Such a global role of UPF1 could explain, better than its involvement in NMD, why this protein is universally conserved in eukaryotes, why its depletion affects the expression of a large fraction of the genome, and possibly why expression of human UPF1 in rat models of amyotrophic lateral sclerosis (ALS) overcomes the pathology caused by over-expression or mutation of the RNA-binding protein TDP-43 (Barmada et al., 2015; Jackson et al., 2015). The gene discussed is UPF1; the disease is amyotrophic lateral sclerosis.