Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis.
Shuo-Chien Ling, Somasish Ghosh Dastidar, Seiya Tokunaga, Wan Yun Ho, Kenneth Lim, Hristelina Ilieva, Philippe A Parone, Sheue-Houy Tyan, Tsemay M Tse, Jer-Cherng Chang, Oleksandr Platoshyn, Ngoc B Bui, Anh Bui, Anne Vetto, Shuying Sun, Melissa McAlonis-Downes, Joo Seok Han, Debbie Swing, Katannya Kapeli, Gene W Yeo, Lino Tessarollo, Martin Marsala, Christopher E Shaw, Greg Tucker-Kellogg, Albert R La Spada, Clotilde Lagier-Tourenne, Sandrine Da Cruz, Don W Cleveland
eLife · 2019 · Vol. 8
Abstract
Mutations in coding and non-coding regions of FUS cause amyotrophic lateral sclerosis (ALS). The latter mutations may exert toxicity by increasing FUS accumulation. We show here that broad expression within the nervous system of wild-type or either of two ALS-linked mutants of human FUS in mice produces progressive motor phenotypes accompanied by characteristic ALS-like pathology. FUS levels are autoregulated by a mechanism in which human FUS downregulates endogenous FUS at mRNA and protein levels. Increasing wild-type human FUS expression achieved by saturating this autoregulatory mechanism produces a rapidly progressive phenotype and dose-dependent lethality. Transcriptome analysis reveals mis-regulation of genes that are largely not observed upon FUS reduction. Likely mechanisms for FUS neurotoxicity include autophagy inhibition and defective RNA metabolism. Thus, our results reveal that overriding FUS autoregulation will trigger gain-of-function toxicity via altered autophagy-lysosome pathway and RNA metabolism function, highlighting a role for protein and RNA dyshomeostasis in FUS-mediated toxicity.
Linked datasets 1
Overriding FUS autoregulation triggers gain-of-toxic dysfunctions in autophagy-lysosome axis and RNA metabolism
Mus musculus
38 data files
| File | Type | Size |
|---|---|---|
| KQ_23_ATCACG_L006_R1.fastq.gz | RNA-Seq | 384.9 MB |
| KQ_24_TTAGGC_L006_R1.fastq.gz | RNA-Seq | 475.3 MB |
| KQ_25_ACTTGA_L006_R1.fastq.gz | RNA-Seq | 663.2 MB |
| KQ_27_TAGCTT_L006_R1.fastq.gz | RNA-Seq | 496.2 MB |
| KQ_28_GGCTAC_L006_R1.fastq.gz | RNA-Seq | 547.8 MB |
| Sc_157.fastq.gz | RNA-Seq | 930.3 MB |
| Sc_163.fastq.gz | RNA-Seq | 927.0 MB |
| Sc_166.fastq.gz | RNA-Seq | 872.7 MB |
| SC_540.fastq.gz | RNA-Seq | 884.3 MB |
| Sc_545.fastq.gz | RNA-Seq | 851.5 MB |
| Sc_821.fastq.gz | RNA-Seq | 802.4 MB |
| Sc_825.fastq.gz | RNA-Seq | 1.1 GB |
| Sc_858.fastq.gz | RNA-Seq | 803.9 MB |
| Sc_882.fastq.gz | RNA-Seq | 900.3 MB |
| SRR8444929 | RNA-Seq | 930.3 MB |
| SRR8444929_GSM3563903 | RNA-Seq | 930.0 MB |
| SRR8444930 | RNA-Seq | 927.0 MB |
| SRR8444930_GSM3563904 | RNA-Seq | 927.0 MB |
| SRR8444931 | RNA-Seq | 802.4 MB |
| SRR8444931_GSM3563905 | RNA-Seq | 802.0 MB |
| SRR8444932 | RNA-Seq | 884.3 MB |
| SRR8444932_GSM3563906 | RNA-Seq | 884.0 MB |
| SRR8444933 | RNA-Seq | 851.5 MB |
| SRR8444933_GSM3563907 | RNA-Seq | 851.0 MB |
| SRR8444934_GSM3563908 | RNA-Seq | 1.1 GB |
| SRR8444935 | RNA-Seq | 872.7 MB |
| SRR8444935_GSM3563909 | RNA-Seq | 872.0 MB |
| SRR8444936 | RNA-Seq | 803.9 MB |
| SRR8444936_GSM3563910 | RNA-Seq | 803.0 MB |
| SRR8444937_GSM3563911 | RNA-Seq | 900.0 MB |
| SRR8444938 | RNA-Seq | 384.9 MB |
| SRR8444938_GSM3563912 | RNA-Seq | 384.0 MB |
| SRR8444939_GSM3563913 | RNA-Seq | 475.0 MB |
| SRR8444939.sralite | RNA-Seq | 475.3 MB |
| SRR8444940_GSM3563914 | RNA-Seq | 663.0 MB |
| SRR8444941 | RNA-Seq | 496.2 MB |
| SRR8444941_GSM3563915 | RNA-Seq | 496.0 MB |
| SRR8444942_GSM3563916 | RNA-Seq | 547.0 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.
Analysis pipelines 1
| Pipeline | Assay | Steps | Dataset |
|---|---|---|---|
| GSE125125 RNA-seq Data Processing geo_data_processing | RNA-seq | 3 | GSE125125 |
Funding 11 grants
| Grant | Funder |
|---|---|
| Wellcome Trust (United Kingdom) | |
| MC_G1000733 | Medical Research Council (United Kingdom) |
| NMRC/OFIRG/0001/2016 | National Medical Research Council (International) |
| R01 AG033082 | NIA NIH HHS (United States) |
| R01 NS027036 | NINDS NIH HHS (United States) |
| G0500289 | Medical Research Council (United Kingdom) |
| R01 AG033082 | NIH HHS (United States) |
| R01 NS100023 | NINDS NIH HHS (United States) |
| R01 NS041648 | NIH HHS (United States) |
| R01 NS041648 | NINDS NIH HHS (United States) |
| MOE2016-T2-1-024 | Ministry of Education - Singapore (International) |