Original Paper

Acta Neuropathologica

, Volume 122, Issue 5, pp 591-600

Transportin1: a marker of FTLD-FUS

  • Jack BrelstaffAffiliated withQueen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London
  • , Tammaryn LashleyAffiliated withQueen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London
  • , Janice L. HoltonAffiliated withQueen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College LondonReta Lila Weston Institute, UCL Institute of Neurology
  • , Andrew J. LeesAffiliated withQueen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College LondonReta Lila Weston Institute, UCL Institute of Neurology
  • , Martin N. RossorAffiliated withDementia Research Centre, UCL Institute of Neurology
  • , Rina BandopadhyayAffiliated withReta Lila Weston Institute, UCL Institute of Neurology
  • , Tamas ReveszAffiliated withQueen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London Email author 

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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.

Keywords

Fused in sarcoma FUS Transportin1 TRN1 TNP01 Biochemistry FTLD Frontotemporal dementia Frontotemporal lobar degeneration