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How ‘toxic’ proteins could protect neurons

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.

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Researchers suggest that proteins thought to destroy neurons in people with ALS may actually have the opposite effect.

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.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disease that is estimated to affect around 14,000–15,000 people in the United States.

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.”

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