Journal
EMBO JOURNAL
Volume 35, Issue 14, Pages 1504-1521Publisher
WILEY
DOI: 10.15252/embj.201593791
Keywords
amyotrophic lateral sclerosis; FUS; minor intron splicing
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Funding
- NOMIS Foundation
- NCCR RNA and Disease - Swiss National Science Foundation
- Holcim Stiftung zur Foderung der wissenschaftlichen Fortbildung
- Swiss Life Jubilaums-stiftung
- Fondation Dufloteau
- Canton Bern
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Fused in sarcoma (FUS) is a ubiquitously expressed RNA-binding protein proposed to function in various RNA metabolic pathways, including transcription regulation, pre-mRNA splicing, RNA transport and microRNA processing. Mutations in the FUS gene were identified in patients with amyotrophic lateral sclerosis (ALS), but the pathomechanisms by which these mutations cause ALS are not known. Here, we show that FUS interacts with the minor spliceosome constituent U11 snRNP, binds preferentially to minor introns and directly regulates their removal. Furthermore, a FUS knockout in neuroblastoma cells strongly disturbs the splicing of minor intron-containing mRNAs, among them mRNAs required for action potential transmission and for functional spinal motor units. Moreover, an ALS-associated FUS mutant that forms cytoplasmic aggregates inhibits splicing of minor introns by trapping U11 and U12 snRNAs in these aggregates. Collectively, our findings suggest a possible pathomechanism for ALS in which mutated FUS inhibits correct splicing of minor introns in mRNAs encoding proteins required for motor neuron survival.
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