| First Author | Shiihashi G | Year | 2016 |
| Journal | Brain | Volume | 139 |
| Issue | Pt 9 | Pages | 2380-94 |
| PubMed ID | 27368346 | Mgi Jnum | J:287782 |
| Mgi Id | MGI:6423636 | Doi | 10.1093/brain/aww161 |
| Citation | Shiihashi G, et al. (2016) Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice. Brain 139(Pt 9):2380-94 |
| abstractText | 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 (DeltaNLS-FUS), which developed progressive spastic motor deficits and neuronal loss in the motor cortex. The DeltaNLS-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 DeltaNLS-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. DeltaNLS-FUS mice are promising tools for understanding amyotrophic lateral sclerosis pathogenesis and testing new therapeutic approaches. |
