title: Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice.
abstract: Mutations in RNA-binding proteins, including fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43, encoded by TARDBP), are associated with sporadic and familial amyotrophic lateral sclerosis. A major question is whether neuronal loss is caused by toxic gain-of-function cytoplasmic aggregates or loss of nuclear RNA-binding protein function. We generated a transgenic mouse overexpressing exogenous FUS without a nuclear localization signal (ΔNLS-FUS), which developed progressive spastic motor deficits and neuronal loss in the motor cortex. The ΔNLS-FUS protein was restricted to the cytoplasm and formed ubiquitin/p62-positive aggregates. Endogenous FUS expression, nuclear localization, and splicing activity were not altered, indicating that mislocated FUS is sufficient for proteinopathy. Crossing ΔNLS-FUS with wild-type human TDP-43 transgenic mice exacerbated pathological and behavioural phenotypes, suggesting that both proteins are involved in a common cascade. RNA-sequence analysis revealed specific transcriptome alterations, including genes regulating dynein-associated molecules and endoplasmic reticulum stress. ΔNLS-FUS mice are promising tools for understanding amyotrophic lateral sclerosis pathogenesis and testing new therapeutic approaches.
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku,Tokyo 160-8582, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Shiihashi
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku,Tokyo 160-8582, Japan d-ito@jk9.so-net.ne.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku,Tokyo 160-8582, Japan 2 Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yagi
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku,Tokyo 160-8582, Japan 3 Biomedical Research Center, Biochemistry, Ludwig-Maximilians-University Munich, Feodor-Lynen-Strasse 17, 81377 Munich, Germany.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nihei
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku,Tokyo 160-8582, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Ebine
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku,Tokyo 160-8582, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D019913:Nuclear Localization Signals / Q000378:metabolism*; D010641:Phenotype; D034702:RNA-Binding Protein FUS / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C000599550:FUS protein, human; D019913:Nuclear Localization Signals; D034702:RNA-Binding Protein FUS; C000598624:TARDBP protein, human
keywords: RNA processing; TDP-43; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; protein aggregation