Researchers have now investigated the mechanisms of a protein called SOD1 that is known to play a role in amyotrophic lateral sclerosis, and they uncovered some surprising findings.
The scientists found that while small aggregates of SOD1 can drive the neurological disease, it is possible that larger aggregates may actually help to protect neurons.
Lead study author Cheng Zhu, Ph.D. — from the University of North Carolina at Chapel Hill (UNC-Chapel Hill) — and colleagues recently reported their results in the Proceedings of the National Academy of Sciences.
In ALS, motor neurons — which are the nerve cells that control voluntary muscle movement — will gradually deteriorate. As the disease progresses, symptoms will worsen, and people with the condition eventually lose their ability to walk, talk, and breathe.
There is no cure for ALS, and the majority of people with the condition pass away as a result of respiratory failure. This most commonly occurs within 3–5 years of symptom onset.
The exact cause of ALS remains unclear, but researchers have identified mutations in the SOD1 gene as a possible culprit.
Studies have suggested that these mutations lead to the production of toxic SOD1 proteins, and that these form fibrous aggregates that can destroy motor neurons.
Trimers, fibrils, and neurons
As Zhu and colleagues explain, there are two types of fibrous aggregates formed by SOD1 proteins: small aggregates, which are made of only a few SOD1 proteins; and larger aggregates, or fibrils, which comprise several SOD1 proteins.
In a previous study, the team found that fibrous aggregates made of just three SOD1 proteins — referred to as "trimers" — can destroy motor neuron-like cells. Evidence for the toxicity of larger fibrils, however, has been sparse, with many studies failing to show that they cause neurons harm.
What is more, the team notes that drugs developed to clear larger fibrous aggregates from motor neurons have shown no success in clinical trials.
This begs the question: are larger fibrous aggregates really a cause of neuronal death? To find out, Zhu and colleagues set out to compare the effects of trimers and larger fibrils on neurons — but this was not without its difficulties.
"One challenge," notes Zhu, "is that the smaller structures such as trimers tend to exist only transiently on the way to forming larger structures."
"But we were able to find an SOD1 mutation," he adds, "that stabilizes the trimer structure and another mutation that promotes the creation of the larger fibrils at the expense of smaller structures."
"So, we were able to separate the effects of these two species of the protein."
Larger fibrils protect, not destroy
In their study, the researchers assessed the effects of mutant SOD1 proteins on cells that mimicked the motor neurons that are destroyed in people with ALS.
Compared with motor neuron-like cells that possessed normal SOD1 proteins, the scientists found that mutant SOD1 proteins that primarily formed trimers killed motor neuron-like cells.
"Looking at various SOD1 mutants, we observed that the degree of toxicity correlated with the extent of trimer formation," says Zhu.
However, they discovered that when mutant SOD1 produced proteins formed larger fibrils that suppress trimers, the functioning of motor neuron-like cells was comparable with cells with normal SOD1. This suggests that larger fibrils protect neurons, not destroy them.
According to the researchers, these findings indicate that promoting fibril formation in the brain might be a potential treatment for ALS that is triggered by mutations in the SOD1 gene.
"Although SOD1-associated ALS represents a small fraction of all ALS cases, uncovering the origins of neurotoxicity in SOD1 aggregation may shed light on the underlying causes of an entire class of neurodegenerative diseases."
Senior author Nikolay Dokholyan, Ph.D., UNC-Chapel Hill
The researchers now plan to find out more about how mutant SOD1 proteins produce trimers and identify drugs that can block their formation.