This study was undertaken to test three hypotheses: (1) DNA and RNA epigenetic markers and epigenetic regulatory mechanisms are aberrant in skeletal muscle and spinal cord of hSOD1 mouse models of ALS; (2) epigenetic anomalies occur in human ALS postmortem brain and spinal cord; and (3) DNA methylation is therapeutically targetable and disease-modifying in mice, thus implicating epigenetics as a mechanism of disease in ALS. This evidence concerns the gene SOD1 and amyotrophic lateral sclerosis.