Originally identified as a pro-oncogene, FUS came to the attention of neurodegenerative disease research in 2009, when mutations in this gene were linked to amyotrophic lateral sclerosis (ALS). FUS mutations account for about 4 percent of inherited ALS, including some juvenile-onset cases. FUS mutations in sporadic ALS are rare. FUS protein forms part of disease-related aggregates in most kinds of ALS, regardless of whether a FUS mutation is present. An exception to this is ALS caused by mutations in superoxide dismutase 1, SOD1. In FTD, mutations in FUS are rare; however, the FUS protein has become the characteristic pathological marker for neuronal inclusions in the subset of sporadic FTD cases that lack the more established aggregate markers TDP-43 and tau.
FUS is a member of a protein family called FET, which includes FUS, Ewing’s sarcoma or EWS, and TATA-binding protein-associated factor 15 or TAF15. These are RNA-binding proteins that participate in transcription, processing and nucleus-to-cytoplasm transport of mRNAs. One emerging difference between ALS-FUS and FTD-FUS is that only the latter typically involves co-aggregation of the FET proteins EWS and TAF15 along with FUS itself.
More than 40 FUS mutations have been identified in ALS. Many occur in a terminal nuclear localization sequence or in a glycine-rich region that forms part of a prion-like domain involved in protein-protein interactions. Like TDP-43, another ALS gene and RNA-binding protein, FUS is normally a nuclear protein but in disease states it redistributes to the cytoplasm and forms RNA-protein granules.
Researchers have used yeast, Drosophila, nematodes, zebrafish, rats and mice to model FUS biology. FUS knockouts in rodents indicate that the gene is required for normal development. Mice expressing FUS mutatations develop a progressive motor neuron degeneration and paralysis somewhat like ALS, whereas those overexpressing wild-type FUS showing a milder phenotype. Currently, researchers are investigating whether mutant FUS toxicity results from a loss of normal nuclear function, a toxic gain of function in the cell body, or both. Scientists are also studying the more than 5,000 known mRNAs that are targets of FUS for clues about the protein’s normal function and role in disease.
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