In genetic mouse models, the presence of two different ALS mutations can modify the disease phenotype in a complex manner: We and others have previously shown that expression of mutant SOD1 or TARDBP/TDP-43 in mice interacts with heterozygous loss-of-function (LoF) mutations in TBK1 to alter the motor neuron disease phenotype in mice [5–7]. The gene discussed is TBK1; the disease is amyotrophic lateral sclerosis.