C9orf72 and amyotrophic lateral sclerosis: In C9ORF72-ALS/FTD, hyperactivation, inhibition or no changes in the NMD pathway have all been reported, and the protective role of UPF1 has been proposed to be exerted through NMD-mediated or NMD-independent mechanisms (Ortega et al, 2020; Sun et al, 2020; Zaepfel et al, 2021).