormalities of FUS transport in the pathogenesis of FTLD-FUS.

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Acknowledgments

The authors wish to thank the MRC London Brain Bank for Neurodegenerative Diseases, Institute of Psychiatry, King’s College, London, UK, NeuroResource, UCL Institute of Neurology, London, UK and the Department of Neuropathology, Århus Kommunehospital, Århus, Denmark for allowing them to investigate some of the cases used in this study. TR, MNR, JLH and AJL are recipients of a research grant from the Alzheimer’s Research UK, which supported this work. JLH is supported by the Reta Lila Weston Institute for Neurological Studies. The Queen Square Brain Bank receives support from the Reta Lila Weston Institute for Neurological Studies and the Progressive Supranuclear Palsy (Europe) Association and is supported by further research grants from the Multiple System Atrophy Trust and Parkinson’s UK. The Dementia Research Centre is an Alzheimer’s Research UK Coordinating Centre. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme.

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Authors and Affiliations

  1. Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK

    Jack Brelstaff, Tammaryn Lashley, Janice L. Holton, Andrew J. Lees & Tamas Revesz

  2. Reta Lila Weston Institute, UCL Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK

    Janice L. Holton, Andrew J. Lees & Rina Bandopadhyay

  3. Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Martin N. Rossor

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  1. Jack Brelstaff
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  2. Tammaryn Lashley
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Correspondence to Tamas Revesz.

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J. Brelstaff and T. Lashley contributed equally to this work.

R. Bandopadhyay and T. Revesz are shared senior authors.

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Brelstaff, J., Lashley, T., Holton, J.L. et al. Transportin1: a marker of FTLD-FUS. Acta Neuropathol 122, 591–600 (2011). https://doi.org/10.1007/s00401-011-0863-6

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  • DOI: https://doi.org/10.1007/s00401-011-0863-6

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