The key to developing treatments to any disease is understanding the underlying causes of the faulty biology that drives them. Researchers from the University of North Carolina have created the first-ever evidence-based description of the neuronal protein clumps that are thought to be the key biological drivers behind Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, a deadly neurodegenerative condition.
"One of the biggest puzzles in health care is how to address neurodegenerative diseases; unlike many cancers and other conditions, we currently have no leverage against these neurodegenerative diseases," Nikolay Dokholyan, senior author of the study, said in a press release. "This study is a big breakthrough because it sheds light on the origin of motor neuron death and could be very important for drug discovery."
ALS patients suffer from a progressive paralysis that leads to an early death as a result of the loss of motor neurons. The current study focused on a specific subset of ALS cases - 1 to 2 percent - that are linked to variations of the SOD1 protein. The researchers discovered that the protein forms temporary clumps of three, referred to as a "trimer," and when introduced in laboratory settings these clumps can kill motor neuron-like cells.
"This is a major step because nobody has known exactly what toxic interactions are behind the death of motor neurons in patients with ALS," said Elizabeth Proctor, first author of the paper. "Knowing what these trimers look like, we can try to design drugs that would stop them from forming, or sequester them before they can do damage. We are very excited about the possibilities."
The researchers used a combination of computational modeling and live experimentation on cells to create a custom algorithm that led to the determination of the trimers' structure. Until this finding, scientists were unaware of what the clumps looked like or their effects on cells due to their instability.
"It is thought that part of what makes them so toxic is their instability," Proctor said. "Their unstable nature makes them more reactive with parts of the cell that they should not be affecting."
The team plans to continue investigating the trimers as well as the glue that holds them together in order to provide research that could help in the development of drugs that can break them apart. The findings could also shed light on other neurodegenerative diseases.
"There are many similarities among neurodegenerative diseases," Dokholyan said. "What we have found here seems to corroborate what is known about Alzheimer's already, and if we can figure out more about what is going on here, we could potentially open up a framework to be able to understand the roots of other neurodegenerative diseases."
The findings were published in the Dec. 28 issue of the Proceedings of the National Academy of Sciences.
