SOD1

Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or SOD1 is an is_associated_with::enzyme that in humans is encoded by the SOD1 is_associated_with::gene, located on is_associated_with::chromosome 21. SOD1 is one of three human is_associated_with::superoxide dismutases.

Function
SOD1 binds copper and zinc ions and is one of three superoxide dismutases responsible for destroying free is_associated_with::superoxide radicals in the body. The encoded is_associated_with::isozyme is a soluble is_associated_with::cytoplasmic and mitochondrial intermembrane space protein, acting as a homodimer to convert naturally occurring, but harmful, superoxide radicals to molecular oxygen and is_associated_with::hydrogen peroxide. Hydrogen peroxide can then be broken down by another enzyme called catalase.

Clinical significance
In one study, deletions in the gene were reported in two familial cases of is_associated_with::keratoconus.

Mice lacking SOD1 have increased age-related muscle mass loss (is_associated_with::sarcopenia), early development of is_associated_with::cataracts, is_associated_with::macular degeneration, is_associated_with::thymic involution, is_associated_with::hepatocellular carcinoma, and shortened lifespan.

Amyotrophic lateral sclerosis (Lou Gehrig's disease)
Mutations (over 150 identified to date) in this gene have been linked to familial is_associated_with::amyotrophic lateral sclerosis. However, several pieces of evidence also show that wild-type SOD1, under conditions of cellular stress, is implicated in a significant fraction of sporadic ALS cases, which represent 90% of ALS patients. The most frequent mutation are is_associated_with::A4V (in the U.S.A.) and is_associated_with::H46R (Japan). In Iceland only is_associated_with::SOD1-G93S has been found. The most studied ALS mouse model is is_associated_with::G93A. Rare transcript variants have been reported for this gene.

Virtually all known ALS-causing SOD1 mutations act in a dominant fashion; a single mutant copy of the SOD1 gene is sufficient to cause the disease. The exact molecular mechanism (or mechanisms) by which SOD1 mutations cause disease are unknown. It appears to be some sort of toxic gain of function, as many disease-associated SOD1 mutants (including G93A and A4V) retain enzymatic activity and Sod1 knockout mice do not develop ALS (although they do exhibit a strong age-dependent distal motor neuropathy).

A4V mutation
A4V (is_associated_with::alanine at codon 4 changed to is_associated_with::valine) is the most common ALS-causing mutation in the U.S. population, with approximately 50% of SOD1-ALS patients carrying the A4V mutation. Approximately 10 percent of all U.S. familial ALS cases are caused by heterozygous A4V mutations in SOD1. The mutation is rarely if ever found outside the Americas.

It was recently estimated that the A4V mutation occurred 540 generations (~12,000 years) ago. The haplotype surrounding the mutation suggests that the A4V mutation arose in the Asian ancestors of native Americans, who reached the Americas through the is_associated_with::Bering Strait.

The A4V mutant belongs to the WT-like mutants. Patients with A4V mutations exhibit variable age of onset, but uniformly very rapid disease course, with average survival after onset of 1.4 years (versus 3–5 years with other dominant SOD1 mutations, and in some cases such as H46R, considerably longer). This survival is considerably shorter than non-mutant SOD1 linked ALS.

H46R mutation
H46R (is_associated_with::histidine at codon 46 changed to is_associated_with::arginine) is the most common ALS-causing mutation in the Japanese population, with about 40% of Japanese SOD1-ALS patients carrying this mutation. H46R causes a profound loss of copper binding in the active site of SOD1, and as such, H46R is enzymatically inactive. The disease course of this mutation is extremely long, with the typical time from onset to death being over 15 years. Mouse models with this mutation do not exhibit the classical mitochondrial vacuolation pathology seen in G93A and G37R ALS mice and unlike G93A mice, defeciency of the major mitochondrial antioxidant enzyme, is_associated_with::SOD2, has no effect on their disease course.

G93A mutation
G93A (glycine 93 changed to alanine) is a comparatively rare mutation, but has been studied very intensely as it was the first mutation to be modeled in mice. G93A is a pseudo-WT mutation that leaves the enzyme activity intact. Because of the ready availability of the G93A mouse from is_associated_with::Jackson Laboratory, many studies of potential drug targets and toxicity mechanisms have been carried out in this model. At least one private research institute (is_associated_with::ALS Therapy Development Institute) is conducting large-scale drug screens exclusively in this mouse model. Whether findings are specific for G93A or applicable to all ALS causing SOD1 mutations is at present unknown. It has been argued that certain pathological features of the G93A mouse are due to overexpression artefacts, specifically those relating to mitochondrial vacuolation (the G93A mouse commonly used from Jackson Lab has over 20 copies of the human SOD1 gene). At least one study has found that certain features of pathology are idiosyncratic to G93A and not extrapolatable to all ALS causing mutations. Further studies have shown that the pathogenesis of the G93A and H46R models are clearly distinct; some drugs and genetic interventions that are highly beneficial/detrimental in one model have either the opposite or no effect in the other.

Interactions
SOD1 has been shown to interact with CCS and is_associated_with::Bcl-2.