TY - JOUR
T1 - Nuclear export and translation of circular repeat-containing intronic RNA in C9ORF72-ALS/FTD
AU - Wang, Shaopeng
AU - Latallo, Malgorzata J.
AU - Zhang, Zhe
AU - Huang, Bo
AU - Bobrovnikov, Dmitriy G.
AU - Dong, Daoyuan
AU - Livingston, Nathan M.
AU - Tjoeng, Wilson
AU - Hayes, Lindsey R.
AU - Rothstein, Jeffrey D.
AU - Ostrow, Lyle W.
AU - Wu, Bin
AU - Sun, Shuying
N1 - Funding Information:
We thank Target ALS Human Postmortem Tissue Core to provide us postmortem samples. We thank the Sun and Wu lab members for helpful discussion. This work is supported by Johns Hopkins University School of Medicine Discovery Fund Synergy Award, National Institute of Health (RF1NS113820 to S.S. and B.W.; R01NS107347 to S.S.; K08NS104273 to L.R.H.; NS099114, NS094239, AG057623 to J.D.R.), National Science Foundation (MCB 1817447 to B.W.), Department of Defense (J.D.R.), Pew Charitable Trust (00030601 to B.W.), Target ALS (S.S.), ALS Association (S.S.) and the Packard Center for ALS Research. Z.Z. was a recipient of the Milton Safenowitz PostDoctoral Fellowship from the ALS Association. M.J.L. and D.G.B. were supported by NIH Training Grant (T32 GM008403), N.M.L. was supported by NIH Training Grant (T32 GM007445).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85112690017&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85112690017&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-25082-9
DO - 10.1038/s41467-021-25082-9
M3 - Article
C2 - 34389711
AN - SCOPUS:85112690017
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4908
ER -