title: Transportin1: a marker of FTLD-FUS.
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.
authors.affiliation: Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Brelstaff
authors.forename: Tammaryn
authors.initials: T
authors.lastname: Lashley
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lees
authors.forename: Martin N
authors.initials: MN
authors.lastname: Rossor
authors.forename: Rina
authors.initials: R
authors.lastname: Bandopadhyay
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
mesh_terms: D000328:Adult; D000368:Aged; D001344:Autopsy; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D028961:beta Karyopherins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C108121:TNPO1 protein, human; D028961:beta Karyopherins