A research study involving a small roundworm may open up new possibilities for treating neurodegenerative diseases. Scientists have found a connection between the gene swip-10 in the worm and the regulation of copper, an essential element for maintaining brain health, commonly found in everyday objects like wires and cooking pots. By further investigating the roles of swip-10 and MBLAC1, a protein involved in cellular processes, researchers could develop effective therapies for neurodegenerative conditions. This discovery provides fresh opportunities for advancing treatments for brain diseases.
Research on simple organisms frequently leads to new therapeutic discoveries. For example, the 2020 Nobel Prize in Chemistry was awarded to Emmanuelle Charpentier, Ph.D., and Jennifer Doudna, Ph.D., for their CRISPR-based DNA editing work, which began with studies using bacteria just a decade ago. Today, numerous CRISPR therapies are approved for various disorders, with more on the horizon.
Understanding the potential of simpler animal models, a research team led by Randy D. Blakely, Ph.D., at Florida Atlantic University’s Schmidt College of Medicine and the FAU Stiles-Nicholson Brain Institute, has made significant progress toward developing treatments for human neurodegenerative disorders. Their research focuses on a tiny, unassuming roundworm.
Known scientifically as Caenorhabditis elegans, this nematode is commonly used by neuroscientists to explore and manipulate genes that influence neural signaling and well-being. In a recent study published in the Proceedings of the National Academy of Sciences, Blakely and his team established a link between the function of the worm gene swip-10 and the regulation of copper. While copper is prominently used in electrical systems and cookware, it is also a crucial micronutrient involved in numerous cellular functions, including those within the human brain.
“Copper is vital for mitochondrial function, which is necessary for producing ATP—the energy source for numerous bodily functions, including muscle movement, digestion, and cardiac activity, as well as neuronal signaling that enables us to think and feel,” stated Blakely, who is the senior author and holds the David J.S. Nicholson Distinguished Professorship in Neuroscience at FAU. “Additionally, copper plays a role in shielding cells from harmful reactive oxygen species, or ROS, which in excessive amounts can damage proteins and DNA, ultimately leading to cell death, including in neurons affected by Parkinson’s and Alzheimer’s diseases.”
Copper exists primarily in two states: cuprous (Cu(I)) and cupric (Cu(II)). Different proteins in the body manage these two forms, converting them to support various essential chemical reactions for human health. Researchers continue to investigate how the body maintains the appropriate balance of these copper forms since imbalances could harm cells, especially neurons. This is where the swip-10 gene becomes relevant.
The worm research team, led by former member Andrew Hardaway, Ph.D., first identified the swip-10 gene in 2015 while examining molecules that regulate the activity of worm dopamine neurons responsible for movement.
“Worms with a damaging swip-10 mutation initially swim normally, but unlike healthy worms that can swim for over 30 minutes, the mutants experience swimming-induced paralysis within a minute,” explained Blakely. “We traced this paralysis to heightened dopamine neuron activity and published what we thought was a comprehensive finding.”
However, further investigations by Chelsea Gibson, Ph.D., another previous graduate student in the Blakely lab, revealed that the overactive dopamine neurons in swip-10 mutants deteriorate significantly earlier than those in normal worms, similar to the progression seen in Parkinson’s disease (PD). Additionally, other types of neurons in swip-10 mutant worms also showed signs of degeneration, leading Blakely’s team to propose that there might be connections to other neurodegenerative disorders beyond PD.
A critical insight arose when the swip-10 gene sequence was analyzed, revealing a strong human equivalent known as MBLAC1. In 2019, geneticist Iris Broce, Ph.D., at the University of California, San Francisco, identified MBLAC1 as a risk factor for a specific type of Alzheimer’s disease (AD) associated with cardiovascular problems (AD-CDV). Notably, they found a substantial reduction in MBLAC1 expression in the frontal cortex of individuals with AD-CDV, indicating a potential role for MBLAC1 in supporting brain and heart health. So, what’s the connection to copper?
“MBLAC1 encodes an enzyme essential for producing histones, proteins that compact DNA into chromosomes,” noted Blakely.
Interestingly, certain histones have an added function: the ability to convert Cu(II) into Cu(I). When mutations occurred in these proteins due to the efforts of Narsis Attar, M.D., Ph.D., at UCLA, the affected cells showed a marked decrease in Cu(I) production, increased ROS levels, poor mitochondrial function, and an inability to prosper.
Connecting insights over time, Peter Rodriguez Jr., a current graduate student and leading researcher on the study in the Blakely lab, theorized that swip-10 mutants also wouldn’t generate sufficient histones, resulting in a Cu(I) deficit, mitochondrial dysfunction, and increased ROS. The latest findings from Rodriguez Jr. and collaborators confirm this hypothesis; they demonstrate that supplementing the worms’ diet with Cu(I) or using a drug that raises cellular Cu(I) levels can rescue ATP production, lower ROS levels, and enhance dopamine neuron survival.
Rodriguez Jr. stated, “Surprisingly, the implications of swip-10 loss on Cu(I), worm bioenergetics, and oxidative stress aren’t limited to dopamine neurons. Rather, the benefits of Cu(I) are significantly reduced throughout the entire body. Another remarkable observation is that despite these widespread effects, the deficits stem from the loss of swip-10 in a tiny number of cells in the head region known as glial cells, which represent only 5% of the organism’s total cellular makeup.”
Glial cells are known for their role in supporting neuronal signaling and health across many species. In fact, Rodriguez Jr. was able to restore health to the worms and normalize Cu(I) levels throughout the body by expressing a normal version of the swip-10 gene solely in the glial cells.
“The significant influence of swip-10 on Cu(I) suggests a promising new strategy to maintain neuronal health,” remarked Blakely.
Interestingly, the antibiotic ceftriaxone, identified by the Blakely lab as a binder to the MBLAC1 protein, has been found by various groups to be neuroprotective in lab settings and animal studies, although its precise mechanism remains unknown. The Blakely team believes that ceftriaxone’s effects may pertain to its role in regulating copper levels.
“Ceftriaxone isn’t a particularly strong drug, doesn’t effectively penetrate the brain compared to other treatments, and can lead to antibiotic resistance and other side effects. Therefore, it’s understandable that it hasn’t shown clinical benefits,” commented Blakely. “Now that we have a clearer understanding of the functions of swip-10 and MBLAC1, we hope to design a more effective medication for treating neurodegenerative diseases.”
