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Nat Commun. 2018 Jan 11;9(1):152. doi: 10.1038/s41467-017-02643-5.

CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts.

Author information

1
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease (MIND), Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
2
Broad Institute of Harvard University and MIT, Cambridge, MA, 02142, USA.
3
Architecture et Réactivité de l'ARN, UPR 9002, Université de Strasbourg, CNRS, F-67000, Strasbourg, France.
4
Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, 92093, USA.
5
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
6
Therapeutic Innovation Laboratory (UMR 7200), Faculty of Pharmacy, CNRS/University of Strasbourg, 67401, Illkirch, Cedex, France.
7
Architecture et Réactivité de l'ARN, UPR 9002, Université de Strasbourg, CNRS, F-67000, Strasbourg, France. f.martin@ibmc-cnrs.unistra.fr.
8
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease (MIND), Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. clagier-tourenne@mgh.harvard.edu.
9
Broad Institute of Harvard University and MIT, Cambridge, MA, 02142, USA. clagier-tourenne@mgh.harvard.edu.

Abstract

Expansion of G4C2 repeats in the C9ORF72 gene is the most prevalent inherited form of amyotrophic lateral sclerosis and frontotemporal dementia. Expanded transcripts undergo repeat-associated non-AUG (RAN) translation producing dipeptide repeat proteins from all reading frames. We determined cis-factors and trans-factors influencing translation of the human C9ORF72 transcripts. G4C2 translation operates through a 5'-3' cap-dependent scanning mechanism, requiring a CUG codon located upstream of the repeats and an initiator Met-tRNAMeti. Production of poly-GA, poly-GP, and poly-GR proteins from the three frames is influenced by mutation of the same CUG start codon supporting a frameshifting mechanism. RAN translation is also regulated by an upstream open reading frame (uORF) present in mis-spliced C9ORF72 transcripts. Inhibitors of the pre-initiation ribosomal complex and RNA antisense oligonucleotides selectively targeting the 5'-flanking G4C2 sequence block ribosomal scanning and prevent translation. Finally, we identified an unexpected affinity of expanded transcripts for the ribosomal subunits independently from translation.

PMID:
29323119
PMCID:
PMC5764992
DOI:
10.1038/s41467-017-02643-5
[Indexed for MEDLINE]
Free PMC Article

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