Johns Hopkins scientists say that a newly discovered "survival protein" protects the brain against the effects of stroke in rodent¹ brain tissue by interfering² with a particular kind of cell death that's also implicated⁴ in complications from diabetes⁶ and heart attack. Reporting in the May 22 advance online edition of Nature Medicine, the Johns Hopkins team says it exploited the fact that when brain tissue is subjected to a stressful but not lethal⁷ insult a defense⁸ response occurs that protects cells from subsequent insult. The scientists dissected⁹ this preconditioning pathway to identify the most critical molecular¹⁰ players, of which a newly identified protein protector – called Iduna -- is one.

Named for a mythological¹¹（神话的） Norwegian goddess who guards a tree full of golden apples used to restore health to sick and injured gods, the Iduna protein increased three- to four-fold in preconditioned mouse brain tissue, according to the scientists.

"Apparently¹², what doesn't kill you makes you stronger," says Valina Dawson, Ph.D., professor of neurology and neuroscience in the Johns Hopkins Institute of Cell Engineering. "This protective response was broad in its defense of neurons and glia and blood vessels¹³ – the entire brain. It's not just a delay of death, but real protection that lasts for about 72 hours."

The team noted¹⁴ that Iduna works by interrupting a cascade¹⁵（层叠，小瀑布） of molecular events that result in a common and widespread type of brain cell death called parthanatos often found in cases of stroke, Parkinson's Disease, diabetes and heart attack. By binding¹⁷ with a molecule¹⁸ known as PAR³ polymer, Iduna prevents the movement of cell-death-inducing factor (AIF) into a cell's nucleus¹⁹.

In some of the experiments, Dawson and her team exposed mouse brain cells to short bursts of a toxic²⁰ chemical, and then screened these "preconditioned" cells for genes²¹ that turned on as a result of the insult. Focusing on Iduna, the researchers turned up the gene's activity in the cells during exposure to the toxic chemical that induced preconditioning. Cells deficient²² in Iduna did not survive, but those with more Iduna did.

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 genetically²³ 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 susceptible²⁴ to brain cell death: They had more functional²⁵ tissue and markedly reduced stroke damage in their brains. In addition, the Iduna mice were less impaired²⁶ in their ability to move around in their cages.

"Identifying protective molecules²⁷ such as Iduna might someday lead to drugs that trigger the brain survival mechanism²⁸ when people have a stroke or Parkinson's disease," says Ted⁵ 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 previously²⁹ revealed the mechanism that underpins³⁰ 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 swapped³¹ 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 bind¹⁶ 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 could not bind PAR did not, revealing that PAR binding to AIF is required for parthanatos.

"These findings suggest that identifying chemicals that block PAR binding to AIF could be very protective," says Ted Dawson. "On the other hand, identifying chemicals that mimic³²（模仿） the effect of PAR polymer could be novel therapeutic³³ agents that would kill cancers by causing cell death."