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Scientists discover possible link between oxidative stress and non-hereditary degenerative disease

April 28, 2006

ATLANTA-The irreversible neurological degeneration associated with Parkinson's and Alzheimer's diseases may be the consequence of oxidative stress-the imbalance of antioxidants and pro-oxidants in cells. This imbalance results in an excess of reactive oxygen species-harmful oxygen-containing molecules that can cause damage to proteins. In the April 21 issue of the Journal of Biological Chemistry, scientists from the Emory University School of Medicine report that the protein DJ-1 is oxidatively damaged in non-hereditary (sporadic) Parkinson's disease.

While scientists do not know the function of DJ-1, they have previously identified abnormalities in DJ-1 that directly cause hereditary (familial) Parkinson's disease. About 10 percent of Parkinson's disease cases are hereditary forms caused by either a genetic deletion or mutations that result in amino acid substitutions, which can dramatically affect protein structure or function.

The cause of the 90 percent of Parkinson's Disease cases not influenced by genetics has remained more of a mystery. Lian Li, PhD, is associate professor of pharmacology at Emory University School of Medicine and lead author of this study, which was funded by a grant from the National Institutes of Health. "One popular theory has suggested that these sporadic cases result from exposure to environmental toxins, such as herbicides or pesticides," she says. "Previous research has indicated that these toxins lead to oxidative stress. While oxidative stress does occur naturally as humans age, further oxidation caused by toxins may overwhelm the body's antioxidants."

Until now, attempts to link environmental toxins to oxidation and neurological disorders have been only somewhat successful, in part because scientists have been unable to identify the molecular target of oxidation. "This theory [that toxins cause oxidative stress] has been around for a long time," says Dr. Li. "But what's been damaged by this oxidative stress?"

Aware of the connection between DJ-1 mutations and familial Parkinson's disease, Dr. Li and her collaborators examined the oxidation levels of the protein in sporadic cases. Their hypothesis that DJ-1 was the missing link proved to be correct: DJ-1 in patients who had Parkinson's disease showed signs of oxidative damage, including structural changes as the protein accumulated additional oxygen molecules (carbonylation and methonine oxidation).

These modifications to DJ-1 caused by the oxidative stress are irreversible and irreparable. Like familial Parkinson's disease, the structural changes to the DJ-1 protein in sporadic Parkinson's disease signal an abnormality, leading to the eventual degradation and loss of the protein. "The protein unfolds and cannot function normally," Dr. Li explains. "Not recognizing the unfamiliar shape, the protein is broken down by the cell. The end result is the same: you lose your protein. Any mutation or modification causing this protein to lose its function will then lead to neurodegeneration in Parkinson's disease."

Now that Dr. Li and her team are clear that a relationship between DJ-1 and neurodegeneration exists, they are preparing to extend their examination into the protein's role. Based on biochemical analysis, Dr. Li believes DJ-1 may serve as a protease, activating and deactivating a protein by cleaving the bonds that connect its amino acids. Dr. Li is also currently exploring the possibility that DJ-1 may serve as an antioxidant, and that when mutated or damaged, the protein cannot defend the cell.

Future information about the role of DJ-1 may enable the development of drugs to specifically target the protein, perhaps stopping or reversing Parkinson's disease or Alzheimer's disease, which also may be impacted by the oxidation of DJ-1. In the meantime, says Dr. Li, people looking to prevent neurological degeneration might do well by looking to the kitchen cabinet, not the pharmacy: green tea and vitamin C supplements are two bountiful sources of antioxidants.

Emory University Health Sciences Center