RESEARCHERS USE NEW TECHNOLOGY TO LINK BRAIN CELL ENERGY DEFICITS TO PARKINSON'S DISEASE

November 18, 1996

Media Contacts: Sarah Goodwin, 404/727-3366 - sgoodwi@emory.edu
Kathi Ovnic, 404/727-9371 - covnic@emory.edu
http://www.emory.edu/WHSC/

WASHINGTON, D.C. -- Researchers at Emory University report at this week's Society for Neuroscience meeting on the use of new technology to link brain cell energy deficits to Parkinson's disease.

In the 1970s, some users of intravenous drugs suddenly developed severe, permanent parkinsonism after injecting narcotics. Astute medical detective work eventually found that the narcotics used by these drug users were contaminated with a chemical called MPTP that killed the dopamine cells of the brain. These are the same nerve cells that die in Parkinson's disease.

Laboratory research showed that MPTP killed the nerve cells by blocking the cells' "power plants," called mitochondria. This finding then led researchers to examine whether a similar problem with mitochondrial energy production might cause Parkinson's disease, a debilitating illness that affects about one million people in North America.

Several laboratories have found that the same mitochondrial energy deficits caused by MPTP are found in the brains of patients who have died with Parkinson's disease. It has been impossible, however, to determine whether mitochondria in the brains of living Parkinson's patients are abnormal.

Emory University School of Medicine researchers have developed a new method to examine mitochondria in the living brain using a technique called PET (positron emission tomography) scanning. Shortly after intravenous injection of a minute quantity of a radioactive "tracer," the tracer sticks to the mitochondria and can be imaged with the PET scanner.

"Although only studies in animals have been performed so far, we expect to be able to perform studies in Parkinson's patients soon," says Tim Greenamyre, M.D., Ph.D., associate professor of Neurology at Emory. "This new technique should also be useful for studying Alzheimer's disease, Huntington's disease, stroke and epilepsy."

The question of why and how nerve cells die when they cannot produce enough energy is also being examined. It turns out that when nerve cells cannot produce sufficient energy they become susceptible to damage by one of the brain's most abundant chemicals, glutamate.

Normally, glutamate is harmless and simply acts as a chemical messenger, or neurotransmitter, for communication between nerve cells. However, when mitochondria are not working properly, glutamate becomes a toxin that can kill nerve cells. The researchers found that very mild mitochondrial damage converts glutamate from a transmitter to a toxin.

Mitochondria normally produce their own toxic chemicals, known as "free radicals." These free radicals usually cause little harm because mitochondria also contain defense mechanisms against these toxins. One of the most important is a chemical called glutathione, which detoxifies free radicals. When mitochondria are damaged, as researchers believe is the case in Parkinson's disease, they produce more free radicals. At the same time, researchers have found that they make much less glutathione. In other words, they make more toxin and have less ability to withstand it.

Besides functioning as cellular "power plants," mitochondria protect nerve cells in other ways. One of the most important is protecting the cell from too much calcium. The amount of calcium in a cell is normally controlled very closely because excessive calcium can cause cell damage or death. When calcium levels in a cell rise, mitochondria, in essence, vacuum up the calcium to protect the cell. When mitochondria don't function optimally, calcium in a cell can rise to abnormally high levels. Dr. Greenamyre and his Emory colleagues are using a technique called laser scanning confocal microscopy to directly study how living nerve cell mitochondria take up calcium and determine what happens when the mitochondria malfunction. They are also using this technique to study living cells from patients known to have abnormal mitochondria.

"As we begin to understand how nerve cells die when their mitochondria malfunction, we are exploring ways to protect the nerve cells," Dr. Greenamyre says. "We have shown that drugs that block glutamate toxicity, glutamate antagonists, are profoundly protective. This may provide a way to slow or stop the normally progressive worsening of Parkinson's disease."

Amantadine, a drug used commonly to treat the symptoms of Parkinson's disease, has been found to be a glutamate antagonist. A recent study found that the use of amantadine was a predictor of improved survival in Parkinson's disease. Similarly, drugs that prevent free radical damage are very protective against mitochondrial damage, and there is great interest in testing their ability to slow the progression of Parkinson's disease.

For more general information on The Robert W. Woodruff Health Sciences Center, call Health Sciences News and Information at 404-727-5686, or send e-mail to hsnews@emory.edu.