Mutations in the SOD1 gene, a major copper-binding protein, are a known cause of familial amyotrophic lateral sclerosis (ALS). An extensive review from Keio University in Japan explores the possible role of copper homeostasis in SOD1-linked ALS, as seen in mice studies, and highlights the need for similar studies in people.
The review, “Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations,” was published in the International Journal of Molecular Sciences.
Scientists are in agreement that mutated SOD1 causes disease by somehow mediating toxicity, rather than by a loss of its function. Experiments in mice have shown that a total deletion of the SOD1 gene does not lead to ALS-like disease. Scientists have looked closely at the enzyme, attempting to figure out what kind of toxic effects the more than 180 known mutations in SOD1 can cause.
SOD1 is an enzyme that regulates reactive oxygen species, preventing them from causing tissue damage. For this, the enzyme must first bind copper and zinc ions. Copper is a trace element that needs an array of other molecules to be absorbed and then transported into the central nervous system and cells, where it can contribute to various functions.
SOD1 binds copper particularly strongly. Given that levels of the enzyme are relatively high in humans, the ability of SOD1 to bind these ions could affect total levels. But the relationship is not at all simple.
In mouse models, mutations in the SOD1 gene that do not disrupt the enzyme’s copper-binding ability are still associated with high levels of the trace element in the spinal cord of affected mice, particularly the form of copper not bound to SOD1. The same holds true for mutations that do disrupt the enzyme’s binding ability.
Triggering a high production of normal human SOD1 in mice is toxic, and leads to a massive loss of motor neurons. Researchers also realized that the levels of copper not bound to SOD1 seemed to reflect disease progression in some mouse models.
Instead, scientists have observed that mutations in SOD1 alter the levels of proteins working to import and export the trace element from cells, as well as copper-sequestering proteins, called MTs, leading to higher level of these metal ions in cells.
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