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.