Copper Influx Key to Brain Cell Development

Chemical changes spur rapid transport of copper.

Researchers at Johns Hopkins have used a precision sensor in a chicken embryo to find dramatic differences in the use of copper between developing and fully mature neurons.

In a report published online today in Nature Communications, the investigators say their findings reveal how brain cells quickly adjust copper allocation from a predominant use in energy production and defense against free radicals to a use in activating enzymes that make neurons neurons.

“Biochemical studies had shown that many proteins involved in neural differentiation require copper, and we also knew there is a big spike in the brain’s copper levels at a certain stage of development,” says Svetlana Lutsenko, Ph.D., professor of physiology at the Johns Hopkins University School of Medicine. “With these new results, we now know a lot more about how developing neurons use copper for their various needs.”

Yuta Hatori, Ph.D., a postdoctoral fellow on Lutsenko’s team, used a protein sensor that changes its fluorescence to signal the so-called redox state of cells, which refers to the ability of molecules to exchange electrons, driving many processes. Cells control their internal redox states by precisely tuning the ratio of two small molecules: glutathione and glutathione disulfide. Working with colleagues in the school of medicine’s Department of Neuroscience and led by Shanthini Sockanathan, D.Phil., a professor in the department, the team infected chicken embryos at different stages of development with a gene encoding a tiny sensor and found that the redox state of neurons that control movement changes as they mature.

Image shows a brain.
Researchers say their findings reveal how brain cells quickly adjust copper allocation from a predominant use in energy production and defense against free radicals to a use in activating enzymes that make neurons neurons. Image is for illustrative purposes only.

Delving deeper, Lutsenko says, they found that one effect of the changed redox state was to expose the copper-binding site on a protein called Atox1, which shuttles the metal around the cell. Differentiating cells also turned out to make more Atox1 and a related protein, ATP7A, another copper transporter that works together with Atox1 to direct copper into a “secretory pathway.” The net effect was increase copper supply to the copper-requiring enzyme responsible for signaling between neurons.

The importance of getting copper to the right place in the cell at the right time may shed light on processes beyond development, Lutsenko says. For example, aging is known to wear on cells’ precision control of their redox states. “Our study suggests that small redox changes may have big effects on proteins in the secretory pathway, which are very important for brain function,” she says.

Armed with a better understanding of how normal neurons use copper, Lutsenko’s team plans to look next at what happens when that process goes wrong, using cells from patients with a copper-processing disorder known as Wilson disease.

About this neuroscience research

Other authors on the paper are Ye Yan, Katharina Schmidt, Eri Furukawa, Nesrin M. Hasan, Nan Yang and Chin-Nung Liu, all of the Johns Hopkins University School of Medicine.

Funding: The study was funded by the National Institute of General Medical Sciences (grant number R01 GM101502), the National Institute of Diabetes and Digestive and Kidney Diseases (grant number DK071865), and the National Institute of Neurological Disorders and Stroke (grant number NS046336).

Source: Shawna Williams – Johns Hopkins Medicine
Image Credit: The image is in the public domain.
Original Research: Full open access research for “Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway” by Yuta Hatori, Ye Yan, Katharina Schmidt, Eri Furukawa, Nesrin M. Hasan, Nan Yang, Chin-Nung Liu, Shanthini Sockanathan and Svetlana Lutsenko in Nature Communications. Published online February 16 2016 doi:10.1038/ncomms10640


Abstract

Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway

Brain development requires a fine-tuned copper homoeostasis. Copper deficiency or excess results in severe neuro-pathologies. We demonstrate that upon neuronal differentiation, cellular demand for copper increases, especially within the secretory pathway. Copper flow to this compartment is facilitated through transcriptional and metabolic regulation. Quantitative real-time imaging revealed a gradual change in the oxidation state of cytosolic glutathione upon neuronal differentiation. Transition from a broad range of redox states to a uniformly reducing cytosol facilitates reduction of the copper chaperone Atox1, liberating its metal-binding site. Concomitantly, expression of Atox1 and its partner, a copper transporter ATP7A, is upregulated. These events produce a higher flux of copper through the secretory pathway that balances copper in the cytosol and increases supply of the cofactor to copper-dependent enzymes, expression of which is elevated in differentiated neurons. Direct link between glutathione oxidation and copper compartmentalization allows for rapid metabolic adjustments essential for normal neuronal function.

“Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway” by Yuta Hatori, Ye Yan, Katharina Schmidt, Eri Furukawa, Nesrin M. Hasan, Nan Yang, Chin-Nung Liu, Shanthini Sockanathan and Svetlana Lutsenko in Nature Communications. Published online February 16 2016 doi:10.1038/ncomms10640

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