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 W. Ostrow, Bin Wu () and Shuying Sun ()
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Shaopeng Wang: Johns Hopkins University School of Medicine
Malgorzata J. Latallo: Johns Hopkins University School of Medicine
Zhe Zhang: Johns Hopkins University School of Medicine
Bo Huang: Johns Hopkins University School of Medicine
Dmitriy G. Bobrovnikov: Johns Hopkins University School of Medicine
Daoyuan Dong: Johns Hopkins University School of Medicine
Nathan M. Livingston: Johns Hopkins University School of Medicine
Wilson Tjoeng: Johns Hopkins University School of Medicine
Lindsey R. Hayes: Brain Science Institute, Johns Hopkins University School of Medicine
Jeffrey D. Rothstein: Brain Science Institute, Johns Hopkins University School of Medicine
Lyle W. Ostrow: Johns Hopkins University School of Medicine
Bin Wu: Johns Hopkins University School of Medicine
Shuying Sun: Johns Hopkins University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25082-9

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