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
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.
Publication Types
["Journal Article", "Research Support, N.I.H., Extramural", "Research Support, Non-U.S. Gov't"]
Keywords
MeSH Terms
["Alternative Splicing", "Amino Acid Motifs", "Amino Acids", "Amyotrophic Lateral Sclerosis", "Animals", "Chromatography, Affinity", "Fibroblasts", "HeLa Cells", "Humans", "Isotope Labeling", "Mice, Transgenic", "Models, Biological", "Mutant Proteins", "Mutation", "Protein Binding", "Protein Interaction Maps", "Protein Structure, Tertiary", "Proteomics", "RNA Precursors", "RNA Processing, Post-Transcriptional", "RNA-Binding Protein FUS", "Ribonucleoprotein, U1 Small Nuclear", "SMN Complex Proteins", "Spinal Cord"]
Funding
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)
Linked Datasets (1)
ALS-causative mutations in FUS/TLS confer gain- and loss-of-function by altered association with SMN and U1-snRNP
Homo sapiens98 data files
| File | Type | Size |
|---|---|---|
| Fibroblast_H517Q_1.fastq.gz | OTHER | 57.6 MB |
| Fibroblast_H517Q_1.fastq.gz | OTHER | 57.6 MB |
| Fibroblast_H517Q_2.fastq.gz | OTHER | 69.5 MB |
| Fibroblast_M511nfs_1.fastq.gz | OTHER | 172.1 MB |
| Fibroblast_M511nfs_1.fastq.gz | OTHER | 172.1 MB |
| Fibroblast_M511nfs_2.fastq.gz | OTHER | 159.5 MB |
| Fibroblast_M511nfs_2.fastq.gz | OTHER | 159.5 MB |
| Fibroblast_R521G_1.fastq.gz | OTHER | 145.4 MB |
| Fibroblast_R521G_1.fastq.gz | OTHER | 145.4 MB |
| Fibroblast_R521G_2.fastq.gz | OTHER | 143.9 MB |
| Fibroblasts_Ctrl-1_1.fastq.gz | OTHER | 107.3 MB |
| Fibroblasts_Ctrl-1_1.fastq.gz | OTHER | 107.3 MB |
| Fibroblasts_Ctrl-1_2.fastq.gz | OTHER | 128.9 MB |
| Fibroblasts_Ctrl-1_FUS-siRNA_1.fastq.gz | OTHER | 116.3 MB |
| Fibroblasts_Ctrl-1_FUS-siRNA_1.fastq.gz | OTHER | 116.3 MB |
| Fibroblasts_Ctrl-1_FUS-siRNA_2.fastq.gz | OTHER | 159.1 MB |
| Fibroblasts_Ctrl-1_FUS-siRNA_2.fastq.gz | OTHER | 159.1 MB |
| Fibroblasts_Ctrl-1_notreat_1.fastq.gz | OTHER | 151.2 MB |
| Fibroblasts_Ctrl-1_notreat_1.fastq.gz | OTHER | 151.2 MB |
| Fibroblasts_Ctrl-1_notreat_2.fastq.gz | OTHER | 135.8 MB |
| Fibroblasts_Ctrl-1_notreat_2.fastq.gz | OTHER | 135.8 MB |
| Fibroblasts_Ctrl-1_sham-siRNA_1.fastq.gz | OTHER | 88.3 MB |
| Fibroblasts_Ctrl-1_sham-siRNA_1.fastq.gz | OTHER | 88.3 MB |
| Fibroblasts_Ctrl-1_sham-siRNA_2.fastq.gz | OTHER | 88.8 MB |
| Fibroblasts_Ctrl-1_sham-siRNA_2.fastq.gz | OTHER | 88.8 MB |
| Fibroblasts_Ctrl-1_SMN-siRNA_1.fastq.gz | OTHER | 176.2 MB |
| Fibroblasts_Ctrl-1_SMN-siRNA_1.fastq.gz | OTHER | 176.2 MB |
| Fibroblasts_Ctrl-1_SMN-siRNA_2.fastq.gz | OTHER | 172.5 MB |
| Fibroblasts_Ctrl-1_SMN-siRNA_2.fastq.gz | OTHER | 172.5 MB |
| Fibroblasts_Ctrl-2_1.fastq.gz | OTHER | 137.5 MB |
| Fibroblasts_Ctrl-2_2.fastq.gz | OTHER | 174.6 MB |
| Fibroblasts_Ctrl-2_2.fastq.gz | OTHER | 174.6 MB |
| Fibroblasts_Ctrl-2_FUS-siRNA_1.fastq.gz | OTHER | 194.9 MB |
| Fibroblasts_Ctrl-2_FUS-siRNA_1.fastq.gz | OTHER | 194.9 MB |
| Fibroblasts_Ctrl-2_FUS-siRNA_2.fastq.gz | OTHER | 256.2 MB |
| Fibroblasts_Ctrl-2_notreat_1.fastq.gz | OTHER | 184.8 MB |
| Fibroblasts_Ctrl-2_notreat_1.fastq.gz | OTHER | 184.8 MB |
| Fibroblasts_Ctrl-2_notreat_2.fastq.gz | OTHER | 129.1 MB |
| Fibroblasts_Ctrl-2_notreat_2.fastq.gz | OTHER | 129.1 MB |
| Fibroblasts_Ctrl-2_sham-siRNA_1.fastq.gz | OTHER | 186.0 MB |
| Fibroblasts_Ctrl-2_sham-siRNA_2.fastq.gz | OTHER | 121.2 MB |
| Fibroblasts_Ctrl-2_sham-siRNA_2.fastq.gz | OTHER | 121.2 MB |
| Fibroblasts_Ctrl-2_SMN-siRNA_1.fastq.gz | OTHER | 87.6 MB |
| Fibroblasts_Ctrl-2_SMN-siRNA_1.fastq.gz | OTHER | 87.6 MB |
| Fibroblasts_Ctrl-2_SMN-siRNA_2.fastq.gz | OTHER | 89.2 MB |
| Fibroblasts_Ctrl-3_1.fastq.gz | OTHER | 247.1 MB |
| Fibroblasts_Ctrl-3_1.fastq.gz | OTHER | 247.1 MB |
| Fibroblasts_Ctrl-3_2.fastq.gz | OTHER | 234.6 MB |
| Fibroblasts_Ctrl-3_2.fastq.gz | OTHER | 234.6 MB |
| FLP-IN_FUS-RNAi_1.fastq.gz | OTHER | 135.7 MB |
| FLP-IN_FUS-RNAi_1.fastq.gz | OTHER | 135.7 MB |
| FLP-IN_FUS-RNAi_2.fastq.gz | OTHER | 137.2 MB |
| FLP-IN_FUS-RNAi_3.fastq.gz | OTHER | 122.5 MB |
| FLP-IN_FUS-RNAi_3.fastq.gz | OTHER | 122.5 MB |
| FLP-IN_P525L_FUS-RNAi_1.fastq.gz | OTHER | 186.2 MB |
| FLP-IN_P525L_FUS-RNAi_1.fastq.gz | OTHER | 186.2 MB |
| FLP-IN_P525L_FUS-RNAi_2.fastq.gz | OTHER | 175.7 MB |
| FLP-IN_P525L_FUS-RNAi_2.fastq.gz | OTHER | 175.7 MB |
| FLP-IN_P525L_FUS-RNAi_3.fastq.gz | OTHER | 243.4 MB |
| FLP-IN_P525L_FUS-RNAi_3.fastq.gz | OTHER | 243.4 MB |
| FLP-IN_parental_1.fastq.gz | OTHER | 151.6 MB |
| FLP-IN_parental_2.fastq.gz | OTHER | 173.5 MB |
| FLP-IN_parental_3.fastq.gz | OTHER | 195.4 MB |
| FLP-IN_R495X_FUS-RNAi_1.fastq.gz | OTHER | 242.7 MB |
| FLP-IN_R495X_FUS-RNAi_2.fastq.gz | OTHER | 186.6 MB |
| FLP-IN_R495X_FUS-RNAi_2.fastq.gz | OTHER | 186.6 MB |
| FLP-IN_R495X_FUS-RNAi_3.fastq.gz | OTHER | 213.4 MB |
| FLP-IN_R495X_FUS-RNAi_3.fastq.gz | OTHER | 213.4 MB |
| FLP-IN_R514G_FUS-RNAi_1.fastq.gz | OTHER | 245.9 MB |
| FLP-IN_R514G_FUS-RNAi_1.fastq.gz | OTHER | 245.9 MB |
| FLP-IN_R514G_FUS-RNAi_2.fastq.gz | OTHER | 194.6 MB |
| FLP-IN_R514G_FUS-RNAi_3.fastq.gz | OTHER | 170.8 MB |
| FLP-IN_R521G_FUS-RNAi_1.fastq.gz | OTHER | 145.2 MB |
| FLP-IN_R521G_FUS-RNAi_1.fastq.gz | OTHER | 145.2 MB |
| FLP-IN_R521G_FUS-RNAi_2.fastq.gz | OTHER | 201.3 MB |
| FLP-IN_R521G_FUS-RNAi_3.fastq.gz | OTHER | 164.7 MB |
| FLP-IN_WT-FUS_FUS-RNAi_1.fastq.gz | OTHER | 175.6 MB |
| FLP-IN_WT-FUS_FUS-RNAi_2.fastq.gz | OTHER | 59.4 MB |
| FLP-IN_WT-FUS_FUS-RNAi_3.fastq.gz | OTHER | 162.3 MB |
| SRR1708193 | OTHER | 151.6 MB |
| SRR1708194 | OTHER | 173.5 MB |
| SRR1708195 | OTHER | 195.4 MB |
| SRR1708197 | OTHER | 137.2 MB |
| SRR1708199 | OTHER | 175.6 MB |
| SRR1708200 | OTHER | 59.4 MB |
| SRR1708201 | OTHER | 162.3 MB |
| SRR1708202 | OTHER | 242.7 MB |
| SRR1708206 | OTHER | 194.6 MB |
| SRR1708207 | OTHER | 170.8 MB |
| SRR1708209 | OTHER | 201.3 MB |
| SRR1708210 | OTHER | 164.7 MB |
| SRR1708214 | OTHER | 137.5 MB |
| SRR1708219 | OTHER | 128.9 MB |
| SRR1708221 | OTHER | 143.9 MB |
| SRR1708223 | OTHER | 69.5 MB |
| SRR1708228 | OTHER | 186.0 MB |
| SRR1708231 | OTHER | 256.2 MB |
| SRR1708233 | OTHER | 89.2 MB |
Analysis Pipelines (1)
GSE64078 Data Processing
1 step
geo_data_processing
GSE64078