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.