FUS-SMN protein interactions link the motor neuron diseases ALS and SMA

Cell Rep. 2012 Oct 25;2(4):799-806. doi: 10.1016/j.celrep.2012.08.025. Epub 2012 Sep 27.


Mutations in the RNA binding protein FUS cause amyotrophic lateral sclerosis (ALS), a fatal adult motor neuron disease. Decreased expression of SMN causes the fatal childhood motor neuron disorder spinal muscular atrophy (SMA). The SMN complex localizes in both the cytoplasm and nuclear Gems, and loss of Gems is a cellular hallmark of fibroblasts in patients with SMA. Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN. Functionally, we show that FUS is required for Gem formation in HeLa cells, and expression of FUS containing a severe ALS-causing mutation (R495X) also results in Gem loss. Strikingly, a reduction in Gems is observed in ALS patient fibroblasts expressing either mutant FUS or TDP-43, another ALS-causing protein that interacts with FUS. The physical and functional interactions among SMN, FUS, TDP-43, and Gems indicate that ALS and SMA share a biochemical pathway, providing strong support for the view that these motor neuron diseases are related.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • DEAD Box Protein 20 / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • HeLa Cells
  • Humans
  • Muscular Atrophy, Spinal / metabolism*
  • Muscular Atrophy, Spinal / pathology
  • Mutation
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • RNA-Binding Protein FUS / antagonists & inhibitors
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / metabolism*
  • Ribonucleoproteins, Small Nuclear / metabolism
  • SMN Complex Proteins / genetics
  • SMN Complex Proteins / metabolism*


  • DNA-Binding Proteins
  • RNA, Small Interfering
  • RNA-Binding Protein FUS
  • Ribonucleoproteins, Small Nuclear
  • SMN Complex Proteins
  • DEAD Box Protein 20