Inflammation and damage to nerve cells in brain tissue
Iowa State University researchers have described with single-molecule precision how copper ions cause prion proteins to misfold and seed the misfolding and clumping of nearby prion proteins.
The researchers also found the copper-induced misfolding and clumping is associated with inflammation and damage to nerve cells in brain tissue from a mouse model.
Prions are abnormal, pathogenic agents that are transmissible and induce abnormal folding of a specific type of protein called prion proteins, according to the Centers for Disease Control and Prevention. Prion proteins are mostly found in the brain. The abnormal folding of prion proteins leads to brain damage and symptoms of neurodegenerative disease. A similar cycle of neuronal protein misfolding and clumping is observed in other neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases.
Copper exposure and prion protein neurotoxicity
“Our study establishes a direct link, at the molecular level, between copper exposure and prion protein neurotoxicity,” the researchers wrote in a summary of the paper.
The findings were published today in the journal Science Advances. The corresponding author is Sanjeevi Sivasankar, an Iowa State University associate professor of physics and astronomy; the first author is Chi-Fu Yen, an Iowa State doctoral student in electrical and computer engineering. Co-authors are Anumantha Kanthasamy, an Iowa State Clarence Hartley Covault Distinguished Professor in Veterinary Medicine, chair of biomedical sciences and director of the Iowa Center for Advanced Neurotoxicology; and Dilshan Harischandra, an Iowa State doctoral student in biomedical sciences.
Grants from the National Institute of Environmental Health Sciences at the National Institutes of Health supported the project, including one from the Virtual Consortium for Transdisciplinary Environmental Research.
Although this study determined that copper-induced misfolding and clumping of prion proteins is associated with the degeneration of nerve tissues, Sivasankar cautioned that the study does not directly address the infectivity of prion diseases.
“There are different strains of misfolded prion proteins and not all of them are pathogenic,” Sivasankar said. “Although we do not show that the strains generated in our experiments are infectious, we do prove that copper ions trigger misfolding of prion proteins which causes toxicity in nerve cells.”
Copper is essential in all plants and animals. Copper is carried mostly in the bloodstream on a plasma protein called ceruloplasmin. When copper is first absorbed in the gut it is transported to the liver bound to albumin. Copper is found in a variety of enzymes, including the copper centers of cytochrome c oxidase and the enzyme superoxide dismutase (containing copper and zinc). In addition to its enzymatic roles, copper is used for biological electron transport. The blue copper proteins that participate in electron transport include azurin and plastocyanin. The name “blue copper” comes from their intense blue color arising from a ligand-to-metal charge transfer (LMCT) absorption band around 600 nm.
Most molluscs and some arthropods such as the horseshoe crab use the copper-containing pigment hemocyanin rather than iron-containing hemoglobin for oxygen transport, so their blood is blue when oxygenated rather than red.
It is believed that zinc and copper compete for absorption in the digestive tract so that a diet that is excessive in one of these minerals may result in a deficiency in the other. The RDA for copper in normal healthy adults is 0.9 mg/day. Because of its role in facilitating iron uptake, copper deficiency can often produce anemia-like symptoms.
All copper compounds, unless otherwise known, should be treated as if they were toxic. Thirty grams of copper sulfate is potentially lethal in humans. The suggested safe level of copper in drinking water for humans varies depending on the source, but tends to be pegged at 1.5 to 2 mg/L. The DRI Tolerable Upper Intake Level for adults of dietary copper from all sources is 10 mg/day. In toxicity, copper can inhibit the enzyme dihydrophil hydratase, an enzyme involved in haemopoiesis.
In cases of suspected copper poisoning, Ovalbumin is to be administered in either of its forms which can be most readily obtained, as milk or whites of eggs. Vinegar should not be given. The inflammatory symptoms are to be treated on general principles, and so are the nervous.
A significant portion of the toxicity of copper comes from its ability to accept and donate single electrons as it changes oxidation state. This catalyzes the production of very reactive radical ions such as hydroxyl radical in a manner similar to fenton chemistry. This catalytic activity of copper is used by the enzymes that it is associated with and is thus only toxic when unsequestered and unmediated. This increase in unmediated reactive radicals is generally termed oxidative stress and is an active area of research in a variety of diseases where copper may play an important but more subtle role than in acute toxicity.
An inherited condition called Wilson’s disease causes the body to retain copper, since it is not excreted by the liver into the bile. This disease, if untreated, can lead to brain and liver damage. In addition, studies have found that people with mental illnesses such as schizophrenia had heightened levels of copper in their systems. However it is unknown at this stage whether the copper contributes to the mental illness, whether the body attempts to store more copper in response to the illness, or whether the high levels of copper are the result of the mental illness.
Too much copper in water has also been found to damage marine life. The observed effect of these higher concentrations on fish and other creatures is damage to gills, liver, kidneys, and the nervous system. It also interferes with the sense of smell in fish, thus preventing them from choosing good mates or finding their way to mating areas.
Zinc can cancel Copper absorption