Absence of FUS-immunoreactive pathology in frontotemporal dementia linked to chromosome 3 (FTD-3) caused by mutation in the CHMP2B gene

Abstract

Frontotemporal dementia linked to chromosome 3 (FTD-3) is a very rare disease described in a large Danish family [1] and also in an unrelated Belgian patient with familial FTD [12]. A mutation has been identified in the CHMP2B gene that is likely responsible for causing the disease in the Danish family [9] and a different mutation was identified in the Belgian patient [12]. CHMP2B is a component of the endosomal sorting complex required for transport-III (ESCRT-III), which is involved in the degradation of proteins in the endocytic and autophagic pathways [10]. According to the recommended nomenclature, the neuropathology of frontotemporal lobar degeneration (FTLD) is subdivided into major groups on the basis of the protein abnormality that is presumed to be pathogenic or most characteristic [5]. The major groups are: FTLD-tau where the protein is the microtubule-associated protein tau, FTLD-TDP where the protein is the transactive response DNA binding protein with Mr 43 kD (TDP-43), FTLDUPS where inclusions can only be demonstrated with immunohistochemistry against proteins of the ubiquitin proteasome system (UPS), FTLD-IF where the inclusions are immunoreactive for class IV intermediate filaments, and FTLD-ni where no inclusions can be demonstrated. The neuropathology of FTD-3 is characterized by FTLD with neuronal cytoplasmic inclusions (NCI) that are immunoreactive for ubiquitin and p62, but not for tau, TDP-43 or intermediate filaments [2], and therefore, belongs to the FTLD-UPS group [6]. In addition to FTD-3, FTLD-UPS includes a group of sporadic FTD with unique clinical and pathological features, originally designated as atypical FTLD with ubiquitinated inclusions (aFTLD-U) because the NCI are immunoreactive for ubiquitin but negative for TDP-43 [4, 8]. Recently, mutations in the fused in sarcoma (FUS) gene have been identified as the cause of familial amyotrophic lateral sclerosis (ALS) type 6 [3, 11]. Because of the recognized clinical, genetic and pathological overlap between ALS and FTD and since the pathology in cases with FUS mutations was originally described as including NCI that were TDP-43 negative but FUS positive, one of us (I.M.) recently investigated whether FUS might also be the pathological protein in aFTLD-U. In all the aFTLD-U cases studied (N = 15), FUS immunohistochemistry (IHC) labeled all the ubiquitinated NCI and also identified abundant glial inclusions. Biochemical analysis of aFTLDU postmortem brain tissue demonstrated increased levels of insoluble FUS protein. No genetic abnormalities were identified in the FUS gene. These findings suggest that FUS is likely the pathological protein in the majority of sporadic FTLD-UPS cases and that these should now be designated as FTLD-FUS [6]. Furthermore, FUS was recently found in several types of inclusions in postmortem brains from patients with neuronal intermediate filament inclusion On behalf of the FReJA Consortium.