Rho guanine nucleotide exchange factor is an NFL mRNA destabilizing factor that forms cytoplasmic inclusions in amyotrophic lateral sclerosis

Neurobiol Aging. 2013 Jan;34(1):248-62. doi: 10.1016/j.neurobiolaging.2012.06.021. Epub 2012 Jul 24.


Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive disorder of unknown etiology characterized by the selective degeneration of motor neurons. Recent evidence supports the hypothesis that alterations in RNA metabolism in motor neurons can explain the development of protein inclusions, including neurofilamentous aggregates, observed in this pathology. In mice, p190RhoGEF, a guanine nucleotide exchange factor, is involved in neurofilament protein aggregation in an RNA-triggered transgenic model of motor neuron disease. Here, we observed that rho guanine nucleotide exchange factor (RGNEF), the human homologue of p190RhoGEF, binds low molecular weight neurofilament mRNA and affects its stability via 3' untranslated region destabilization. We observed that the overexpression of RGNEF in a stable cell line significantly decreased the level of low molecular weight neurofilament protein. Furthermore, we observed RGNEF cytoplasmic inclusions in ALS spinal motor neurons that colocalized with ubiquitin, p62/sequestosome-1, and TAR (trans-active regulatory) DNA-binding protein 43 (TDP-43). Our results provide further evidence that RNA metabolism pathways are integral to ALS pathology. This is also the first described link between ALS and an RNA binding protein with aggregate formation that is also a central cell signaling pathway molecule.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Cell Line, Transformed
  • DNA-Binding Proteins / metabolism
  • Female
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Immunoprecipitation
  • Inclusion Bodies / metabolism*
  • Inclusion Bodies / pathology
  • Male
  • Mice
  • Middle Aged
  • Neurofilament Proteins / genetics*
  • Protein Binding / genetics
  • RNA Stability / genetics
  • RNA, Messenger / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rho Guanine Nucleotide Exchange Factors
  • Sequestosome-1 Protein
  • Transfection
  • Ubiquitin / metabolism


  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • Guanine Nucleotide Exchange Factors
  • Neurofilament Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Rho Guanine Nucleotide Exchange Factors
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Ubiquitin
  • neurofilament protein L
  • Green Fluorescent Proteins