Point mutations in FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease—but do they do that by a loss of the protein's normal function, or by endowing it with novel toxic functions, or both? In this issue of The EMBO Journal, Scekic‐Zahirovic et al (2016) report that mutant FUS, but not the complete loss of FUS, triggers motor neuron degeneration in mice, arguing for a toxic gain‐of‐function mechanism.
See also: J Scekic‐Zahirovic et al
Patients who suffer from ALS or a related disorder, frontotemporal dementia (FTD), have characteristic protein aggregates in their brains. These aggregates are found in neuronal and glial cells and contain DNA/RNA‐binding proteins, most notably TDP‐43 or, less frequently, FUS (Mackenzie et al, 2010). Both TDP‐43 and FUS are usually located in the cell nucleus, where they regulate transcription and splicing of numerous target genes (Lagier‐Tourenne et al, 2012). However, in ALS/FTD patients, TDP‐43 or FUS is no longer found in the nucleus and instead accumulates in cytoplasmic protein aggregates (Mackenzie et al, 2010). Based on this neuropathology, it is thought that loss of either TDP‐43 or FUS from the nucleus or aberrant function of TDP‐43 or FUS in the cytoplasm, or a combination of …
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