In another series of experiments in live mice, the team injected a toxic chemical into the brains of a control group of normal mice and also into a group that had been genetically engineered to produce three to four times the normal amount of Iduna as if they had been preconditioned. The engineered mice with more Iduna were much less susceptible to brain cell death: They had more functional tissue and markedly reduced stroke damage in their brains. In addition, the Iduna mice were less impaired in their ability to move around in their cages.
"Identifying protective molecules such as Iduna might someday lead to drugs that trigger the brain survival mechanism when people have a stroke or Parkinson's disease," says Ted Dawson, M.D., Ph.D., Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases and scientific director of the Johns Hopkins Institute for Cell Engineering.
In research published April 5 in Science Signaling, the Dawsons' laboratories previously revealed the mechanism that underpins AIF's pivotal role in parthanatos.
By studying the 3-D structure of AIF, the team first identified the molecular pocket that looked like a potential PAR binding site. They then swapped that region out for a different one to see if it indeed took up PAR. Using HeLa cells in addition to mouse nerve and skin cells, the scientists noted that the AIF with the swapped region did not bind PAR and was not able to move into the nucleus.
The team genetically manipulated neurons so that they didn't make any AIF, then in some cells added wild-type AIF, and in others added an AIF that did not bind PAR. When those cells were stressed using the "stroke in a dish" technique, the cells with normal AIF died while those with the AIF that coul
|Contact: Maryalice Yakutchik|
Johns Hopkins Medical Institutions