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 conditions like traumatic brain injury, Parkinson disease, and stroke, says Dawson.
In studying nerve cell death from these and other conditions, scientists around the world had noted that some markers of apoptosis, generically known as "programmed cell death," were present, but others were missing. Scientists knew mitochondria, cells' energy-producing factories, were involved, but no studies had linked a trigger of cell death in neurons to mitochondria.
"This study links PARP activation with mitochondrial function for the first time," says Dawson. "We thought AIF was a good candidate for that link, and we've shown that it's required for cell death after PARP activation, and conversely that PARP activation is required for its release from the mitochondria."
An intriguing finding was that AIF transfer to the nucleus came before release of a molecule called caspase, an initial step in classically defined apoptosis. Caspase is involved in PARP cell death, too, but at the very end of the road: almost like a mortician for the neuron, caspase packages up parts of the dying cell for destruction and recycling.
"The classic definitions of necrosis and apoptosis are meaningless in the nervous system because the terms were defined in tissues outside of it," says Dawson. "Cell death in the nervous system uses some of the pathways of necrosis and apoptosis, but in a slightly different sequence."
The scientists showed that preventing PARP activation and blocking AIF release protected cells from dying, but blocking caspase did not.
Other authors on the study are Seong-Woon Yu, Hongmin Wang, Marc Poitras, Carmen Coombs, and Ted Dawson, all of Hopkins; William Bowers and Howard Federoff of the University of Rochester; and Guy Poirier of Laval University Medical Research Center, Quebec.
The experiments were funded by grants from the National Institutes of Health, the Robert Packard Center for ALS Research at Johns Hopkins, the American Heart Association, and the Mary Lou McIlhaney Scholar Award.
Under an agreement between The Johns Hopkins University and Guilford Pharmaceuticals, Ted Dawson and Valina Dawson are entitled to a share of sales royalty received by the University from Guilford. Ted Dawson and the University own Guilford stock, and the University stock is subject to certain restrictions under University policy. The terms of this arrangement are being managed by the University in accordance with its conflict of interest policies.
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