Cell-to-cell transmission of C9orf72 poly-(Gly-Ala) triggers key features of ALS/FTD

EMBO J. 2020 Apr 15;39(8):e102811. doi: 10.15252/embj.2019102811. Epub 2020 Mar 16.


The C9orf72 repeat expansion causes amyotrophic lateral sclerosis and frontotemporal dementia, but the poor correlation between C9orf72-specific pathology and TDP-43 pathology linked to neurodegeneration hinders targeted therapeutic development. Here, we addressed the role of the aggregating dipeptide repeat proteins resulting from unconventional translation of the repeat in all reading frames. Poly-GA promoted cytoplasmic mislocalization and aggregation of TDP-43 non-cell-autonomously, and anti-GA antibodies ameliorated TDP-43 mislocalization in both donor and receiver cells. Cell-to-cell transmission of poly-GA inhibited proteasome function in neighboring cells. Importantly, proteasome inhibition led to the accumulation of TDP-43 ubiquitinated within the nuclear localization signal (NLS) at lysine 95. Mutagenesis of this ubiquitination site completely blocked poly-GA-dependent mislocalization of TDP-43. Boosting proteasome function with rolipram reduced both poly-GA and TDP-43 aggregation. Our data from cell lines, primary neurons, transgenic mice, and patient tissue suggest that poly-GA promotes TDP-43 aggregation by inhibiting the proteasome cell-autonomously and non-cell-autonomously, which can be prevented by inhibiting poly-GA transmission with antibodies or boosting proteasome activity with rolipram.

Keywords: C9orf72; antibody therapy; neurodegeneration; nucleocytoplasmic transport; proteasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • C9orf72 Protein / genetics
  • C9orf72 Protein / metabolism*
  • Cytoplasm / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dipeptides / metabolism*
  • Female
  • Frontotemporal Dementia / metabolism
  • Frontotemporal Dementia / pathology*
  • HeLa Cells
  • Humans
  • Male
  • Mice
  • Neurons / metabolism
  • Nuclear Localization Signals
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Aggregation, Pathological
  • Ubiquitin / metabolism


  • C9orf72 Protein
  • DNA-Binding Proteins
  • Dipeptides
  • Nuclear Localization Signals
  • TARDBP protein, human
  • TDP-43 protein, mouse
  • Ubiquitin
  • N-glycylalanine
  • Proteasome Endopeptidase Complex