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

Nat Commun. 2015 Jan 27:6:6171. doi: 10.1038/ncomms7171.


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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Amino Acid Motifs
  • Amino Acids / metabolism
  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Chromatography, Affinity
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • HeLa Cells
  • Humans
  • Isotope Labeling
  • Mice, Transgenic
  • Models, Biological
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Protein Binding
  • Protein Interaction Maps
  • Protein Structure, Tertiary
  • Proteomics
  • RNA Precursors / genetics
  • RNA Precursors / metabolism
  • RNA Processing, Post-Transcriptional
  • RNA-Binding Protein FUS / chemistry
  • RNA-Binding Protein FUS / genetics*
  • RNA-Binding Protein FUS / metabolism
  • Ribonucleoprotein, U1 Small Nuclear / metabolism*
  • SMN Complex Proteins / metabolism*
  • Spinal Cord / metabolism
  • Spinal Cord / pathology


  • Amino Acids
  • Mutant Proteins
  • RNA Precursors
  • RNA-Binding Protein FUS
  • Ribonucleoprotein, U1 Small Nuclear
  • SMN Complex Proteins

Associated data

  • GEO/GSE64078