Structural basis for repeat-associated non-AUG translation initiation on C9orf72 mRNA

Cryo-EM structures of a human C9orf72 translation initiation complex show RAN translation initiates mainly at a near-cognate CUG 24 nucleotides upstream of G4C2, at 3.2–3.5 Å resolution.

• Why it matters: RAN translation of C9orf72 repeat RNA produces neurotoxic DPR proteins linked to ALS/FTD, but the structural rules for initiation remain unclear.
• What they did: Using cryo-electron microscopy, the authors mapped an in vitro assembled complex (3.2 Å) and a near-native complex from human cell lysate (3.5 Å), identifying a G4C2–18S ES9S kissing-loop interaction.
• The result: Blocking the RNA-RNA interaction with complementary antisense oligonucleotides significantly reduces RAN translation in vitro and in patient-derived iNeurons, suggesting a therapeutic route to lower toxic DPR production.