Journal
BRAIN
Volume 139, Issue -, Pages 2380-2394Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/aww161
Keywords
TDP-43; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; protein aggregation; RNA processing
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Funding
- Eisai Co. Ltd.
- Foundation of Japan Amyotrophic Lateral Sclerosis Association
- Novartis Pharma
- Brain Science Foundation
- Life Science Foundation of Japan
- Ministry of Education, Culture, Sports, Science and Technology of Japan [15K09323]
- Nakabayashi Trust for ALS Research
- Kaken Grants-in-AID for Scientific Research [24890228]
- Grants-in-Aid for Scientific Research [16J05812, 24890228, 15K09323] Funding Source: KAKEN
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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.
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