c9RAN translation: a potential therapeutic target for the treatment of amyotrophic lateral sclerosis and frontotemporal dementia

A hexanucleotide (GGGGCC) repeat expansion within a non-coding region of the C9ORF72 gene is the most common mutation associated with both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Elucidating how these expanded repeats (GGGGCCexp) cause 'c9FTD/ALS' has since become an important goal of the FTD/ALS field. GGGGCCexp transcripts aggregate into discrete nuclear structures, termed RNA foci. This phenomenon, observed in various repeat expansion disorders, is associated with RNA-binding protein sequestration. Of note, recent findings show that GGGGCCexp transcripts also succumb to an alternative fate: repeat-associated non-ATG translation (RAN translation). This unconventional mode of translation, which occurs in the absence of an initiating codon, results in the production of polyGA, polyGP and polyGR peptides. Antibodies generated against these peptides detect high molecular weight, insoluble material in brain homogenates, as well as neuronal inclusions throughout the central nervous system of c9FTD/ALS cases. Given that both foci formation and RAN translation in c9FTD/ALS require the synthesis of GGGGCCexp RNA, therapeutic strategies that target these transcripts and result in their neutralization or degradation could effectively block these two potential pathogenic mechanisms and provide a much needed treatment for c9FTD/ALS.