The results are published in the March 28 issue of the journal Molecular Cell.
Finding drugs that block AEP may help doctors limit permanent brain damage following strokes or seizures, says senior author Keqiang Ye, PhD, associate professor of pathology and laboratory medicine at Emory.
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."
AEP is a protease, a class of enzymes that cuts other proteins. AEP is also called legumain because of its relatives in plants, and is found at its highest levels in the kidney, says Ye.
He and his co-workers had suspected that another class of proteases called caspases, involved in programmed cell death, controlled DNA damage after a stroke.
At first, he and postdoctoral fellow Zhixue Liu, PhD, 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," Dr. Ye says, adding that follow-up work allowed them to set aside caspases as suspects and focus on AEP.
The researchers began by looking for proteins that stick to another protein called PIKE-L, which they previously had studied because of its ability to interfere with programmed cell death in brain cells.
They discovered that PIKE-L sticks to SET, a protein that other scientists had found regulates DNA-eating enzymes involved in programmed cell death. In addition, PIKE-L appears to protect SET from attack by AEP.
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.
This outcome suggests "that AEP might be the major proteinase mediating this devastating process," the authors wrote.
Holly Korschun | EurekAlert!
The birth of a new protein
20.10.2017 | University of Arizona
Building New Moss Factories
20.10.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
20.10.2017 | Information Technology
20.10.2017 | Materials Sciences
20.10.2017 | Interdisciplinary Research