Production of the protein TDP-43, mislocated cytoplasmic aggregates of which are the defining signature common to nearly all cases of ALS, has been noted to be upregulated as part of the normal cellular response to neuronal injury.10 Thus, in the light of our findings, we raise the possibility that the activation of cerebral neuronal injury-response pathways, which might occur from a variety of insults, is part of a multiple-hit model of pathogenesis in ALS. The gene discussed is TARDBP; the disease is amyotrophic lateral sclerosis.