Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes paralysis and respiratory failure (Petrov et al., 2017). The driving mechanisms are unknown, and there are no effective treatments (Petrov et al., 2017). Aging and a few gene mutations, a common one being missense mutations in superoxide dismutase-1 (SOD1), are risk factors for ALS (Figure 1). The recent Food and Drug Administration approval of edaravone for the treatment of ALS putatively supports a role for oxidative and nitrative stresses in the disease processes (Figure 1A). DNA damage, abnormalities in DNA repair, and other nuclear abnormalities are implicated also in the pathogenesis of human ALS (Bradley and Krasin, 1982; Kim et al., 2020). DNA damage as an upstream pathogenic event in human ALS is supported by evidence for p53 activation and its import into the nucleus of motor neurons (Martin, 2000), and hyperactivation and nuclear accumulation of apurinic/apyrimidinic endodeoxyribonuclease-1 (Shaikh and Martin, 2002). Kim et al. (2020) discovered that upper and lower motor neurons in postmortem central nervous system (CNS) from ALS patients, mostly sporadic ALS in comparison to age-matched controls, accumulate several different types of DNA lesions and engage a prominent DNA damage response (DDR), as evidenced by accumulation of nuclear Abelson non-receptor tyrosine kinase and breast cancer type 1 susceptibility protein, and the serine/threonine protein kinase ataxia telangiectasia mutated activation (Figure 1A). Apyriminidinic sites, single-stranded DNA, oxidized DNA, and DDR proteins are present in motor neurons at pre-attritional stages and throughout the somatodendritic attritional stages of neurodegeneration (Kim et al., 2020). Motor neurons with DNA damage are also positive for activated p53 and cleaved caspase-3 (Figure 1A). These recent findings support the concept that, in human ALS, the motor neuron degeneration is a cell-autonomous form of programmed cell death (Martin, 1999).