Figures & data
Figure 1. Potential mechanisms of disease in c9FTD/ALS. Expansion of the GGGGCC hexanucleotide repeat within intron 1 of the C9ORF72 gene may cause c9FTD/ALS via RNA-dependent mechanisms. RNA transcripts resulting from transcription of GGGGCCexp aggregate into nuclear RNA foci that can sequester RNA-binding proteins and cause their loss of function. GGGGCCexp RNA transcripts are also susceptible to repeat-associated non-ATG translation, producing polyGA, polyGP and polyGR peptides, which form neuronal inclusions in c9FTD/ALS. Therapeutic strategies that target GGGGCCexp RNA transcripts may block both these putative pathogenic mechanisms. Moreover, while the mechanisms regulating RAN translation are poorly understood, and the means by which GGGGCCexp transcripts make their way to the cytoplasm are not yet known, targeting these events may also provide an approach to block RAN translation.
