Role of Superoxide Dismutase in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig's disease, is an adult‐onset neurodegenerative disorder that has been linked to over 200 mutations from the SOD1 gene. The protein created from this gene is superoxide dismutase (SOD1), an enzyme responsible for breaking down toxic superoxide radicals by facilitating the binding to zinc and copper. Superoxide dismutase is a homodimer, composed of two identical subunits, and is located in the cytoplasm of the cell, Each subunit has 154 amino acid residues with a β‐barrel core, formed by 8 beta‐sheets, and three outer loops which are linked together by a disulfide bond, a hydrogen bond network, and a metal‐binding site for both zinc and copper. This metal‐binding site is responsible for the catalyzation of superoxide radicals to hydrogen peroxide and dioxygen. The redox reactions that SOD1 allows to occur are the oxidation of superoxide to dioxygen and the reduction of superoxide to hydrogen peroxide while alternating the oxidation states of Copper. The zinc molecule acts as a structural element for the reaction. The catalyzation of superoxide radicals to safer components occurs because the accumulation of superoxide radicals is toxic to the cell, and can lead to cell death. Another role of SOD1 is its responsibility in preventing oxidative stress. Oxidative stress is the result of the imbalance between reactive oxygen species such as superoxide, and the activity of superoxide dismutase to detoxify the affected areas. In cases of ALS, mutations cause this accumulation, which leads to motor neuron death. The most common mutation of SOD1 in the United States, as well as the one that causes the fastest onset for ALS to occur, is A5V, which is the replacement of the alanine residue with valine at position 5. This mutation can result in not only the accumulation of superoxide radicals but also the production of more neurotoxic radicals and fibrillar aggregates of misfolded SOD1, which can occur due to the absence of the disulfide bond or bound zinc ions. These effects lead to motor neuron death, which manifests as the symptoms of ALS. The symptoms of ALS are progressive muscle weakness, loss of voluntary muscle control, the decline of the ability to initiate movement, and paralysis. ALS, especially as a result of the A5V mutation, often leads to a shorter life expectancy. Amyotrophic Lateral Sclerosis currently has no cure, but there are many evolving therapies for the disease. Patients with ALS are encouraged to participate in gentle, low‐impact physical therapies and use special equipment to support communication, nutrition, and breathing. The drugs approved by the FDA to help treat ALS include Riluzole (Rilutek), which reduces damage to cells by blocking the release of glutamate, and Edaravone (Radicava) which removes free radicals. In addition, small‐molecule therapies are being developed to stabilize the native form of SOD1 in the absence of zinc or in the presence of protein mutations, which may reduce the effects of the manifestation of the disease. Further research is needed to determine specifically how mutations of SOD1 lead to motor neuron death, and the resulting symptoms of Amyotrophic Lateral Sclerosis.