Nuclear trafficking in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Brain. 2017 Jan;140(1):13-26. doi: 10.1093/brain/aww197. Epub 2016 Aug 6.


Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are two ends of a phenotypic spectrum of disabling, relentlessly progressive and ultimately fatal diseases. A key characteristic of both conditions is the presence of TDP-43 (encoded by TARDBP) or FUS immunoreactive cytoplasmic inclusions in neuronal and glial cells. This cytoplasmic mislocalization of otherwise predominantly nuclear RNA binding proteins implies a perturbation of the nucleocytoplasmic shuttling as a possible event in the pathogenesis. Compromised nucleocytoplasmic shuttling has recently also been associated with a hexanucleotide repeat expansion mutation in C9orf72, which is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and leads to accumulation of cytoplasmic TDP-43 inclusions. Mutation in C9orf72 may disrupt nucleocytoplasmic shuttling on the level of C9ORF72 protein, the transcribed hexanucleotide repeat RNA, and/or dipeptide repeat proteins translated form the hexanucleotide repeat RNA. These defects of nucleocytoplasmic shuttling may therefore, constitute the common ground of the underlying disease mechanisms in different molecular subtypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

Keywords: C9ORF72; FUS; TDP-43; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; nucleocytoplasmic transport.

Publication types

  • Review

MeSH terms

  • Active Transport, Cell Nucleus*
  • Amyotrophic Lateral Sclerosis / metabolism*
  • C9orf72 Protein
  • Cell Nucleus / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Frontotemporal Lobar Degeneration / metabolism*
  • Humans
  • Proteins / metabolism*
  • RNA-Binding Protein FUS / metabolism*


  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA-Binding Proteins
  • FUS protein, human
  • Proteins
  • RNA-Binding Protein FUS
  • TARDBP protein, human