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. The gene discussed is ARF1; the disease is amyotrophic lateral sclerosis.