We suggest that the key to both the prevention and management of sporadic ALS will require an understanding of the separate processes of the motor-neuronal cytosolic deposition of TDP-43 and the several metabolic cellular derangements that lead to inexorable motor neuronal death, including their associated inhibitory interneurons, both in the UMN and LMN systems and in prefrontal neuronal systems, as well as in related neuronal systems in the basal ganglia and the spinocerebellar nuclei of Clarke’s column. The gene discussed is TARDBP; the disease is amyotrophic lateral sclerosis.