A new study may open the door for Amyotrophic Lateral Sclerosis (ALS) drug treatment. Researchers from the University of North Carolina School of Medicine announced the discovery
of a toxic protein clump that kills motor neuron cells in the brain.
Also known as Lou Gehrig's disease, ALS is a fatal motor neuron disease that causes nerve cells to gradually break down and die. All muscles under voluntary control are affected, leading to muscle weakness and severe impairments in daily functions. There is no known cure and most ALS patients die from respiratory failure within 3 to 5 years from the onset of symptoms.
"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," said senior study author Nikolay Dokholyan. "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."
Of the 12,000 patients with ALS in the U.S., only a small percentage (5-10%) inherits the disease. Though the cause is still unknown, mutations in a handful of genes have been implicated for the familial cases of ALS, one of which is SOD1. The gene SOD1 encodes the enzyme copper-zinc superoxide dismutase 1, and SOD1-related mutations are implicated in about 20% of familial cases of ALS.
In examining at a subset of ALS patients with mutations in the SOD1 gene, researchers found the presence of a protein clump that exists in groups of three, a “tri-mer.” Dr. Elizabeth Proctor, first author of the study, deduced the structure of the tri-mer based on complex computational modeling and experiments in live cells.
They then tested the function of this tri-mer and found that this SOD1 protein aggregate killed the motor neuron-like cells in the lab. In contrast, non-clumped SOD1 proteins were not lethal to the cells. The results suggest a toxic interaction between the SOD1 trimeric protein clump and the motor neurons.
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. Elizabeth Proctor, first author of the study.
Protein aggregates have been implicated in other neurodegenerative diseases like Alzheimer and Parkinson’s disease. But this is the first time that researchers have been able to zero in on a toxic protein clump for ALS disease. Part of the difficulty is the fleeting nature of these protein clumps, which only exist in its trimeric state for a short amount of time.
"It is thought that part of what makes them so toxic is their instability," said Dr. Proctor. "Their unstable nature makes them more reactive with parts of the cell that they should not be affecting."
Knowing the structure and function of the tri-mer is a huge step for ALS research. Researchers now have a target to test compounds that may prevent the clumps from forming, or compounds that may break up clumps that have already formed. In addition, the unique presence of these protein clumps could serve as a biomarker for diagnosing ALS.
The similarities between ALS and other neurodegenerative conditions make this discovery even more impactful.
"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.” – Dr. Dokholyan
Source: UNC Press Release