C9 and amyotrophic lateral sclerosis: Three hypotheses have been proposed for the pathogenesis underlying C9-ALS/FTD: (1) the loss-of-function of C9ORF72 that is caused by the G4C2 repeat expansion-mediated reduction in the expression of C9ORF72 protein, (2) the gain-of-toxic-function of RNA foci that is caused by the load of expanded G4C2 transcripts, and (3) the accumulation of dipeptide repeat (DPR) proteins, which are produced by the G4C2 repeat-associated non-ATG (RAN) translation and toxic to neurons8.