title: Accumulation of insoluble forms of FUS protein correlates with toxicity in Drosophila.
abstract: Recently, the fused in sarcoma/translated in liposarcoma (FUS) protein has been identified as a major constituent of nuclear and/or cytoplasmic ubiquitin-positive inclusions in patients with frontotemporal lobar degeneration or amyotrophic lateral sclerosis. The molecular mechanisms underlying FUS toxicity are currently not understood. To address aspects of FUS pathogenesis in vivo, we have generated new Drosophila transgenic models expressing a full-length wild-type isoform of human FUS protein. We found that when expressed in retinal cells, FUS proteins are mainly recovered as soluble forms, and their overexpression results in a mild eye phenotype, with malformed interommatidial bristles and the appearance of ectopic extensions. On the other hand, when FUS proteins are specifically targeted to adult differentiated neurons, they are mainly recovered as insoluble forms, and their overexpression drastically reduces fly life span. Importantly, FUS neurotoxicity occurs regardless of inclusion formation. Lastly, we showed that molecular chaperones reduce FUS toxicity by modulating protein solubility. Altogether, our data indicate that accumulation of insoluble non-aggregated FUS forms might represent the primary toxic species in human FUS proteinopathies.
authors: UMR Inserm U614, IFRMP23, Rouen Institute for Medical Research and Innovation, Faculty of Medicine, University of Rouen, Rouen, France.
authors: Laetitia
authors: L
authors: Miguel
authors: Tracey
authors: T
authors: Avequin
authors: Morgane
authors: M
authors: Delarue
authors: Sébastien
authors: S
authors: Feuillette
authors: Thierry
authors: T
authors: Frébourg
authors: Dominique
authors: D
authors: Campion
authors: Magalie
authors: M
authors: Lecourtois
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001928:Brain Diseases, Metabolic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D012995:Solubility
chemical_list: D034702:RNA-Binding Protein FUS