Research ReportFET proteins in frontotemporal dementia and amyotrophic lateral sclerosis

Mutations in the fused in sarcoma gene (FUS) cause amyotrophic lateral sclerosis (ALS) with TDP-43-negative, FUS-positive pathology. FUS is also the pathological protein in most tau/TDP-43-negative subtypes of frontotemporal lobar degeneration (FTLD-FUS). FUS, together with Ewing's sarcoma protein (EWS) and TATA-binding protein associated factor 15 (TAF15), make up the FET family of DNA/RNA binding proteins that share functional homology and have the potential to interact. We recently investigated the role of the other FET proteins in the clinicopathological spectrum of FUS-opathies. In all FTLD-FUS subtypes, FUS-positive pathology was also labeled for TAF15 and EWS and cells with inclusions showed a reduction in the normal nuclear staining of all FET proteins. In contrast, in cases of ALS-FUS, TAF15 and EWS remained localized to the nucleus and did not label FUS-positive inclusions. Cell culture models replicated the human diseases. These findings indicate that ALS-FUS and FTLD-FUS have different pathomechanisms and add TAF15 and EWS to the growing list of RNA-binding proteins involved in neurodegeneration.This article is part of a Special Issue entitled: RNA-Binding Proteins.

► FUS is the pathological protein in most tau/TDP-43-negative FTLD cases (FTLD-FUS). ► The neuropathology in ALS-FUS correlates with the specific mutation. ► In FTLD-FUS, the other FET proteins colocalize with FUS in cellular inclusions. ► In ALS-FUS there is selective accumulation of FUS with no abnormality of TAF15/EWS. ► FUS, TAF15 and EWS are all RNA-binding proteins involved in neurodegeneration.