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

Ricardos Tabet, Laure Schaeffer, Fernande Freyermuth, Melanie Jambeau, Michael Workman, Chao-Zong Lee, Chun-Chia Lin, Jie Jiang, Karen Jansen-West, Hussein Abou-Hamdan, Laurent Désaubry, Tania Gendron, Leonard Petrucelli, Franck Martin () and Clotilde Lagier-Tourenne ()
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Ricardos Tabet: Massachusetts General Hospital and Harvard Medical School
Laure Schaeffer: Université de Strasbourg, CNRS
Fernande Freyermuth: Massachusetts General Hospital and Harvard Medical School
Melanie Jambeau: Massachusetts General Hospital and Harvard Medical School
Michael Workman: Massachusetts General Hospital and Harvard Medical School
Chao-Zong Lee: Massachusetts General Hospital and Harvard Medical School
Chun-Chia Lin: Massachusetts General Hospital and Harvard Medical School
Jie Jiang: University of California San Diego
Karen Jansen-West: Mayo Clinic
Hussein Abou-Hamdan: CNRS/University of Strasbourg
Laurent Désaubry: CNRS/University of Strasbourg
Tania Gendron: Mayo Clinic
Leonard Petrucelli: Mayo Clinic
Franck Martin: Université de Strasbourg, CNRS
Clotilde Lagier-Tourenne: Massachusetts General Hospital and Harvard Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02643-5

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