Copper is an essential mineral that supports healthy brain development and function. When the brain doesn’t receive enough copper, this can result in Menkes disease, which is characterized by brain damage (neurodegeneration) and seizures that often begin in early infancy.
Scientists are actively researching how brain cells respond to copper deficiency with the goal of developing therapies for Menkes disease and other childhood neurodegenerative disorders.
A new study, published in Molecular Biology of the Cell, provides insight into how brain cells adapt to a lack of copper. This collaborative research was conducted by scientists at Emory University, Georgia State University, Georgia Institute of Technology, and the Linus Pauling Institute. The team used three different research models for this work: human cells grown in culture, mice, and fruit flies (Drosophila).
To simulate copper deficiency in human brain cells, researchers engineered cells that lacked the copper transporter 1 (CTR1) protein, which transports copper into cells. They observed a shift in how these copper-deficient cells produced energy, moving from efficient oxidative phosphorylation (a copper-dependent process in mitochondria) to less efficient glycolysis (a copper-independent pathway).
This is notable because healthy brain development normally involves the opposite shift — from glycolysis to oxidative phosphorylation — shortly after birth.
This study recently received the 2025 Molecular Biology of the Cell (MBoC) Early Career Paper Award, which is given to the most impactful trainee-led work. Congratulations to lead author Dr. Alicia Lane and colleagues!
The copper-deficient cells also increased activities of the mTORC1 and S6K pathways that promote protein production and decreased activity of the PERK pathway that slows protein production. Together, these changes indicate a significant increase in the cell’s ability to create new proteins. This is important because the increased protein production acts as a pro-survival mechanism: the brain cells adapt and show resilience when copper is scarce.
The researchers extended their findings to a mouse model of Menkes disease, where they saw similar increases in mTORC1 and S6K signaling in the Purkinje neurons of the cerebellum, a brain region affected by the disease.
Further insights on these adaptive responses came from genetic experiments in fruit flies, led by the Institute’s Dr. Alysia Vrailas-Mortimer and performed by undergraduate student and co-author, Lauren Clayton. By overexpressing ATP7A, a transporter that exports copper from cells, the team induced copper deficiency in the flies’ epidermis (skin and underlying tissue), which results in loss of skin pigmentation and bristles (hair), similar to what occurs in people with Menkes disease.
When the researchers genetically manipulated a decrease in the cells’ ability to make proteins, this caused the tissue to collapse and degenerate. This supports observations from the tissue culture and mouse studies: increasing protein synthesis protects the cells from copper deficiency, and preventing this increase worsens symptoms.
This study reveals a protective mechanism in cells: when copper is scarce, cells increase their protein production to help maintain function and promote survival. These findings may help explain why symptoms of copper-deficiency disorders like Menkes disease may be delayed, typically appearing two to three months after birth. The brain appears to initially adapt to copper scarcity before it becomes overwhelmed with damage.
This work continues a long-standing collaboration between the laboratories of the Institute’s Vrailas-Mortimer and Dr. Victor Faundez at Emory University and adds to the understanding of devastating childhood brain disorders linked to copper deficiency.
To learn more about copper deficiency, see the Micronutrient Information Center article on copper.
Reference:
Lane et al. Mol Biol Cell. 36:3 (2025); doi: 10.1091/ mbc.E24-11-0512
