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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, Don W Cleveland

Nature communications · 2015 · Vol. 6 · pp. 6171

PubMed ↗ DOI ↗ PMC full text ↗

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.

Linked datasets 1

GSE64078 GSE · via ncbi_elink
GEO ↗

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

Homo sapiens

119 data files
FileTypeSize
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SRR1708240_GSM1563944 OTHER 176.0 MB
SRR1708241_GSM1563945 OTHER 172.0 MB

Potentially related datasets 1

These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.

Accession Source Title
GSE64078 GSE · GEO GEO ↗ ALS-causative mutations in FUS/TLS confer gain- and loss-of-function by altered association with SMN and U1-snRNP

Analysis pipelines 1

Pipeline Assay Steps Dataset
GSE64078 Data Processing geo_data_processing — 1 GSE64078
Funding 10 grants
Grant Funder
R01 HG004659 NHGRI NIH HHS (United States)
R01 NS075449 NINDS NIH HHS (United States)
R01 NS027036 NINDS NIH HHS (United States)
HG004659 NHGRI NIH HHS (United States)
NS075449 NINDS NIH HHS (United States)
T32 AG 000216 NIA NIH HHS (United States)
R21 OD011915 NIH HHS (United States)
I21 BX001625 BLRD VA (United States)
089701 Wellcome Trust (United Kingdom)
T32 AG000216 NIA NIH HHS (United States)