Although the crystal structures of the TDP-43 RRM1 and RRM2 bound to a single-stranded DNA8, 9 as well as the NMR solution structure of RRM1-RRM2 bound to a single-stranded RNA38 have revealed how the two RNA recognition motifs interact with nucleic acids, they do not provide a clear link between missense mutations in TDP-43 and ALS. Here, RRM1 is linked to amyotrophic lateral sclerosis.