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

Shaopeng Wang, Malgorzata J. Latallo, Zhe Zhang, Bo Huang, Dmitriy G. Bobrovnikov, Daoyuan Dong, Nathan M. Livingston, Wilson Tjoeng, Lindsey R. Hayes, Jeffrey D. Rothstein, Lyle Ostrow, Bin Wu, Shuying Sun

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number4908
JournalNature communications
Issue number1
StatePublished - Dec 1 2021

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General
  • General Physics and Astronomy


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