Different triggers spark stroke, injuries, and neurodegenerative diseases, but the molecular chain of events responsible for brain cell death in these conditions are the same. Johns Hopkins researchers have isolated the single protein at the end of the chain that delivers the fatal blow and hacks up a cell's DNA.
The findings - published in the journal Science - could pave the way for new therapies to stop the process in its tracks and potentially prevent brain cell death.
Research partners Dr. Ted Dawson, Ph.D., now director of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine, and Valina Dawson, Ph.D., professor of neurology, and their research group conducted experiments on laboratory-grown cells to determine the culprit in the event chain that ultimately causes cell death.
The new research builds on a growing body of knowledge of a distinct form of programmed brain cell death dubbed "parthanatos" by the team in earlier work to distinguish it from other types of cell death, such as apoptosis, necrosis, or autophagic death.
The research teams found that while stroke, injury, Alzheimer's disease, Parkinson's disease, and Huntington's disease have very different causes and symptoms, they share the brain cell death mechanism, parthanatos, and PARP, an enzyme involved in the process.
"I can't overemphasize what an important form of cell death it is; it plays a role in almost all forms of cellular injury," says Dr. Dawson. The combined research groups have spent years breaking down each link in the parthanatos chain of events and tracing what roles proteins play in the process.
Previous research indicated that when a protein - mitochondrial apoptosis-inducing factor (AIF) - moves from its residing location in the energy-producing mitochondria of the cell to the nucleus, it causes the genome housed in the nucleus to be carved up, leading to cell death.
MIF protein 'chops up DNA,' triggers parthanatos cell death
While the transfer of AIF into the nucleus leads to cell death, AIF is not responsible for the DNA being carved. Yingfei Wang, Ph.D., an assistant professor at the University of Texas Southwestern Medical Center, screened thousands of human proteins to identify those that strongly interacted with AIF and could, therefore, be responsible for cutting up the DNA.
Wang identified 160 possible protein candidates and stopped each of them being produced one by one in lab-grown human cells, in order to determine whether cell death would be prevented if one protein was eliminated.
Of all the 160 proteins, the team identified macrophage migration inhibitory factor (MIF) at the heart of the cell-death process.
"We found that AIF binds to MIF and carries it into the nucleus, where MIF chops up DNA. We think that's the final execution step in parthanatos."
Dr. Ted Dawson, Ph.D.
Additionally, Dr. Dawson and colleagues have discovered chemical compounds that can block the action of MIF in the lab-grown cells and, as a result, protect them from cell death. Future work will focus on testing these effects in animals and modifying the process to increase safety and efficacy.
Dr. Dawson cautions that although parthanatos has been established to cause cell death in several brain conditions, the ability of MIF to chop up DNA has, at present, only been conclusively linked with stroke. Researchers previously found that when the MIF gene was immobilized in mice, stroke damage was significantly lessened.
"We're interested in finding out whether MIF is also involved in Parkinson's, Alzheimer's and other neurodegenerative diseases," Dr. Dawson says. If there is found to be a link, and an MIF inhibitor proves to be a success, there is the potential for treating many conditions, he concludes.