Scientists are learning how metals' actions in the brain can be a factor in diseases, memory

05/26/2003

By SUSAN GAIDOS / Special Contributor to The Dallas Morning News

When most people think about metal in the brain, they see visions of Robocop or The Terminator. But it turns out that metals are just as important in ordinary brains.

Scientists have known for decades that certain metals, such as iron, were important to biological functioning, but many others had been dismissed as inconsequential trace elements. In recent years, scientists have tracked metals' migration through cells, revealing that the materials used to brace buildings and wire your home are also used to prop up proteins and boost the body's biochemical circuitry.

For example, many enzymes and proteins contain metal ions at their active sites, scientists have discovered. Such findings have inspired researchers to think more about the place of metals in biology, especially in the brain and nervous system, where metals help regulate neural signaling and memory formation.

Brain metal studies are also providing new clues about the causes of a wide array of neurodegenerative diseases. A new study shows how proteins barred from binding to metals bring about an inherited form of amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease.

Other studies show how a biochemical brew of copper, zinc and iron conspires with aging in the development of Alzheimer's disease. Yet another study suggests that pumping excess iron from the brains of Parkinson's patients may alleviate some symptoms of the disease.

Such studies point the way to new targets for developing therapies, diagnostic applications and drug development, says Ashley Bush, a neurologist at Harvard Medical School who researches the role of metals in Alzheimer's disease and other age-related disorders.

"What we've found is, there are common links with abnormal metabolism of metals in these neurodegenerative disorders," he says.

The brain is an unusual organ in that it holds high concentrations of metals such as zinc, copper and iron within its tissue, he notes.

"We propose that as a consequence of aging, the handling of those metals becomes prone to error, and the metals wind up in the wrong parts of the cell or in the wrong parts of the tissue and can abnormally combine with specific protein targets, and that may lead to a disease."

Because metal ions like to react with other molecules, cells have devised ways to keep tabs on them. Special proteins, called "chaperones," deliver metals to work sites in the cell and prevent them from mingling with other molecules.

A study to appear in the June issue of Nature Structural Biology shows how the absence of metals may also cause problems by changing a protein's structure. The study further reveals how this change may potentially trigger the formation of protein deposits in the brain.

Researchers John Hart of the University of Texas Health Science Center at San Antonio, working with collaborators from California, Massachusetts and England, developed three-dimensional crystal structures of an enzyme called copper-zinc superoxide dismutase, or SOD1. The enzyme normally serves as a protective agent, sopping up highly reactive molecules called "free radicals" that can damage DNA and proteins. People with some inherited forms of ALS carry a mutated form of this protein.

Comparing mutated SOD1 with normal versions of the enzyme, Dr. Hart and his team found that defects near the metal-binding site hindered the mutant's ability to bind to metals. Without these metal supports, the enzyme's structure can't fold properly, and it uncoils. That exposes normally covered areas, which allows the enzyme to "touch itself" and combine with other SOD1 enzymes in unnatural ways, Dr. Hart says.

"That sounds kind of dirty, but it is," he explains. "The molecules now are allowed to interact in a way they shouldn't be, and that causes them to stick together and make these filaments. After a while these filaments come out of solution and they get deposited in the cell."

Scientists believe that such protein deposits kill motor neurons in ALS patients by interfering with normal cellular activities.

In a separate study, published online in The Journal of Biological Chemistry, Dr. Hart and his colleagues looked at another SOD1 mutant linked to ALS. Although this enzyme initially binds to metals, it generates a "bad chemistry," producing a harmful agent that acts with oxygen to damage proteins and other cell parts. Their findings showed that the agent, called an oxidant, attacked the SOD1 protein itself, damaging it and causing it to drop its metal. Once the metal is lost, the enzyme becomes misfolded and forms clumps just like the other mutant enzymes, Dr. Hart says.

Though genetic mutations cause only a fraction of ALS cases, understanding the molecular mechanism behind the development of the disease may provide insight into other ALS cases, Dr. Hart says.

"Everyone knew for a long time that the mutations were somehow toxic to motor neurons, but they didn't know how," Dr. Hart says. "This is the first time anyone has shown, at a molecular level, how these kind of protein aggregates might form."

The findings may provide clues to the other neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's. In each of these ailments, the body's mechanism for processing metals goes awry. These diseases share another characteristic, oxidative stress, a condition brought on by too many damaging free radicals.

A part of aging

Last year, Dr. Bush published findings that show brain levels of copper and iron rise with age, setting up the chemical conditions that can generate oxidative stress.

"We've seen this in animal studies, but there's evidence that it happens in humans, too. Sometime in early adulthood, these levels of copper and iron begin to rise steadily for no apparent reason," Dr. Bush says.

Rising levels of copper and iron in the brain not only produce stress on the tissues, but also increase the workload on the cellular systems designed to keep them in check. When these systems fail, proteins and other molecules can mix with metals to produce harmful substances in the brain.

For example, in 1999, Dr. Bush and his research team showed how beta-amyloid, a protein associated with the plaques formed in Alzheimer's disease, interacts with copper and iron to convert oxygen into hydrogen peroxide, the same substance you buy at the drugstore. In the brain, the hydrogen peroxide acts as a bleaching agent that is toxic to cells.

Halting the process

The group has since developed a way to decrease hydrogen peroxide levels in the brain and is now testing it in humans. The method uses a decades-old antibiotic, called Clioquinolin or CQ, to bind with the metals and dissolve them. CQ, rarely used since the 1970s, targets the copper in beta-amyloid while leaving other copper alone, Dr. Bush says.

The drug was recently used in a preliminary clinical trial, in which it was administered to 36 people with mild to moderate Alzheimer's. Colin Masters of the University of Melbourne, the project leader of the study, reported at a conference last year that the interim results looked encouraging.

Researchers studying Parkinson's disease at the Buck Institute for Age Research in Novato, Calif., are also looking at ways to use CQ to curtail metals that can generate oxidative stress in the brain. In this case, their target is excess iron.

Julie Andersen, a biochemist with the institute, says cells that make the neurotransmitter dopamine are especially prone to oxidative stress.

"In the Parkinson's brain, you have cells containing dopamine and high levels of iron, and that's a kind of double whammy," she says. "Dopamine can interact with itself or other molecules to produce hydrogen peroxide. The hydrogen peroxide then reacts with iron to produce an even stronger toxin that damages proteins and fats in cells."

In March, Dr. Andersen's group published a study in the journal Neuron that showed keeping iron levels in check may help prevent the oxidative stress that leads to cell death in Parkinson's.

Lighting the path

Still other studies aim to track zinc, a metal found in high concentrations in a brain region associated with learning and memory. Free-floating zinc is also released into the brain when nerve cells communicate and has been linked to the development of amyloid plaques in Alzheimer's disease. Scientists are now interested in tracking zinc throughout the body to see where it accumulates or where it's released.

Stephen Lippard, a chemist at the Massachusetts Institute of Technology, has developed a series of fluorescent sensors that glow brightly when zinc is present. The sensors have been used in studies to track zinc in brain cell tissue cultures, and are now being adapted for other chemical messengers.

"One of our goals long term is to see if we might be able to use the zinc-release as a way of tracking the formation of neural networks which underlie memory formation in the brain," Dr. Lippard says.

Dr. Lippard says he envisions a day when such sensors might be used to glean information about signaling events in the brain as they occur.

"That's the big challenge of the future, to use optical imaging to study the brain," he says. "In that case you might be able to study the brain in live animals rather than post-mortem."

Susan Gaidos is a free-lance writer in Maine.