Spliceosome integrity is defective in the motor neuron diseases ALS and SMA

EMBO Mol Med. 2013 Feb;5(2):221-34. doi: 10.1002/emmm.201202303. Epub 2013 Jan 25.


Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism, TDP-43 and FUS/TLS, and SMN, respectively. However, whether there is a shared defective mechanism in RNA metabolism common to these two diseases remains unclear. Here, we show that TDP-43 and FUS/TLS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei, but not in the temporal lobe of FTLD with TDP-43 pathology. This aberrant accumulation of U snRNAs in ALS motor neurons is in direct contrast to SMA motor neurons, which show reduced amounts of U snRNAs, while both have defects in the spliceosome. These findings indicate that a profound loss of spliceosome integrity is a critical mechanism common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Motor Neurons / metabolism
  • Muscular Atrophy, Spinal / genetics
  • Muscular Atrophy, Spinal / metabolism*
  • Protein Binding
  • RNA, Small Nuclear / genetics
  • RNA, Small Nuclear / metabolism
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / metabolism
  • SMN Complex Proteins / genetics
  • SMN Complex Proteins / metabolism
  • Spliceosomes / genetics
  • Spliceosomes / metabolism*


  • DNA-Binding Proteins
  • RNA, Small Nuclear
  • RNA-Binding Protein FUS
  • SMN Complex Proteins