Nuclear export and translation of circular repeat-containing intronic RNA in C9ORF72-ALS/FTD

Nat Commun. 2021 Aug 13;12(1):4908. doi: 10.1038/s41467-021-25082-9.


C9ORF72 hexanucleotide GGGGCC repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-containing RNA mediates toxicity through nuclear granules and dipeptide repeat (DPR) proteins produced by repeat-associated non-AUG translation. However, it remains unclear how the intron-localized repeats are exported and translated in the cytoplasm. We use single molecule imaging approach to examine the molecular identity and spatiotemporal dynamics of the repeat RNA. We demonstrate that the spliced intron with G-rich repeats is stabilized in a circular form due to defective lariat debranching. The spliced circular intron, instead of pre-mRNA, serves as the translation template. The NXF1-NXT1 pathway plays an important role in the nuclear export of the circular intron and modulates toxic DPR production. This study reveals an uncharacterized disease-causing RNA species mediated by repeat expansion and demonstrates the importance of RNA spatial localization to understand disease etiology.

Publication types

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

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • C9orf72 Protein / genetics*
  • C9orf72 Protein / metabolism
  • Cell Line, Tumor
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • DNA Repeat Expansion / genetics
  • Dipeptides / genetics
  • Dipeptides / metabolism
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism
  • Genetic Predisposition to Disease / genetics
  • HEK293 Cells
  • Humans
  • Introns / genetics*
  • Microscopy, Fluorescence
  • Nucleocytoplasmic Transport Proteins / genetics
  • Nucleocytoplasmic Transport Proteins / metabolism
  • Protein Biosynthesis / genetics*
  • RNA / genetics*
  • RNA / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics


  • C9orf72 Protein
  • C9orf72 protein, human
  • Dipeptides
  • NXF1 protein, human
  • NXT1 protein, human
  • Nucleocytoplasmic Transport Proteins
  • RNA-Binding Proteins
  • RNA