Frontotemporal dementia (FTD) is a clinical syndrome characterized by progressive changes in behaviour, personality and/or language with relative preservation of memory (Neary et al.
; McKhann et al.
). The neuropathology associated with clinical FTD is heterogeneous, with the common feature being relatively selective degeneration of the frontal and temporal lobes (frontotemporal lobar degeneration, FTLD) (Trojanowski and Dickson, 2001
; Cairns et al.
). As with many other neurodegenerative conditions, the pathology in most cases of FTLD also includes the presence of abnormal intracellular protein aggregates. This feature is the basis of recently published consensus recommendations for the nomenclature of FTLD in which classification is based on the molecular defect that is presumed to be pathogenic or most characteristic (Mackenzie et al.
). Approximately half of cases show accumulation of hyperphosphorylated tau protein in neurons and glia (FTLD-tau). The majority of tau-negative cases have neuronal inclusions that were originally identified by their immunoreactivity for ubiquitin (FTLD-U) (Jackson et al.
; Josephs et al.
; Johnson et al.
; Mackenzie et al.
). Recently, the transactive response (TAR) DNA-binding protein with Mr
43 kDa (TDP-43) was identified as the pathological protein in both FTLD-U (now referred to as FTLD-TDP) and amyotrophic lateral sclerosis (ALS) (Arai et al.
; Neumann et al.
). This finding has provided strong evidence that FTD with FTLD-TDP pathology, ALS with dementia and classical ALS are all part of a clinicopathological spectrum of disease.
Although TDP-43 was initially thought to be the pathological protein in all cases of FTLD-U and ALS (Arai et al.
; Neumann et al.
; Davidson et al.
), subsequent studies identified some important exceptions (Cairns et al.
; Holm et al.
; Mackenzie et al.
; Josephs et al.
; Pikkarainen et al.
). In two recent papers, we described a subgroup of patients with sporadic FTD and FTLD-U pathology that was negative for TDP-43, accounting for 10%–20% of our respective FTLD-U series (Mackenzie et al.
; Roeber et al.
). The unusual and highly consistent clinical and pathological phenotype suggested to us that these cases represent a specific disease entity, which we referred to as ‘atypical’ FTLD-U (aFTLD-U). Identification of this group indicated that there was at least one additional FTD-related protein yet to be discovered.
Recently, two studies identified mutations in the gene encoding the fused in sarcoma
(FUS) protein (also known as translated in liposarcoma
, TLS), as the cause of familial ALS (FALS) type 6 (Kwiatkowski et al.
; Vance et al.
). These studies reported that a total of 14 different mutations were found in 26 unrelated families (~4% of FALS in these combined series). Most were missense mutations, affecting highly conserved regions in exon 15 that encodes the C-terminus. With the exception of one family with autosomal recessive disease, caused by the c.1551C>G mutation (Kwiatkowski et al.
), all other mutations produced autosomal dominant ALS, although with incomplete penetrance. No mutations were found in 293 sporadic ALS (SALS) cases screened in one study (Kwiatkowski et al.
). The clinical phenotype was classical ALS, with a mean age of onset of 46 years and mean disease duration of 33 months. There was no associated cognitive dysfunction. Post-mortem pathology was described in four patients and included degeneration of both upper and lower motor neurons. One study reported only increased neuronal cytoplasmic FUS-immunoreactivity in a single affected individual (Kwiatkowski et al.
), while the other described FUS-ir dystrophic neurites (DN) and globular neuronal cytoplasmic inclusions (NCI) in lower motor neurons, in the absence of TDP-43 pathology (Vance et al.
). In vitro
experiments from both groups suggested increased cytoplasmic FUS localization in cells expressing mutations and one study reported increased levels of insoluble FUS (Kwiatkowski et al.
gene, located on chromosome 16, consists of 15 exons that encode a 526 amino-acid protein (Aman et al.
). The C-terminus region contains multiple domains involved in RNA–protein interactions, while the N-terminus functions in transcriptional activation (Prasad et al.
). FUS is a ubiquitously expressed protein (Aman et al.
; Andersson et al.
) that binds to RNA (Crozat et al.
; Zinszner et al.
) and DNA (Perrotti et al.
) and is involved in diverse cellular processes including cell proliferation (Bertrand et al.
), DNA repair (Baechtold et al.
), transcription regulation, RNA splicing (Yang et al.
) and the transport of RNA between intracellular compartments (Zinszner et al.
). In most cell types, FUS is present in both the nucleus and cytoplasm, however in neurons there is proportionally more in the nucleus and expression in glia is exclusively nuclear (Andersson et al.
). FUS may be involved in neuronal plasticity and maintenance of dendritic integrity by transporting mRNA, including those that encode actin-related proteins, to dendritic spines for local translation in response to synaptic stimulation (Fujii et al.
). In contrast, FUS deficient neurons show decreased spine arborization and morphology (Fujii et al.
). Chromosomal translocation of the 5′ portion of FUS
results in several fusion oncogenes that are each associated with specific types of human cancer, including myxoid liposarcoma, Ewing's sarcoma and acute myeloid leukemia (Law et al.
). FUS knock-out mice show perinatal mortality (Hicks et al.
). The finding that FUS
mutations cause FALS is the first association between this protein and a neurodegenerative condition.
The recognized clinical, genetic and pathological overlap between ALS and FTD, and the high degree of functional homology between FUS and another ALS/FTD-related protein (TDP-43) (Lagier-Tourenne and Cleveland, 2009
), led us to speculate that FUS might also be the pathological protein in some cases of tau/TDP-43-negative FTLD. In this study, we investigate the possible role of FUS in our aFTLD-U cases.