title: ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function mechanism.
abstract: It is unclear whether mutations in fused in sarcoma (FUS) cause familial amyotrophic lateral sclerosis via a loss-of-function effect due to titrating FUS from the nucleus or a gain-of-function effect from cytoplasmic overabundance. To investigate this question, we generated a series of independent Caenorhabditis elegans lines expressing mutant or wild-type (WT) human FUS. We show that mutant FUS, but not WT-FUS, causes cytoplasmic mislocalization 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 WT-FUS, even though WT-FUS had physiological intracellular localization, 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.
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Murakami
authors.forename: Seung-Pil
authors.initials: SP
authors.lastname: Yang
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Taizo
authors.initials: T
authors.lastname: Kawano
authors.forename: Donald
authors.initials: D
authors.lastname: Fu
authors.forename: Asuka
authors.initials: A
authors.lastname: Mukai
authors.forename: Christopher
authors.initials: C
authors.lastname: Bohm
authors.forename: Fusheng
authors.initials: F
authors.lastname: Chen
authors.forename: Janice
authors.initials: J
authors.lastname: Robertson
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Gian Gaetano
authors.initials: GG
authors.lastname: Tartaglia
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.forename: Gabriele S
authors.initials: GS
authors.lastname: Kaminski Schierle
authors.forename: Fiona T S
authors.initials: FT
authors.lastname: Chan
authors.forename: Aileen
authors.initials: A
authors.lastname: Moloney
authors.forename: Damian
authors.initials: D
authors.lastname: Crowther
authors.forename: Clemens F
authors.initials: CF
authors.lastname: Kaminski
authors.forename: Mei
authors.initials: M
authors.lastname: Zhen
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D009046:Motor Neurons / Q000166:cytology* / Q000378:metabolism; D009154:Mutation; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism*
chemical_list: D034702:RNA-Binding Protein FUS