Author
Listed:
- Shuying Sun
(Ludwig Institute for Cancer Research, University of California at San Diego
University of California at San Diego)
- Shuo-Chien Ling
(Ludwig Institute for Cancer Research, University of California at San Diego
University of California at San Diego
National University of Singapore)
- Jinsong Qiu
(University of California at San Diego)
- Claudio P. Albuquerque
(Ludwig Institute for Cancer Research, University of California at San Diego
University of California at San Diego)
- Yu Zhou
(University of California at San Diego)
- Seiya Tokunaga
(Ludwig Institute for Cancer Research, University of California at San Diego)
- Hairi Li
(University of California at San Diego)
- Haiyan Qiu
(University of California at San Francisco)
- Anh Bui
(Ludwig Institute for Cancer Research, University of California at San Diego)
- Gene W. Yeo
(University of California at San Diego
Institute for Genomic Medicine, University of California at San Diego)
- Eric J. Huang
(University of California at San Francisco)
- Kevin Eggan
(Harvard Stem Cell Institute, Harvard University)
- Huilin Zhou
(Ludwig Institute for Cancer Research, University of California at San Diego
University of California at San Diego)
- Xiang-Dong Fu
(University of California at San Diego)
- Clotilde Lagier-Tourenne
(Ludwig Institute for Cancer Research, University of California at San Diego
University of California at San Diego)
- Don W. Cleveland
(Ludwig Institute for Cancer Research, University of California at San Diego
University of California at San Diego)
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.
Suggested Citation
Shuying Sun & Shuo-Chien Ling & Jinsong Qiu & Claudio P. Albuquerque & Yu Zhou & Seiya Tokunaga & Hairi Li & Haiyan Qiu & Anh Bui & Gene W. Yeo & Eric J. Huang & Kevin Eggan & Huilin Zhou & Xiang-Dong, 2015.
"ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP,"
Nature Communications, Nature, vol. 6(1), pages 1-14, May.
Handle:
RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7171
DOI: 10.1038/ncomms7171
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