SOD1

About SOD1

SOD1 on chromosome 21q22.11 encodes copper zinc superoxide dismutase, an abundant cytoplasmic antioxidant enzyme that converts superoxide radicals into hydrogen peroxide and oxygen. In 1993 SOD1 became the first gene linked to amyotrophic lateral sclerosis, and well over 100 different pathogenic variants have since been described. SOD1 variants account for a notable share of familial ALS and a small fraction of apparently sporadic cases. Disease is caused not by loss of antioxidant activity but by a toxic gain of function of the misfolded protein, which leads to motor neuron death through protein aggregation, mitochondrial dysfunction, endoplasmic reticulum stress, impaired axonal transport, and neuroinflammation involving glial cells. The progression rate varies widely between variants, with some, such as A4V in North America, causing rapidly progressive disease and others, such as D90A in Scandinavia, a slower and often recessive form. Mice expressing mutant SOD1 were the first widely used animal model of ALS. Tofersen, an antisense oligonucleotide that lowers SOD1 production in the nervous system, received accelerated approval in the United States in 2023 based on reduction of neurofilament levels. Other major ALS genes include C9orf72, the most common genetic cause, as well as TARDBP and FUS.