Transportin 1 (TNPO 1) is an abundant component of the Fused in Sarcoma (FUS)-immunopositive inclusions seen in a subgroup of frontotemporal lobar degeneration (FTLD-FUS). TNPO 1 has been shown to bind to the C-terminal nuclear localising signal (NLS) of FUS and mediate its nuclear import. ALS-linked C-terminal mutants disrupt TNPO 1 binding to the NLS and impair nuclear import in cell culture. Aggregates of TNPO 1 were abundant and co-localised with FUS inclusions in the cortex of all FTLD-FUS cases in our study. In contrast, no TNPO 1-positive aggregates or FUS co-localisation was evident in 2/3, ALS-FUS cases and was rare in one ALS-FUS case. No increase in the levels of TNPO 1 was seen in Western blots of spinal cord tissues from all ALS cases compared to controls. These findings confirm that C-terminal FUS mutations prevent TNPO 1 binding to the NLS, inhibiting nuclear import and promoting cytoplasmic aggregation. The presence of TNPO 1 in wild-type FUS aggregates in FTLD-FUS distinguishes the two pathologies and implicates different disease mechanisms.
COBISS.SI-ID: 26072871
TDP-43 proteinopathies describe a clinico-pathological spectrum that spans amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We have identified four male patients who presented with the clinical features of a pure ALS phenotype (without dementia) but who had distinctive cortical and cerebellar pathology that was different from other TDP-43 proteinopathies. Neuropathological investigation revealed lower motor neuron involvement with TDP-43-positive inclusions typical of ALS. In contrast, the cerebral pathology was atypical, with abundant star-shaped p62-immunoreactive neuronal cytoplasmic inclusions in the cerebral cortex, basal ganglia and hippocampus, while TDP-43-positive inclusions were sparse. This pattern was also seen in the cerebellum where p62-positive, TDP-43-negative inclusions were frequent in granular cells. Genetic investigations revealed that all four of the cases show a repeat expansion of C9orf72, the recently reported cause of chromosome 9-linked ALS and FTLD. We conclude that these chromosome 9-linked ALS cases represent a pathological sub-group with abundant p62 pathology in the cerebral cortex, hippocampus and cerebellum but with no significant associated cognitive decline.
COBISS.SI-ID: 25554727
Fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43) are RNA-binding proteins pathogenetically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but it is not known if they regulate the same transcripts. We addressed this question using crosslinking and immunoprecipitation (iCLIP) as well as alternative splicing analysis, and compared with TDP-43 binding. We did not observe a significant overlap in the RNA binding sites or the exons regulated by FUS and TDP-43. Nevertheless, we found that both proteins regulate genes that function in neuronal development.
COBISS.SI-ID: 26042663