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Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or SOD1 is an enzyme that in humans is encoded by the SOD1 gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis and amyotrophic lateral sclerosis.
SOD1 is a 32 kDa homodimer which forms a β-barrel and contains an intramolecular disulfide bond and a binuclear Cu/Zn site in each subunit. This Cu/Zn site holds the copper and a zinc ion and is responsible for catalyzing the disproportionation of superoxide to hydrogen peroxide and dioxygen. The maturation process of this protein is complex and not fully understood, involving the selective binding of copper and zinc ions, formation of the intra-subunit disulfide bond between Cys-57 and Cys-146, and dimerization of the two subunits. The copper chaperone for Sod1 (CCS) facilitates copper insertion and disulfide oxidation. Though SOD1 is synthesized in the cytosol can mature there, the fraction of expressed, and still immature, SOD1 targeted to the mitochondria must be inserted into the intermembrane space. There, it forms the disulfide bond, though not metallation, required for its maturation. The mature protein is highly stable, but unstable when in its metal-free and disulfide-reduced forms. This manifests in vitro, as the loss of metal ions results in increased SOD1 aggregation, and in disease models, where low metallation is observed for insoluble SOD1. Moreover, the surface-exposed reduced cysteines could participate in disulfide crosslinking and, thus, aggregation.
SOD1 binds copper and zinc ions and is one of three superoxide dismutases responsible for destroying free superoxide radicals in the body. The encoded isozyme is a soluble cytoplasmic and mitochondrial intermembrane space protein, acting as a homodimer to convert naturally occurring, but harmful, superoxide radicals to molecular oxygen and hydrogen peroxide. Hydrogen peroxide can then be broken down by another enzyme called catalase.
SOD1 has been postulated to localize to the outer mitochondrial membrane (OMM), where superoxide anions would be generated, or the intermembrane space. The exact mechanisms for its localization remains unknown, but its aggregation to the OMM has been attributed to its association with BCL-2. Wildtype SOD1 has demonstrated antiapoptotic properties in neural cultures, while mutant SOD1 has been observed to promote apoptosis in spinal cord mitochondria, but not in liver mitochondria, though it is equally expressed in both. Two models suggest SOD1 inhibits apoptosis by interacting with BCL-2 proteins or the mitochondria itself.
The SOD1 enzyme is an important constituent in apoptotic signaling and oxidative stress, most notably as part of the mitochondrial death pathway and cardiac myocyte apoptosis signaling. Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
Role in oxidative stress
Most notably, SOD1 is pivotal in reactive oxygen species (ROS) release during oxidative stress by ischemia-reperfusion injury, specifically in the myocardium as part of a heart attack (also known as ischemic heart disease). Ischemic heart disease, which results from an occlusion of one of the major coronary arteries, is currently still the leading cause of morbidity and mortality in western society. During ischemia reperfusion, ROS release substantially contribute to the cell damage and death via a direct effect on the cell as well as via apoptotic signals. SOD1 is known to have a capacity to limit the detrimental effects of ROS. As such, SOD1 is important for its cardioprotective effects. In addition, SOD1 has been implicated in cardioprotection against ischemia-reperfusion injury, such as during ischemic preconditioning of the heart. Although a large burst of ROS is known to lead to cell damage, a moderate release of ROS from the mitochondria, which occurs during nonlethal short episodes of ischemia, can play a significant triggering role in the signal transduction pathways of ischemic preconditioning leading to reduction of cell damage. It has even observed that during this release of ROS, SOD1 plays an important role hereby regulating apoptotic signaling and cell death.
In one study, deletions in the gene were reported in two familial cases of keratoconus. Mice lacking SOD1 have increased age-related muscle mass loss (sarcopenia), early development of cataracts, macular degeneration, thymic involution, hepatocellular carcinoma, and shortened lifespan. Research suggests that increased SOD1 levels could be a biomarker for chronic heavy metal toxicity in women with long-term dental amalgam fillings.
Amyotrophic lateral sclerosis (Lou Gehrig's disease)
Mutations (over 150 identified to date) in this gene have been linked to familial 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 A4V (in the U.S.A.) and H46R (Japan). In Iceland only SOD1-G93S has been found. The most studied ALS mouse model is 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 (alanine at codon 4 changed to 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 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 (histidine at codon 46 changed to 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, SOD2, has no effect on their disease course.
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 Jackson Laboratory, many studies of potential drug targets and toxicity mechanisms have been carried out in this model. At least one private research institute (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.
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