Loss of C9orf72 perturbs the Ran-GTPase gradient and nucleocytoplasmic transport, generating compositionally diverse Importin β-1 granules

Cell Rep. 2023 Mar 28;42(3):112134. doi: 10.1016/j.celrep.2023.112134. Epub 2023 Feb 22.


A hexanucleotide (GGGGCC)n repeat expansion in C9orf72 causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), eliciting toxic effects through generation of RNA foci, dipeptide repeat proteins, and/or loss of C9orf72 protein. Defects in nucleocytoplasmic transport (NCT) have been implicated as a pathogenic mechanism underlying repeat expansion toxicity. Here, we show that loss of C9orf72 disrupts the Ran-GTPase gradient and NCT in vitro and in vivo. NCT disruption in vivo is enhanced by the presence of compositionally different types of cytoplasmic Importin β-1 granule that exhibit neuronal subtype-specific properties. We show that the abundance of Importin β-1 granules is increased in the context of C9orf72 deficiency, disrupting interactions with nuclear pore complex proteins. These granules appear to associate with the nuclear envelope and are co-immunoreactive for G3BP1 and K63-ubiquitin. These findings link loss of C9orf72 protein to gain-of-function mechanisms and defects in NCT.

Keywords: ALS; C9orf72; CP: Neuroscience; FG-Nups; FTD; G3BP1; Importin; Ran-GTPase; RanGAP; nucleocytoplasmic transport; ubiquitin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amyotrophic Lateral Sclerosis* / pathology
  • C9orf72 Protein* / genetics
  • C9orf72 Protein* / metabolism
  • DNA Helicases / metabolism
  • DNA Repeat Expansion
  • Frontotemporal Dementia* / metabolism
  • Humans
  • Poly-ADP-Ribose Binding Proteins / metabolism
  • RNA Helicases / metabolism
  • RNA Recognition Motif Proteins / metabolism
  • beta Karyopherins / metabolism


  • beta Karyopherins
  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA Helicases
  • G3BP1 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • RNA Helicases
  • RNA Recognition Motif Proteins