Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice

Shiihashi, Gen; Ito, Daisuke; Yagi, Takuya; Nihei, Yoshihiro; Ebine, Taeko und Suzuki, Norihiro (2016): Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice. In: Brain, Bd. 139: S. 2380-2394

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 (Delta NLS-FUS), which developed progressive spastic motor deficits and neuronal loss in the motor cortex. The Delta NLS-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 Delta NLS-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. Delta NLS-FUS mice are promising tools for understanding amyotrophic lateral sclerosis pathogenesis and testing new therapeutic approaches.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0006-8950
• Sprache: Englisch