Thus, DNA damage accumulation is a major phenotype of human motor neuron degeneration in ALS that is associated with significant epigenetic and post-translational DDRs that are mobilized and recruited to the nucleus in human ALS motor neurons in vivo and that DDR and DNA repair are engaged and functional in human mutant SOD1 ALS motor neurons in cell culture. The gene discussed is SOD1; the disease is amyotrophic lateral sclerosis.