Ultimate Killer of Nerve Cells Spotted in Early Study

The key factor that deals the final death blow to nerve cells exposed to all sorts of injuries, including neurodegeneration in Parkinson’s disease, has been identified. The factor’s finding, and the molecular pathway leading to its activation, may open up new research into ways of stopping or mitigating such events and preserving neurons.

The study, “A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1,” was published in the journal Science.

The identification of the molecular pathway is the result of earlier work by two research team from Johns Hopkins University School of Medicine. The teams found that no matter what type of insult a nerve cell encounters, the cell dies as a consequence of a self-destruction program. Researchers named the processes parthanatos, a combination of Thanatos — the personification of death in Greek mythology — and the enzyme PARP, which is a key player 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,” Ted Dawson, MD, PhD, and director of the Institute for Cell Engineering at Johns Hopkins, said in a news release. Together with colleague Valina Dawson, PhD, a professor of neurology, Dawson spent years mapping all the factors running the parthanatos machinery, and the two scientists were only lacking a few pieces to complete the puzzle.

The team already knew that when a factor called AIF (apoptosis-inducing factor) leaves the mitochondria, where it normally resides, and gets transferred to the cell nucleus, cell death is near. They had also noted that the final blow came as a shredding of the cell’s genome, but since AIF is not able to cut DNA, they knew another molecule had to be at work.

To find that missing piece, they screened thousands of proteins to identify which ones interacted with AIF. The screening, done by Yingfei Wang, PhD, who is now an assistant professor at the University of Texas Southwestern Medical Center, identified 160 proteins. Then, to determine which one was responsible, Wang inactivated them one by one in cells grown in a dish.

When she came to a protein called MIF (macrophage migration inhibitory factor), cell death could no longer occur. “We found that AIF binds to MIF and carries it into the nucleus, where MIF chops up DNA,” said Dawson. “We think that’s the final execution step in parthanatos.”

Dawson is, however, cautious in interpreting the results, since MIF has, so far, only been convincingly linked to stroke, where researchers showed that blocking MIF reduced nerve cell damage in mice.

“We’re interested in finding out whether MIF is also involved in Parkinson’s, Alzheimer’s and other neurodegenerative diseases,” said Dawson, who also identified compounds that could block MIF in cells in a dish. If such compounds turn out to work this way in animals, they could open up a whole new way of treating Parkinson’s, as well as numerous other diseases.

The two research teams also recently found that a cancer drug, currently in clinical trials, could prevent alpha-synuclein spread between cells in a mouse model of Parkinson’s disease. Its spread is believed to be at the core of the progressive neurodegeneration seen in the disease.