Oxidation-induced Misfolding and Aggregation of Superoxide Dismutase and Its Implications for Amyotrophic Lateral Sclerosis

Abstract

The presence of intracellular aggregates that contain Cu/Zn superoxide dismutase (SOD1) in spinal cord motor neurons is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Although SOD1 is abundant in all cells, its half-life in motor neurons far exceeds that in any other cell type. On the basis of the premise that the long half-life of the protein increases the potential for oxidative damage, we investigated the effects of oxidation on misfolding/aggregation of SOD1 and ALS-associated SOD1 mutants. Zinc-deficient wild-type SOD1 and SOD1 mutants were extremely prone to form visible aggregates upon oxidation as compared with wild-type holo-protein. Oxidation of select histidine residues that bind metals in the active site mediates SOD1 aggregation. Our results provide a plausible model to explain the accumulation of SOD1 aggregates in motor neurons affected in ALS. ALS1 is a fatal neuromuscular disease that presents as weakness, spasticity, and muscle atrophy. The disease is caused by selective degeneration of motor neurons in the brain, brainstem, and spinal cord. Although ALS presents mostly as a sporadic disease, a familial form of ALS is seen in ϳ10% of cases. Twenty percent of familial ALS (FALS) cases are caused by point mutations in the SOD1 gene. More than 90 distinct amino acid mutations spread throughout the sequence of this 153-residue protein have been identified (1). The finding that many FALS-associated SOD1 mutants possess full specific enzyme activity (2) suggests that the disease is not caused by loss of normal dismutase activity. Further support for this idea has come from transgenic mice studies. Transgenic mice that harbor FALS-associated SOD1 mutations develop ALS-like symptoms despite having greater than normal levels of SOD1 activity, including the normal complement of endogenous mouse SOD1 enzyme (3). Furthermore, SOD1 knockout mice do not develop ALS-like symptoms. Thus, it has been proposed that mutations in SOD1 cause FALS by a gain, rather than a loss, of function (reviewed in Ref.

Common molecular signature in SOD1 for both sporadic and familial amyotrophic lateral sclerosis

“…Our data demonstrate that an aberrant SOD1 species is present (or associated with) human ALS pathology, suggesting a possible involvement in that pathology. This conclusion extends previous results from in vitro cellular and animal models of ALS indicating that SOD1 WT or its oxidized form can be toxic in ALS disease mechanisms (22)(23)(24)(25)(26)(27)(28). Interestingly, the WT normal ␣-synuclein proteins, when produced by an additional locus in human, can also cause PD (29).…”

Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: Relevance to Alzheimer's disease

“…The toxic gain of function of mutant SOD (mSOD) leads to the generation of reactive oxygen/ nitrogen species [83,91,114]. Some researchers believe that the elevated oxidative activity associated with mSOD occurs by enzymes acting as peroxidases [114] or as superoxide reductases [70] or by producing O 2 ·− to form peroxynitrite [94]. In the wild type form, SOD dismutates superoxide to oxygen and water, hence reducing the levels of oxidative stress and protecting proteins, lipid and DNA from the toxic superoxide molecule [48].…”

Overexpression of mutated Cu,Zn-SOD in neuroblastoma cells results in cytoskeletal change

“…Thus the motor neuron dysfunction observed in FALS is generally thought to be due to the newly acquired neurotoxicity of mutant Cu,Zn-SOD. Several hypotheses have been proposed to explain this toxic gain of function of mutated Cu,Zn-SOD in FALS (6,18,19,29). For example, oxidative stress produced by aberrant catalysis (13,36), abnormal Cu chemistry (26), decreased glutamate metabolism (6), and increased cytoplasmic aggregation (7,11,18,20,26,29) have been studied in the setting of mutated Cu,Zn-SOD.…”