Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease

Abstract

Neuronal intermediate filament inclusion disease (NIFID) is an uncommon neurodegenerative condition that typically presents as early-onset, sporadic frontotemporal dementia (FTD), associated with a pyramidal and/or extrapyramidal movement disorder. The neuropathology is characterized by frontotemporal lobar degeneration with neuronal inclusions that are immunoreactive for all class IV intermediate filaments (IF), light, medium and heavy neurofilament subunits and α-internexin. However, not all the inclusions in NIFID are IF-positive and the primary molecular defect remains uncertain. Mutations in the gene encoding the fused in sarcoma (FUS) protein have recently been identified as a cause of familial amyotrophic lateral sclerosis (ALS). Because of the recognized clinical, genetic and pathological overlap between FTD and ALS, we investigated the possible role of FUS in NIFID. We found abnormal intracellular accumulation of FUS to be a consistent feature of our NIFID cases (n = 5). More neuronal inclusions were labeled using FUS immunohistochemistry than for IF. Several types of inclusions were consistently FUS-positive but IF-negative, including neuronal intranuclear inclusions and glial cytoplasmic inclusions. Double-label immunofluorescence confirmed that many cells had only FUS-positive inclusions and that all cells with IF-positive inclusions also contained pathological FUS. No mutations in the FUS gene were identified in a single case with DNA available. These findings suggest that FUS may play an important role in the pathogenesis of NIFID.

FUS mutations in sporadic amyotrophic lateral sclerosis: Clinical and genetic analysis

“…In most cell types, FUS is present in both the nucleus and cytoplasm, but in neurons the proportion of FUS is higher in the nucleus than in the cytoplasm and in glia FUS is exclusively nuclear (Neumann et al, 2009). Neuropathological analysis of brain and spinal cord of ALS patients carrying mutations showed cytoplasmic retention and the formation of FUS ubiquitin-positive neuronal aggregates (DeJesusHernandez et al, 2010).…”

Intermediate Filaments in Neurodegenerative Diseases

“…It now appears that aggregates of FUS (fused in sarcoma) protein, is a more consistent feature of NIFID. Indeed, intracellular accumulations of FUS are more often encountered than IF inclusions and all neurons that contained abnormal IF aggregates also contained FUS inclusions [129]. It should also be noted that clusters of FUS-immunoreactive inclusions are larger than those revealed by NFH or α-internexin [130].…”

Can neurodegenerative disease be defined by four ‘primary determinants’: anatomy, cells, molecules, and morphology?

“…Furthermore, aggregates of abnormal intermediate filaments (IF) immunoreactive for a-internexin have been identified as a component of inclusions in neuronal intermediate filament inclusion disease (NIFID), a rare subtype of FTLD [10,30,36,92]. Subsequently, 'fused in sarcoma' (FUS) protein was identified as a major pathological protein in this disorder [23,132,177]. In addition, a significant number of cases of FTLD are linked to the product of the transcriptional repressor gene (TARDP), viz.…”