Fig. 8

Model of translation mechanisms associated with G₄C₂ expansions in C9ORF72 ALS/FTD. (a) Pre-Initiation ribosomal complex (PIC) assembles on the 5′ cap of mRNA by interacting with eIF4F complex formed by the cap binding factor eIF4E, the platform eIF4G and the RNA helicase eIF4A. The PIC complex scans the 5′ end for an appropriate AUG start codon, where the 60S ribosomal subunit joins the 40S to form a functional 80S ribosome ready to translate the coding sequence. (b) G₄C₂ RAN translation initiation shares the same pathway as the canonical one to translate poly-GA dipeptides, including the need of 5′ cap, eIF4E, eIF4G, eIF4A, initiator methionyl-tRNA, and the scanning mechanism. However, it initiates on a near-cognate CUG codon embedded in a perfect Kozak sequence, in frame with poly-GA, instead of a canonical AUG start codon. The ability of G₄C₂ expansions to form stable G-quaduplex structures forces the ribosome to occasionally undergo frameshifting to translate poly-GP and poly-GR in the +2 and +3 frames, respectively. (c) When G₄C₂ repeats are expanded, a subset of C9ORF72 mRNA is mis-spliced retaining intron 1 with the repeats³⁵. RAN translation from these RNAs is inhibited by a uORF that is translated canonically. (d) G₄C₂ expanded transcripts associate with ribosomal subunits independently from their translation