Three possible non-exclusive mechanisms have been proposed by which the C9orf72 repeat expansion may cause ALS-FTD: 1) haploinsufficiency and loss of C9orf72 protein function, 2) repeat-associated non-AUG (RAN) translation of the hexanucleotide repeats generating dipeptide repeats that aggregate in toxic neuronal cytoplasmic and nuclear aggregates, and 3) toxic gain-of-function from repeat-containing RNA which forms nuclear foci that sequester hexanucleotode repeat-binding proteins (reviewed in [7–10]). Here, C9orf72 is linked to frontotemporal dementia.