Format

Send to

Choose Destination
Brain. 2016 Sep;139(Pt 9):2380-94. doi: 10.1093/brain/aww161. Epub 2016 Jun 30.

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

Author information

1
1 Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku,Tokyo 160-8582, Japan.
2
1 Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku,Tokyo 160-8582, Japan d-ito@jk9.so-net.ne.jp.
3
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.
4
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.

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.

KEYWORDS:

RNA processing; TDP-43; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; protein aggregation

PMID:
27368346
DOI:
10.1093/brain/aww161
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center