Public release date: 27-Apr-2006

Contact: Holly Korschun
hkorsch@emory.edu
404-727-3990
Emory University Health Sciences Center

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

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