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

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 Fu, Clotilde Lagier-Tourenne and Don W. Cleveland ()
Additional contact information
Shuying Sun: Ludwig Institute for Cancer Research, University of California at San Diego
Shuo-Chien Ling: Ludwig Institute for Cancer Research, University of California at San Diego
Jinsong Qiu: University of California at San Diego
Claudio P. Albuquerque: Ludwig Institute for Cancer Research, 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
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
Xiang-Dong Fu: University of California at San Diego
Clotilde Lagier-Tourenne: Ludwig Institute for Cancer Research, University of California at San Diego
Don W. Cleveland: Ludwig Institute for Cancer Research, University of California at San Diego

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7171

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