Murakami T, Yang S, Xie L, Kawano T, Fu D, Mukai A, Bohm C, Chen F, Robertson J, Suzuki H, Tartaglia GG, Vendruscolo M, Kaminski Schierle GS, Chan FTS, Moloney A, Crowther D, Kaminski CF, Zhen M, St. George-Hyslop P, "ALS mutations in FUS causes neuronal dysfunction and death in C. elegans by a dominant gain-of-function mechanism", Hum. Mol. Genet., 21(1), pp 1-9, (2012), DOI: 10.1093/hmg/ddr417 |
It is unclear whether mutations in FUS cause familial ALS via a loss-of-function effect due to titrating FUS from the nucleus, or a gain-of-function effect from cytoplasmic over-abundance. To investigate this question we generated a series of independent C. elegans lines expressing mutant or wild-type human FUS. We show that mutant FUS, but not wild-type FUS, causes cytoplasmic mislocalisation associated with progressive motor dysfunction and reduced lifespan. The severity of the mutant phenotype in C. elegans was directly correlated with the severity of the illness caused by the same mutation in humans, arguing that this model closely replicates key features of the human illness. Importantly, the mutant phenotype could not be rescued by overexpression of wild-type FUS even though wild-type FUS had physiological intracellular localisation, and was not recruited to the cytoplasmic mutant FUS aggregates. Our data suggest that FUS mutants cause neuronal dysfunction by a dominant gain-of-function effect related either to neurotoxic aggregates of mutant FUS in the cytoplasm or to dysfunction in its RNA binding functions.