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Nat Commun. 2015 Jan 27;6:6171. doi: 10.1038/ncomms7171.

ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP.

Author information

1
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093.
2
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093.
3
Department of Physiology, National University of Singapore, 14 Medical Drive, Singapore 117599.
4
Department of Pathology, University of California at San Francisco, San Francisco, CA 94143.
5
Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA 92093.
6
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.
7
Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093.
#
Contributed equally

Abstract

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.

PMID:
25625564
PMCID:
PMC4338613
DOI:
10.1038/ncomms7171
[Indexed for MEDLINE]
Free PMC Article

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