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Copyright Nature Publishing Group Jan 2015

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.

Details

Title
ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP
Author
Sun, Shuying; Ling, Shuo-chien; Qiu, Jinsong; Albuquerque, Claudio P; Zhou, Yu; Tokunaga, Seiya; Li, Hairi; Qiu, Haiyan; Bui, Anh; Yeo, Gene W; Huang, Eric J; Eggan, Kevin; Zhou, Huilin; Fu, Xiang-dong; Lagier-tourenne, Clotilde; Cleveland, Don W
Pages
6171
Publication year
2015
Publication date
Jan 2015
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1648388643
Copyright
Copyright Nature Publishing Group Jan 2015