The finding, in mouse cells, defines for the first time a window of opportunity to prevent a neuron's death and perhaps find new targets to try to treat Parkinson disease, stroke and traumatic brain injury, says Valina Dawson, Ph.D., of Hopkins' Institute for Cell Engineering and professor of neuroscience at the Johns Hopkins School of Medicine.
"All cell death is 'programmed' in that it results from a particular series of events," says Dawson. "But up to a certain point, the outcome is not inevitable and interference with the process can prevent or delay cell death. Knowing when that window of opportunity closes is critical."
Building on knowledge that activation of an enzyme called PARP is a key initiator of neuron death, the scientists have learned that "apoptosis-inducing factor," or AIF, is the final blow. Made in nerve cells' mitochondria in response to excessive DNA damage and PARP activation, AIF is sent into the nucleus, immediately causing the cells' genetic material to collapse.
"AIF entering the nucleus seems to be the point of no return -- once it gets in, the cell is going to die no matter what you do," says Dawson. AIF needs help to escape the mitochondria, travel through the cell and enter the nucleus, she says, and identifying the molecules that accompany it should offer opportunities to interfere and potentially prevent the cell from dying.
PARP, or poly(ADP-ribose)polymerase, is known primarily as the "guardian of the genome," because it recognizes damaged DNA and prepares it for repair. However, in cells with too much damage to their DNA, PARP triggers a cascade of events that causes the cell to die. PARP-controlled cell death is the major death pathway for neurons, particularly in response to
Contact: Joanna Downer
Johns Hopkins Medical Institutions