期刊
NEURON
卷 100, 期 4, 页码 816-+出版社
CELL PRESS
DOI: 10.1016/j.neuron.2018.09.044
关键词
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资金
- The Wellcome Trust
- Medical Research Council
- Target ALS
- Muscular Dystrophy Association [MDA352600]
- Milton Safenowitz postdoctoral fellowship
- UCSD Genetics Training Program from the National Institute for General Medical Sciences [T32 GM008666]
- Ludwig Institute for Cancer Research
- Alzheimer Research UK
- Alzheimer Society through the United Kingdom Dementia Research Institute
- National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust
- King's College London
- NATIONAL CANCER INSTITUTE [ZIABC010390] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008666] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS027036, P30NS047101] Funding Source: NIH RePORTER
- MRC [G0500289, MC_G1000733] Funding Source: UKRI
Through the generation of humanized FUS mice expressing full-length human FUS, we identify that when expressed at near endogenous murine FUS levels, both wild-type and ALS-causing and fronto-temporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of murine FUS with mutant, but not wild-type, human FUS causes stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. Most strikingly, accumulation of mutant human FUS is shown to activate an integrated stress response and to inhibit local, intra-axonal protein synthesis in hippocampal neurons and sciatic nerves. Collectively, our evidence demonstrates that human ALS/ FTD-linked mutations in FUS induce a gain of toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUSbound pre-mRNAs.
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