Johns Hopkins scientists say that a newly discovered “survival protein” protects the brain against the effects of stroke in rodent brain tissue by interfering with a particular kind of cell death that’s also implicated in complications from diabetes 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 lethal insult a defense response occurs that protects cells from subsequent insult. The scientists dissected this preconditioning pathway to identify the most critical molecular players, of which a newly identified protein protector – called Iduna -- is one.
Named for a mythological 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.
“Apparently, 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 vessels – the entire brain. It’s not just a delay of death, but real protection that lasts for about 72 hours.”The team noted that Iduna works by interrupting a cascade 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 binding with a molecule known as PAR polymer, Iduna prevents the movement of cell-death-inducing factor (AIF) into a cell’s nucleus.
In some of the experiments, Dawson and her team exposed mouse brain cells to short bursts of a toxic chemical, and then screened these “preconditioned” cells for genes 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 deficient 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 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 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 mimic the effect of PAR polymer could be novel therapeutic agents that would kill cancers by causing cell death.”
Hopkins authors on the Iduna paper, in addition to Valina and Ted Dawson, are Shaida A. Andrabi, HoChul Kang, Yun-Il Lee, Jian Zhang, Zhikai Chi, Andrew B. West, Raymond C. Koehler and Guy G. Poirier. Other authors include Jean-Francios Haince of Centre Hospitalier Universitaire de Quebec.
Hopkins authors on the AIF paper, in addition to Valina and Ted Dawson, are Yingfei Wang, No Soo Kim, HoChul Kang, Karen K. David and Shaida A. Andrabi. Additional authors are Guy G. Poirier and Jean-Francois Haince of the Laval University Medical Research Center.
The Iduna work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), the McKnight Endowment for the Neurosciences and the National Institute of Drug Abuse.
The AIF research was supported by the National Institute of Neurological Disorders and Stroke, American Heart Association and a Canadian Institutes Health Research grant.
On the Web:Valina Dawson: http://neuroscience.jhu.edu/ValinaDawson.php
Maryalice Yakutchik | Newswise Science News
Bacteria as pacemaker for the intestine
22.11.2017 | Christian-Albrechts-Universität zu Kiel
Researchers identify how bacterium survives in oxygen-poor environments
22.11.2017 | Columbia University
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
22.11.2017 | Business and Finance
22.11.2017 | Physics and Astronomy
22.11.2017 | Physics and Astronomy