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April 21, 2008
Study shows culprit in stroke cell damage

By Quinn Eastman

Emory researchers have identified a key player in the killing of brain cells after a stroke or a seizure. The protein AEP, or asparagine endopeptidase, unleashes enzymes that break down brain cells’ DNA.

Finding drugs that block AEP may help doctors limit permanent brain damage following strokes or seizures, says pathologist Keqiang Ye.

His team’s results were published in the March 28 issue of the journal Molecular Cell.

When a stroke obstructs blood flow to part of the brain, the lack of oxygen causes a buildup of lactic acid, the same chemical that appears in the muscles during intense exercise. In addition, a flood of chemicals that brain cells usually use to communicate with each other over-excites the cells. Epileptic seizures can have similar effects.

While some brain cells die directly because of lack of oxygen, others undergo programmed cell death, a normal developmental process where cells actively destroy their own DNA.

“The mystery was: how do the acidic conditions trigger DNA damage?” Ye says. “This was a very surprising result because previously we had no idea that AEP was involved in this process.”

At first, he and postdoctoral fellow Zhixue Liu thought the results of a critical experiment that led them to AEP were an aberration because the experiment was performed under overly acidic conditions.

“But if you can repeat the mistake, it’s not a mistake,” Ye says.

Liu and Ye found that a drug scientists use to mimic the acidic overload induced by stroke activates AEP, driving it to break down DNA in brain cells. In mice genetically engineered to lack AEP, both the drug and an artificial stroke resulted in reduced DNA damage and less brain cell death than in regular mice.