UPF1 reduces C9orf72 HRE-induced neurotoxicity in the absence of nonsense-mediated decay dysfunction

Cell Rep. 2021 Mar 30;34(13):108925. doi: 10.1016/j.celrep.2021.108925.


Multiple cellular pathways have been suggested to be altered by the C9orf72 GGGGCC (G4C2) hexanucleotide repeat expansion (HRE), including aspects of RNA regulation such as nonsense-mediated decay (NMD). Here, we investigate the role that overexpression of UPF1, a protein involved in NMD, plays in mitigating neurotoxicity in multiple models of C9orf72 ALS/FTD. First, we show that NMD is not altered in our endogenous induced pluripotent stem cell (iPSC)-derived spinal neuron (iPSN) model of C9orf72 ALS (C9-ALS) or postmortem motor cortex tissue from C9-ALS patients. Unexpectedly, we find that UPF1 overexpression significantly reduces the severity of known neurodegenerative phenotypes without altering NMD function itself. UPF1 overexpression reduces poly(GP) abundance without altering the amount of repeat RNA, providing a potential mechanism by which UPF1 reduces dipeptide repeat (DPR) protein-mediated toxicity. Together, these findings indicate that UPF1 is neuroprotective in the context of C9-ALS, albeit independent of known UPF1-mediated NMD pathways.

Keywords: C9ORF72; UPF1; amyotrophic lateral sclerosis; frontotemporal dementia; induced pluripotent cells; neurons; neurotoxicity; nonsense-mediated decay.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • C9orf72 Protein / metabolism*
  • DNA Repeat Expansion / genetics*
  • Disease Models, Animal
  • Drosophila melanogaster
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Induced Pluripotent Stem Cells
  • Motor Cortex / pathology
  • Nerve Degeneration / pathology
  • Neurotoxicity Syndromes / genetics*
  • Neurotoxicity Syndromes / pathology
  • Nonsense Mediated mRNA Decay / genetics*
  • Phenotype
  • Postmortem Changes
  • RNA / metabolism
  • RNA Helicases / metabolism*
  • Trans-Activators / metabolism*


  • C9orf72 Protein
  • Trans-Activators
  • RNA
  • RNA Helicases
  • UPF1 protein, human