Translation of dipeptide repeat proteins in C9ORF72-ALS/FTD through unique and redundant AUG initiation codons [preprint]
Authors
Sonobe, YoshifumiLee, Soojin
Krishnan, Gopinath
Gu, Yuanzheng
Kwon, Deborah Y.
Gao, Fen-Biao
Roos, Raymond P.
Kratsios, Paschalis
UMass Chan Affiliations
NeurologyDocument Type
PreprintPublication Date
2022-08-07Keywords
Molecular Biologyamyotrophic lateral sclerosis (ALS)
frontotemporal dementia (FTD)
AUG initiation codon
Metadata
Show full item recordAbstract
A hexanucleotide repeat expansion in the first intron of C9ORF72 is the most common monogenic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A hallmark of ALS/FTD pathology is the presence of dipeptide repeat (DPR) proteins, produced from both sense GGGGCC (poly-GA, poly-GP, poly-GR) and antisense CCCCGG (poly-PR, poly-PG, poly-PA) transcripts. Although initiation codons and regulatory factors have been identified for sense DPR translation, they remain mostly unknown for antisense DPRs. Here, we show that an AUG initiation codon is necessary for poly-PR synthesis, suggesting canonical AUG dependent translation. Remarkably, although an AUG located 194 base pairs (bp) upstream of the repeat is the main start codon for poly-PG synthesis, two other AUG codons (−212 bp, -113 bp) can also initiate translation, demonstrating a striking redundancy in start codon usage. eIF2D is required for CUG start codon-dependent poly-GA translation from the sense transcript in human motor neurons derived from induced pluripotent stem cells of C9ORF72 ALS/FTD patients, but AUG-dependent poly-PG or poly-PR synthesis does not require eIF2D, indicating that distinct translation initiation factors control DPR synthesis from sense and antisense transcripts. Our findings provide key molecular insights into DPR synthesis from the C9ORF72 locus, which may be broadly applicable to many other nucleotide-repeat expansion disorders.Source
Translation of dipeptide repeat proteins in C9ORF72-ALS/FTD through unique and redundant AUG initiation codons Yoshifumi Sonobe, Soojin Lee, Gopinath Krishnan, Yuanzheng Gu, Deborah Y. Kwon, Fen-Biao Gao, Raymond P. Roos, Paschalis Kratsios bioRxiv 2022.08.06.503063; doi: https://doi.org/10.1101/2022.08.06.503063DOI
10.1101/2022.08.06.503063Permanent Link to this Item
http://hdl.handle.net/20.500.14038/51622Notes
This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Related Resources
Now published in eLife doi: 10.7554/elife.83189Rights
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.; Attribution-NonCommercial-NoDerivatives 4.0 InternationalDistribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1101/2022.08.06.503063
Scopus Count
Collections
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.