San Diego scientists have identified a link between certain molecules and the symptoms seen in brain diseases such as Alzheimer's and Parkinson's.
The researchers are the first to describe how these molecules, called free radicals, wreak havoc on proteins inside cells. Their findings are published today in the journal Nature.
Free radicals are molecules with unstable nitrogen or oxygen atoms. They are natural byproducts of metabolism, but they are also found in environmental toxins such as cigarette smoke and air pollution. Many people attempt to fight them by eating food rich in antioxidant nutrients and taking vitamin supplements.
Researchers at the Burnham Institute in La Jolla found that nitric oxide, one type of free radical, destroys the ability of a protein called PDI to fix other proteins that have folded incorrectly. Proteins are the building blocks of cells, and they must be shaped precisely to work properly. Misshaped proteins that accumulate as clumps inside brain cells are hallmarks of Alzheimer's and other neurological diseases.
The discovery may help answer how free radicals can be as dangerous as gene defects, said Stuart Lipton, who led the study at Burnham.
“There was a puzzle: How could something in the environment mimic what a genetic mutation could do?” Lipton said. “This is an important link.” Scientists have known that nitric oxide might be an important player in many neurodegenerative diseases. But they did not know how free radicals could be at the root of the misshaped proteins that characterize these diseases.
In their study, Lipton and his colleagues showed how nitric oxide attaches itself to PDI – short for “Protein Disulfide Isomerase” – essentially disabling it.
Once a cell loses this housecleaning ability, a chain reaction of cell damage by other free radicals ensues.
“The trick is now to develop a drug that protects PDI or somehow limits nitric oxide's access to PDI,” Lipton said.
Dr. Jonathan Stamler, who studies the effects of nitric oxide on human health at Duke University, said it's been extremely difficult to connect the dots between free radicals and the onset of disease inside cells.
“I like the case he's made,” Stamler said of Lipton's work. “I think it fits well with the emerging idea that nitric oxide can play an important role in. many diseases.”
The human body naturally clears cells of free radicals. But antioxidants such as vitamins E and C, beta-carotene and selenium, which are found in food and supplements, also may help. However, it's unclear how effective these antioxidants are in promoting health in brain cells, Lipton said.
The discovery that free radicals may cause many diseases that typically afflict the elderly makes sense, he said. As people grow older, their natural ability to clear free radicals diminishes and cell damage can follow.
Bruce Lieberman: (619) 293-2836; bruce.lieberman@uniontrib.com
