Toxic ALS Protein Aggregate Structure Uncovered, Raises Hope for Drug Discovery

    A little over twenty years ago scientists discovered that a mutation in the gene that codes for superoxide dismutase (SOD1) was strongly linked to plaques found in amyotrophic lateral sclerosis (ALS)—also known as Lou Gehrig’s disease—neuronal tissue and motor neuron death.

    In the subsequent years since that seminal finding, researchers have significantly advanced their understanding of ALS disease progression, as well as SOD1 folding and plaque association. However, the exact form of aggregated protein that is responsible for killing neurons has been difficult to identify, and many of the clumps that are thought to be toxic disintegrate almost as soon as they form, making them exceedingly difficult to study.

    “It is thought that part of what makes them so toxic is their instability,” notes lead author Elizabeth Proctor, Ph.D., a graduate student in Dr. Dokholyan’s laboratory at the time of the study and currently a postdoctoral researcher at MIT. “Their unstable nature makes them more reactive with parts of the cell that they should not be affecting.”

    Investigators from University of North Carolina (UNC) School of Medicine published their recent results describing in structural detail the neuronal protein clumps thought to be important in ALS. Moreover, the authors provide definitive evidence that these protein clumps are indeed toxic to the type of neurons that die in patients with ALS.

    “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,” explains senior study author Nikolay Dokholyan, Ph.D., professor of biochemistry and biophysics at UNC. “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.” Medicilon's drug discovery services include chemistry (synthetic chemistry, medicinal chemistry) and biology. Our chemistry team can deliver complex activities such as custom synthesis of compounds, compound library construction, SAR analysis and screening, compound structure determination and bioactivity optimization.

    The findings from this study were published recently in PNAS through an article entitled “Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis.”

    The current study focuses on a subset of ALS patients that are associated with variations in SOD1, which is roughly 1–2% of all cases. Yet, even in patients without mutations in their SOD1 gene, this protein has been shown to form potentially toxic clumps. Using some novel algorithms, the researchers discovered that the protein forms a temporary trimer clump and that these aggregates are capable of killing motor neuron-like cells in vitro.

    “This is a major step because nobody has known exactly what toxic interactions are behind the death of motor neurons in patients with ALS,” states Dr. Proctor. “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.”

    To understand the structural intricacies of the mutant SOD trimers, the UNC team utilized a combination of computational modeling and in vitro neuronal cell culturing. For the computational modeling studies, the researchers developed a custom algorithm for determining the trimers’ structure.

    Once the trimers’ structure was established, the team spent several more years developing methods to test the trimers’ effects on motor neuron-like cells grown in the laboratory. Subsequently, the researchers observed that SOD1 proteins that were tightly bound into trimers were lethal to the motor neuron-like cells, while non-clumped SOD1 proteins were not.

    This was an exciting discovery for Dr. Dokholyan and his team, who plan to investigate further the “glue” that holds the trimers together to find drugs that could break them apart or keep them from forming. The researchers hope that their findings will not only help ALS patients but shed light on other neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s.

    “There are many similarities among neurodegenerative diseases,” said Dr. Dokholyan. “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.”