期刊
CELL
卷 173, 期 4, 页码 958-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.03.025
关键词
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资金
- Milton Safenowitz Postdoctoral Fellowship (ALSA)
- F31 NRSA Awards [NS100401, NS103360]
- NSF GRFP [2014178388]
- Thomas Shortman Scholarship
- Axol Science Scholarship
- NIH [R01NS085207, R01NS099320, P01NS09911, R01NS094239, U24NS078736, R01NS082563, NS094239, P30NS050274]
- Target ALS
- Muscular Dystrophy Association
- ALS Association
- Answer ALS
- Robert Packard Center for ALS Research
- ALSA
- Robert Packard Center for ALS
Defects in nucleocytoplasmic transport have been identified as a key pathogenic event in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mediated by a GGGGCC hexanucleotide repeat expansion in C90RF72, the most common genetic cause of ALS/FTD. Furthermore, nucleocytoplasmic transport disruption has also been implicated in other neurodegenerative diseases with protein aggregation, suggesting a shared mechanism by which protein stress disrupts nucleocytoplasmic transport. Here, we show that cellular stress disrupts nucleocytoplasmic transport by localizing critical nucleocytoplasmic transport factors into stress granules, RNA/protein complexes that play a crucial role in ALS pathogenesis. Importantly, inhibiting stress granule assembly, such as by knocking down Ataxin-2, suppresses nucleocytoplasmic transport defects as well as neurodegeneration in C90RF72-mediated ALS/FTD. Our findings identify a link between stress granule assembly and nucleocytoplasmic transport, two fundamental cellular processes implicated in the pathogenesis of C90RF72-mediated ALS/FTD and other neurodegenerative diseases.
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