Researchers at University Of North Carolina School Of Medicine are reporting the first evidence-based description of the neuronal protein clumps thought to be toxic to motor neurons and instigators of the neuronal degeneration seen in patients with amyotrophic lateral sclerosis (ALS). The laboratory discovery of the form of these unstable clumps, known as SOD1 proteins, and evidence of their toxic interaction with motor neurons could lead to drugs that prevent clumping, the researchers say, because non-clumped SOD1 proteins were not found to be toxic.
“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,” the study’s senior author, Nikolay Dokholyan, PhD, professor of Biochemistry and Biophysics at UNC, 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.” Motor neurons are crucial to movement and speech, and the ability to swallow and breathe, and their degeneration leads to the gradual paralysis that is a hallmark of ALS.
The study, titled “Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice,” was published online in Proceedings of the National Academy of Sciences.
The study focused on a subcategory of ALS that is seen in only 1%–2% of all cases, but long known to be linked to SOD1 protein mutations and previously shown to form potentially toxic clumps in patients without SOD1 gene alterations. The researchers discovered that the protein forms temporary clumps of three, what they called a “trimer,” capable of killing motor neuron-like cells grown in the lab.
“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,” said Elizabeth Proctor, PhD, and the paper’s first author.
The precise form of the aggregated protein had been a challenge to pinpoint largely because most of the suspected toxic clumps disintegrate quickly upon forming. “It is thought that part of what makes them so toxic is their instability,” Dr. Proctor said. “Their unstable nature makes them more reactive with parts of the cell that they should not be affecting.” Dr. Proctor spent two years developing a custom algorithm to determine the trimers’ structure — a feat Dr. Dokholyan described as akin to determining a yarn ball’s form by piecing together snippets from its outermost layers.
Once the three-clump, trimer structure was established, the team spent more years devising computational models to test its impact on the motor neuron-like, laboratory-generated cells. The results clearly demonstrated that SOD1 proteins tightly bound into trimers were lethal to the motor neuron-like cells, while non-clumped SOD1 proteins were not. “This is a major step because nobody has known exactly what toxic interactions are behind the death of motor neurons in patients with ALS,” Dr. Proctor added.
The team next plans to look further into the “glue” that holds these trimers together, an essential step to the potential development of drugs that could target the protein clumps and either break them apart or prevent their formation. They also think the findings may be relevant to other neurodegenerative diseases, like Alzheimer’s or Parkinson’s.
“There are many similarities among neurodegenerative diseases,” Dr. Dokholyan concluded. “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.”