Tabet, RicardosSchaeffer, LaureFreyermuth, FernandeJambeau, MelanieWorkman, MichaelLee, Chao-ZongLin, Chun-ChiaJiang, JieJansen-West, KarenAbou-Hamdan, HusseinDésaubry, LaurentGendron, TaniaPetrucelli, LeonardMartin, FranckLagier-Tourenne, Clotilde2018-02-262018Tabet, R., L. Schaeffer, F. Freyermuth, M. Jambeau, M. Workman, C. Lee, C. Lin, et al. 2018. “CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts.” Nature Communications 9 (1): 152. doi:10.1038/s41467-017-02643-5. http://dx.doi.org/10.1038/s41467-017-02643-5.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34868744Expansion 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.en-USJournal Article2018-02-2610.1038/s41467-017-02643-5