Distinct pathological subtypes of FTLD-FUS

Abstract

Most cases of frontotemporal lobar degeneration (FTLD) are characterized by abnormal intracellular accumulation of either tau or TDP-43 protein. However, in ~10% of cases, composed of a heterogenous collection of uncommon disorders, the molecular basis remains to be uncertain. We recently discovered that the pathological changes in several tau/TDP-43-negative FTLD subtypes are immunoreactive (ir) for the fused in sarcoma (FUS) protein. In this study, we directly compared the pattern of FUS-ir pathology in cases of atypical FTLD-U (aFTLD-U, N = 10), neuronal intermediate filament inclusion disease (NIFID, N = 5) and basophilic inclusion body disease (BIBD, N = 8), to determine whether these are discrete entities or represent a pathological continuum. All cases had FUS-ir pathology in the cerebral neocortex, hippocampus and a similar wide range of subcortical regions. Although there was significant overlap, each group showed specific differences that distinguished them from the others. Cases of aFTLD-U consistently had less pathology in subcortical regions. In addition, the neuronal inclusions in aFTLD-U usually had a uniform, round shape, whereas NIFID and BIBD were characterized by a variety of inclusion morphologies. In all cases of aFTLD-U and NIFID, vermiform neuronal intranuclear inclusions (NII) were readily identified in the hippocampus and neocortex. In contrast, only two cases of BIBD had very rare NII in a single subcortical region. These findings support aFTLD-U, NIFID and BIBD as representing closely related, but distinct entities that share a common molecular pathogenesis. Although cases with overlapping pathology may exist, we recommend retaining the terms aFTLD-U, NIFID and BIBD for specific FTLD-FUS subtypes.

ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects

“…The main pathological features in FALS with FUS mutations are FUS-positive protein aggregates in neuronal cytoplasm and dendrites (1,2). While the majority of these aggregates are identified in the spinal motor neurons, FUS-positive aggregates have also been found in neurons in cerebral cortex and brainstem nuclei (3,4), raising the possibility that FUS mutations may have a broader impact on the functions of other neuronal subtypes. Consistent with these observations, a subset of FALS-FUS patients also exhibits cognitive impairments during the developmental or degenerative processes.…”

Astrocytes in Neurodegenerative Disease: Table 1.

“…However, relevant to this review, glial pathology is observed in all cases of familial and sporadic ALS (Neumann et al 2007;Nishihira et al 2008;Zhang et al 2008;Seilhean et al 2009;Hewitt et al 2010;Yamamoto-Watanabe et al 2010;Mackenzie et al 2011;Robertson et al 2011). Genes known to be linked to familial ALS are ubiquitously expressed, and ubiquitinated aggregates of ALScausing mutant proteins (such as SOD1 or TDP-43) are found in both neurons and glial cells (Bruijn et al 1997;Pasinelli et al 2000;Stieber et al 2000;Nishihira et al 2008;Zhang et al 2008;Forsberg et al 2011).…”

Clinico-Pathological Correlations of the Frontal Lobe Syndrome: Results of a Large Brain Bank Study

“…Recent studies, however have clearly demonstrated the involvement of both the white matter and subcortical areas in this disorder. For example, in FTLD-FUS and FTLD caused by C9orf mutation there is marked involvement of the caudate and thalamic nuclei, respectively [30]. …”