Fig. 1Figure 1
Proposed C9ORF72 disease mechanisms. The C9ORF72 (GGGGCC) hexanucleotide repeat expansion is thought to contribute to disease pathogenesis in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) via three non-mutually exclusive mechanisms: (1) a loss of function due to impaired transcription leading to a reduction in C9ORF72 protein levels; (2) a toxic gain of function due to the formation of secondary RNA structures which sequester RNA binding proteins and consequently a loss of function of these proteins; (3) a toxic gain of function due to repeat-associated non-ATG (RAN) translation from both the sense and antisense strand, which generates potentially toxic dipeptide repeats (DPRs; poly-GP, poly-GA, poly-GR, poly-PA, poly-PR)