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 WTFUS 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.

Als mutations in FUS cause neuronal dysfunction and death in caenorhabditis elegans by a dominant gain-of-function mechanism / Murakami, T.; Yang, S. -P.; Xie, L.; Kawano, T.; Fu, D.; Mukai, A.; Bohm, C.; Chen, F.; Robertson, J.; Suzuki, H.; Tartaglia, G. G.; Vendruscolo, M.; Schierle, G. S. K.; Chan, F. T. S.; Moloney, A.; Crowther, D.; Kaminski, C. F.; Zhen, M.; St George-Hyslop, P.. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - 21:1(2012), pp. 1-9. [10.1093/hmg/ddr417]

Als mutations in FUS cause neuronal dysfunction and death in caenorhabditis elegans by a dominant gain-of-function mechanism

Tartaglia G. G.;Vendruscolo M.;
2012

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 WTFUS 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.
2012
Amyotrophic Lateral Sclerosis; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Cell Death; Disease Models, Animal; Female; Humans; Male; Motor Neurons; RNA-Binding Protein FUS; Mutation
01 Pubblicazione su rivista::01a Articolo in rivista
Als mutations in FUS cause neuronal dysfunction and death in caenorhabditis elegans by a dominant gain-of-function mechanism / Murakami, T.; Yang, S. -P.; Xie, L.; Kawano, T.; Fu, D.; Mukai, A.; Bohm, C.; Chen, F.; Robertson, J.; Suzuki, H.; Tartaglia, G. G.; Vendruscolo, M.; Schierle, G. S. K.; Chan, F. T. S.; Moloney, A.; Crowther, D.; Kaminski, C. F.; Zhen, M.; St George-Hyslop, P.. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - 21:1(2012), pp. 1-9. [10.1093/hmg/ddr417]
File allegati a questo prodotto
File Dimensione Formato  
Murakami_ALS_2012.pdf

accesso aperto

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 437.09 kB
Formato Adobe PDF
437.09 kB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1451757
Citazioni
  • ???jsp.display-item.citation.pmc??? 42
  • Scopus 80
  • ???jsp.display-item.citation.isi??? 76
social impact