Revolutionary Research Links Copper Regulation to Neurodegeneration: A Breakthrough for Alzheimer’s and Parkinson’s!

copper brain health neurodegeneration worm research

Copper and Brain Health: New Insights from Worm Research on Neurodegeneration

Researchers have unveiled a connection between copper regulation and neurodegeneration, employing the worm gene swip-10. Their insights indicate that rebalancing copper levels could lead to innovative treatments for neurological conditions such as Parkinson’s and Alzheimer’s.

Investigations into simple organisms often serve as a catalyst for therapeutic advancements. An example lies in the 2020 Nobel Prize in Chemistry awarded to Emmanuelle Charpentier, Ph.D., and Jennifer Doudna, Ph.D., for their development of CRISPR-based DNA editing. This revolutionary work, which stemmed from bacterial research just a decade prior, has since paved the way for CRISPR therapies, now approved for a range of disorders with more on the horizon.

Appreciating the translational significance of research in simpler animal models, a group of scientists led by Randy D. Blakely, Ph.D., at Florida Atlantic University’s Schmidt College of Medicine and FAU Stiles-Nicholson Brain Institute, has embarked on a crucial endeavor that could lead to treatments for human neurodegenerative diseases. Their journey begins with an unassuming roundworm.

The Role of Caenorhabditis elegans in Neuroscientific Research

The nematode, scientifically termed Caenorhabditis elegans, is favored among neuroscientists for its ability to shed light on genes that affect neural signaling and overall health.

In a recent publication in Proceedings of the National Academy of Sciences, Blakely and his team link the function of the worm gene swip-10 to copper control. While copper is commonly associated with its industrial uses in electrical wiring and cookware, it is also a crucial micronutrient that plays pivotal roles in all cellular functions, including those in the human brain.

“Copper is essential for mitochondrial function—the cell’s powerhouse—and the generation of ATP, the molecule that fuels critical processes such as muscle contractions, digestion, heart function, and brain neuron signaling,” noted Blakely, senior author and David J.S. Nicholson Distinguished Professor in Neuroscience at FAU. “Copper also shields cells from the destructive effects of reactive oxygen species (ROS), which, in excess, can damage proteins and DNA, leading to cell death, including the death of neurons seen in Parkinson’s and Alzheimer’s.”

Copper’s Cellular Function and the swip-10 Gene

Copper exists in two primary forms: cuprous (Cu(I)) and cupric (Cu(II)), both regulated by various proteins in the body. These forms are converted to support the chemical reactions necessary for health. Yet, scientists are still grappling with how the body maintains this balance, especially since any excess or deficiency of either form can spell disaster for cells, especially neurons. Enter swip-10.

Blakely’s team, led by Andrew Hardaway, Ph.D., identified the swip-10 gene in 2015 during a screen for molecules necessary to regulate worm dopamine neurons, specifically those involved in swimming.

“Worms with a defective swip-10 mutation initially swim like normal, but unlike typical worms that can swim for 30 minutes or more, these mutants experience swimming-induced paralysis, or Swip, within less than a minute,” Blakely explained. “We traced this paralysis to overactive dopamine neurons and believed we had unraveled the full story.”

However, further investigation by Chelsea Gibson, Ph.D., revealed that swip-10 mutant worms experienced early degeneration in their dopamine neurons—similar to Parkinson’s disease. Additional neurons also showed signs of degeneration, suggesting that the gene’s links to neurodegenerative diseases might go beyond Parkinson’s.

Copper, Histones, and Neuronal Survival: copper brain health neurodegeneration worm research

A key clue emerged when the team decoded the swip-10 gene sequence and discovered that humans possess a related gene, MBLAC1. In 2019, Iris Broce, Ph.D., a geneticist at the University of California, San Francisco, identified MBLAC1 as a risk factor for a form of Alzheimer’s disease (AD) associated with cardiovascular complications (AD-CDV). This discovery, alongside reduced MBLAC1 expression in the frontal cortex of AD-CDV patients, highlighted the gene’s importance for brain and heart health. But how does copper fit into this picture?

“MBLAC1 encodes an enzyme that produces histones, proteins known for compacting DNA into chromosomes,” Blakely stated.

Some histones have an unexpected capability: converting Cu(II) to Cu(I). When mutations were introduced into these proteins by Narsis Attar, M.D., Ph.D., at UCLA, the cells produced less Cu(I), elevated ROS levels, impaired mitochondrial function, and exhibited poor health.

copper brain health neurodegeneration worm research: swip-10’s Influence on Copper and Neuron Vitality

Piecing together findings over the years, Peter Rodriguez Jr., the lead scientist in Blakely’s lab, hypothesized that swip-10 mutants would likely fail to generate the necessary histones, reducing Cu(I) production, impairing mitochondrial function, and raising ROS levels—leading to dopamine neuron death. The latest study confirmed this hypothesis. Additionally, supplementing the worms’ diet with Cu(I) or administering a drug that elevates Cu(I) levels rescued ATP production, reduced ROS, and supported dopamine neuron survival.

“Interestingly, the loss of swip-10 affects Cu(I) levels and energy production body-wide, not just in dopamine neurons,” Rodriguez Jr. explained. “Yet, these widespread deficits stem from the loss of swip-10 in just a few glial cells in the worm’s head, which comprise only 5% of its cells.”

Glial cells are essential for neuron support across many species. Remarkably, Rodriguez Jr. restored worm health and body-wide Cu(I) levels by introducing a functional copy of swip-10 solely into glial cells.

“The profound control swip-10 exerts over Cu(I) offers a unique opportunity to preserve neuronal health,” Blakely added.

The antibiotic ceftriaxone, which Blakely’s lab found to bind the MBLAC1 protein, has shown neuroprotective properties in several studies, though its precise mechanism remains unknown. Blakely’s team suspects it may influence copper homeostasis.

“While ceftriaxone isn’t particularly potent, has limited brain penetration, and carries risks like antibiotic resistance, it offers insights into future drug design,” Blakely noted. “Armed with our new understanding of swip-10 and MBLAC1, we believe we can create more effective therapies for neurodegenerative diseases.”

Reference

“Glial swip-10 controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis” by Peter Rodriguez, Vrinda Kalia, Cristina Fenollar-Ferrer, et al., 17 September 2024, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2320611121

The research received support from Steven and Deborah Schmidt, the Florida Department of Health, FAU Mangurian Center for Brain Health, and the National Institutes of Health.