期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/ncomms7171
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资金
- NIH [NS075449, HG004659]
- Wellcome trust
- Milton Safenowitz Post-Doctoral Fellowship from the Amyotrophic Lateral Sclerosis Association
- NIH Neuroplasticity of Aging [T32 AG 000216]
- Muscular Dystrophy Association
- Target ALS [13-0840]
- Ludwig Institute for Cancer Research
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R01HG004659] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS075449, R01NS027036] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [T32AG000216] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [R21OD011915] Funding Source: NIH RePORTER
- Veterans Affairs [I21BX001625] Funding Source: NIH RePORTER
The RNA-binding protein FUS/TLS, mutation in which is causative of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), is demonstrated to directly bind to the U1-snRNP and SMN complexes. ALS-causative mutations in FUS/TLS are shown to abnormally enhance their interaction with SMN and dysregulate its function, including loss of Gems and altered levels of small nuclear RNAs. The same mutants are found to have reduced association with U1-snRNP. Correspondingly, global RNA analysis reveals a mutant-dependent loss of splicing activity, with ALS-linked mutants failing to reverse changes caused by loss of wild-type FUS/TLS. Furthermore, a common FUS/TLS mutant-associated RNA splicing signature is identified in ALS patient fibroblasts. Taken together, these studies establish potentially converging disease mechanisms in ALS and spinal muscular atrophy, with ALS-causative mutants acquiring properties representing both gain (dysregulation of SMN) and loss (reduced RNA processing mediated by U1-snRNP) of function.
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