G4C2 Repeat RNA Initiates a POM121-Mediated Reduction in Specific Nucleoporins in C9orf72 ALS/FTD

Neuron. 2020 Sep 23;107(6):1124-1140.e11. doi: 10.1016/j.neuron.2020.06.027. Epub 2020 Jul 15.


Through mechanisms that remain poorly defined, defects in nucleocytoplasmic transport and accumulations of specific nuclear-pore-complex-associated proteins have been reported in multiple neurodegenerative diseases, including C9orf72 Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS/FTD). Using super-resolution structured illumination microscopy, we have explored the mechanism by which nucleoporins are altered in nuclei isolated from C9orf72 induced pluripotent stem-cell-derived neurons (iPSNs). Of the 23 nucleoporins evaluated, we observed a reduction in a subset of 8, including key components of the nuclear pore complex scaffold and the transmembrane nucleoporin POM121. Reduction in POM121 appears to initiate a decrease in the expression of seven additional nucleoporins, ultimately affecting the localization of Ran GTPase and subsequent cellular toxicity in C9orf72 iPSNs. Collectively, our data suggest that the expression of expanded C9orf72 ALS/FTD repeat RNA alone affects nuclear POM121 expression in the initiation of a pathological cascade affecting nucleoporin levels within neuronal nuclei and ultimately downstream neuronal survival.

Keywords: ALS; C9orf72; FTD; POM121; neurodegeneration; nuclear pore complex.

Publication types

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

MeSH terms

  • Active Transport, Cell Nucleus
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • C9orf72 Protein / genetics*
  • C9orf72 Protein / metabolism
  • Cells, Cultured
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism*
  • HEK293 Cells
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Nuclear Pore / metabolism
  • Nuclear Pore Complex Proteins / genetics*
  • Nuclear Pore Complex Proteins / metabolism


  • C9orf72 Protein
  • C9orf72 protein, human
  • Membrane Glycoproteins
  • Nuclear Pore Complex Proteins
  • POM121 protein, human

Supplementary concepts

  • Frontotemporal Dementia With Motor Neuron Disease