Journal Article

ALS mutations in FUS cause neuronal dysfunction and death in <i>Caenorhabditis elegans</i> by a dominant gain-of-function mechanism

Tetsuro Murakami, Seung-Pil Yang, Lin Xie, Taizo Kawano, Donald Fu, Asuka Mukai, Christopher Bohm, Fusheng Chen, Janice Robertson, Hiroshi Suzuki, Gian Gaetano Tartaglia, Michele Vendruscolo, Gabriele S. Kaminski Schierle, Fiona T.S. Chan, Aileen Moloney, Damian Crowther, Clemens F. Kaminski, Mei Zhen and Peter St George-Hyslop

in Human Molecular Genetics

Volume 21, issue 1, pages 1-9
Published in print January 2012 | ISSN: 0964-6906
Published online September 2011 | e-ISSN: 1460-2083 | DOI:

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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.

Journal Article.  4686 words.  Illustrated.

Subjects: Genetics and Genomics

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