Fig. 2

Overview of C9ORF72 repeat RNA translation. First, through bi-directional transcription, both sense (GGGGCC) and antisense (CCCCGG) repeat-containing RNA transcripts are produced from the first intron of the c9orf72 gene. The pre-mRNA containing the sense repeats will be processed in the nucleus to produce mature C9ORF72 mRNA and GGGGCC repeat-containing lariat intron. The debranching of the lariat can be inhibited by the GGGGCC repeats. The repeat-containing intron is stabilized and exported to the cytoplasm in the circular form (which does not have Cap structure and poly-A tail). The NXT1-NXF1 pathway, as well as specific RNA-binding proteins (RBPs), play important roles in mediating the export of GGGGCC repeat-containing introns. The GGGGCC repeat-containing circular introns undergo repeat-associated Non-AUG (RAN) translation in all three reading frames to produce poly-GA, poly-GP, and poly-GR dipeptide repeats (DPR) proteins. Many RBPs, translation factors and signal pathways can regulate the translation initiation efficiency. The antisense transcripts likely contain 5’ Cap and 3’ poly-A, similar as regular mRNAs. Translation from all the three reading frames produce poly-GP, poly-PA, and poly-PR. Chimeric DPR proteins may be synthesized due to translational frameshift or disrupted repeat sequences. Due to the repeat sequences and RNA structures, reduced elongation speed and ribosome stalling may occur during the translation through the repeats, which could potentially activate the RQC pathway. Finally, the arginine-containing DPRs, including poly-GR and poly-PR, can impair global translation through different mechanisms