Transportin 1 co-localisation with FUS inclusions is not characteristic for ALS-FUS confirming disrupted nuclear import of mutant FUS and distinguishing it from FTLD-FUS

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

Aims:  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. If this held true for human ALS then we predicted that FUS inclusions in patients with C-terminal FUS mutations would not co-localise with TNPO 1. Methods:  Expression of TNPO 1 and co-localisation with FUS was studied in the frontal cortex of FTLD-FUS (n=3) and brain and spinal cord of ALS-FUS (n=3), ALS-C9orf72 (n=3), sporadic ALS (n=7), and controls (n=7). Expression levels and detergent solubility of TNPO 1 was measured by Western blot. Results:  Aggregates of TNPO 1 were abundant and co-localised with FUS inclusions in the cortex of all FTLD-FUS cases. 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. Nor were they present in C9orf72 or sporadic ALS. No increase in the levels of TNPO 1 was seen in Western blots of spinal cord tissues from all ALS cases compared to controls. Conclusions:  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. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.
Original languageEnglish
Pages (from-to)553-561
Number of pages9
JournalNeuropathology and Applied Neurobiology
Volume39
Issue number5
DOIs
Publication statusPublished - 31 Aug 2012

Fingerprint

Dive into the research topics of 'Transportin 1 co-localisation with FUS inclusions is not characteristic for ALS-FUS confirming disrupted nuclear import of mutant FUS and distinguishing it from FTLD-FUS'. Together they form a unique fingerprint.

Cite this