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.
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.
All the findings mentioned above stem from animal experiments. In humans, increased level of copper, as well as the other metal ions, such as lead and zinc, have been observed in spinal cords of ALS patients. But these cases were not examined for SOD1 mutations, while, in confirmed SOD1 cases, copper levels have not been explored, and studies of associated cellular events show highly variable results. This makes it impossible to state that the metal ions are involved in ALS pathology in humans.
Nevertheless, several attempts to bring altered copper homeostasis in mice into balance have been made. At times, other metabolic diseases affecting the levels of this crucial element have given researchers hints on directions to pursue.
In Wilson disease, copper accumulates in the liver and brain, and drugs binding the ions are effectively used in this condition. While such drugs, called chelators, performed well in delaying disease onset and extending the lifespan of mice, two of the three drugs do not enter the brain, and a small clinical trial of one such drug, D-penicillamine, failed to improve ALS symptoms in patients (who had an unknown SOD1 status).
The third drug, tetrathiomolybdate (TTM), can enter the brain. It showed a slowing of disease progression in mice, but no human trials have explored the drug’s potential in ALS.
Knowledge of Menkes disease, characterized by a severe deficiency of the trace element caused by a defective transport protein, has also given important clues. Crossing SOD1 and Menkes mice produced offspring with better survival and fewer motor neuron deficits.
Our natural copper sequestrators, MTs, might also be employed to control intracellular levels, and have been relatively well-studied in mice, with both genetic and medical manipulation showing benefits in SOD1 mice. Moreover, the gene for two of these factors is controlled by glucocorticoids.
Treatment with the synthetic glucocorticoid dexamethasone lowered copper levels in the spinal cord, slowed progression, and increased survival in a SOD1 mouse model, even when the treatment was started at a symptomatic stage. The effect was mediated via MTs. Given that dexamethasone is already in clinical use, a trial in ALS patients with SOD1 mutations would be a relatively straightforward task.
Another aspect worth mentioning is that, although several mutant SOD1 types could bind copper when studied in a lab dish, the majority of the mutant enzyme isolated from the spinal cord has no ions bound. SOD1 without its copper co-factor is prone to misfolding, so finding a way to increase the binding of the ions to the enzyme might lessen toxicity in ALS.
Attempts to increase the levels of the enzyme that incorporate copper into SOD1, however, led to a worsening of ALS symptoms. Instead, giving SOD1-mutant mice copper in the form of a particular complex prevented and even rescued symptoms. This suggests that the ions need to exist in a specific form to be incorporated into the SOD1 enzyme.
Supplying copper in a form that is available for SOD1, in addition to the removal of accumulated ions, could be an effective means of treating SOD1-based ALS, the review suggests.
It is important to remember, however, that the vast majority of studies exploring this in SOD1-linked ALS have been performed in mice. As is the case with other diseases, translatability of findings between mice and humans, particularly when it comes to therapeutic effects, is generally poor.
Studying copper abnormalities in SOD1-ALS patients is a needed first step in determining how copper homeostasis abnormalities affect human ALS. As the researchers concluded, “More extensive and systematic investigation will be definitely required on possible involvement of copper dyshomeostasis in the SOD1-ALS cases.”