The most common type of FTLD-FUS (aFTLD-U) is associated with a distinct clinical form of frontotemporal dementia but is not related to mutations in the FUS gene

Abstract

Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Recent descriptions of a pathological sub-type that is ubiquitin positive, TDP-43 negative and immunostains positive for the Fused in Sarcoma protein (FUS) raises the question whether it is associated with a distinct clinical phenotype identifiable on clinical grounds, and whether mutations in the Fused in Sarcoma gene (FUS) might also be associated with FTLD. Examination of a pathological series of 118 cases of FTLD from two centres, showing tau-negative, ubiquitin-positive pathology, revealed FUS pathology in five patients, four classified as atypical FTLD with ubiquitin inclusions (aFTLD-U), and one as neuronal intermediate filament inclusion disease (NIFID). The aFTLD-U cases had youthful onset (22-46 years), an absence of strong family history, a behavioural syndrome consistent with frontotemporal dementia (FTD) and severe caudate atrophy. Their cognitive/behavioural profile was distinct, characterised by prominent obsessionality, repetitive behaviours and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behaviour including utilisation behaviour. They conformed to the rare behavioural sub-type of FTD identified previously by us as the "stereotypic" form, and linked to striatal pathology. Cognitive evaluation revealed executive deficits in keeping with subcortical-frontal dysfunction, but no cortical deficits in language, perceptuospatial skills or praxis. The patient with NIFID was older and exhibited aphasia and dyspraxia. No patient had clinical evidence of motor neurone disease during life, or a mutation in the FUS gene. In the complementary clinical study of 312 patients with clinical syndromes of FTLD, genetic analysis revealed a 6 bp deletion in FUS in 3 patients, of questionable significance. One presented a prototypical picture of FTD, another expressive language disorder, and the third semantic dementia. None showed the early onset age or distinctive 'stereotypic' picture of patients with aFTLD-U. We conclude that aFTLD-U is associated with a distinct clinical form of frontotemporal dementia, potentially allowing identification of such patients in life with a high degree of precision. Whether mutations in the FUS gene cause some cases of FTLD remains unresolved.

Phosphorylation of C-terminal tyrosine 526 in FUS impairs its nuclear import

“…Although all ALS-FUS individuals have mutations in FUS, it is curious that no mutations of FUS are reported in FTLD-FUS cases (Neumann et al, 2009a,b;Urwin et al, 2010;Lashley et al, 2011;Snowden et al, 2011). There seems to be a more general dysfunction of TNPO1-mediated import of the three FET proteins because FUS, EWSR1 and TAF15 colocalise with TNPO1 in the cytoplasmic inclusions.…”

“…Cytoplasmic FUS inclusions are also present in 10-15% of FTLD cases that have been previously classified as atypical FTLD with ubiquitylated inclusions (aFTLD-U), basophilic inclusion body disease (BIBID) and neuronal inclusion filament disease (NIFID) (Munoz et al, 2009;Neumann et al, 2009a,b;Seelaar et al, 2010;Urwin et al, 2010;Snowden et al, 2011), which are grouped together under the designation of FTLD-FUS . In contrast to ALS-FUS, FTLD-FUS individuals do not have mutations in the gene encoding FUS (Neumann et al, 2009a,b;Urwin et al, 2010;Lashley et al, 2011;Snowden et al, 2011).…”

“…In contrast to ALS-FUS, FTLD-FUS individuals do not have mutations in the gene encoding FUS (Neumann et al, 2009a,b;Urwin et al, 2010;Lashley et al, 2011;Snowden et al, 2011). Another difference is that cytoplasmic inclusions in FTLD-FUS cases also include the FUS homologues EWS RNA-binding protein 1 (EWSR1) and TATA box binding protein associated factor (TAF15), and nuclear import factor TNPO1, which are absent in ALS-FUS inclusions, implying that there are key differences in the mechanisms underlying inclusion formation in the two disease groups Neumann et al, 2011Neumann et al, , 2012Troakes et al, 2013).…”

Behavioural Variant Frontotemporal Dementia—Defining Genetic and Pathological Subtypes

“…In more recent studies (following the discovery of the TDP-43 and FUS proteins), it appears that type 1 FTLD-TDP (Sampathu classification) is only a rare cause of bvFTD (usually causing SD instead), with both type 2 and type 3 (including GRN mutations) both relatively common causes (with type 3 slightly more predominant than type 2) (Snowden et al 2007;Rohrer et al 2010b;Whitwell et al 2010). FTLD-FUS appears to be a relatively rare cause of bvFTD (probably accounting for only 5-10% of cases), with aFTLD-U the most common subtype Rohrer et al 2011;Urwin et al 2010;Snowden et al 2011). One final important point to make is that in a number of these series, a few cases of non-FTLD pathologies were reported, including cases with Alzheimer's disease (AD) and dementia with Lewy bodies at postmortem.…”

Modeling ALS and FTLD proteinopathies in yeast: An efficient approach for studying protein aggregation and toxicity

“…[15][16][17] The cytoplasmic accumulation of the proteins TDP-43 or FUS, and their link to familial and sporadic forms of ALS and FTLD, demonstrates the existence of common underlying mechanisms in these diseases. 3,[18][19][20][21][22] 26, 28 and 29). In particular, the aggregation and toxicity of α-synuclein and polyglutamine(polyQ )-expanded Huntingtin (associated respectively with PD and HD) have been very thoroughly studied in yeast and both proteins show different patterns of aggregation with distinctive mechanisms of toxicity.…”