Overall, our observations suggest that the regulation of Golgi-to-ER trafficking by ArfGAP-1 might be a target of mutant C9orf72 toxicity in ALS, and they support a multiple-hit model in which the gain-of-toxic effects exerted by C9orf72 RNA repeats or DPRs on Arf1GAP-1 are added to the loss of GAP activity associated with C9orf72 haploinsufficiency, eventually converging on the same membrane trafficking pathway governed by Arf1. Here, C9orf72 is linked to amyotrophic lateral sclerosis.