Fwd:OT helpful- NERVE CELL'S DEATH IS DIFFERENT

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Nerve Cells' Death Different from Other Cells'

Library: MED

Keywords: NEURONS CELL DEATH APOPTOSIS NECROSIS PARP AIF

Description: Hopkins-led researchers say they have identified in neurons a

novel form of "programmed" cell death unlike those already known --

apoptosis and necrosis. (Science, 12-Jul-2002)

July 16, 2002

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NERVE CELLS' DEATH DIFFERENT FROM OTHER CELLS'

Writing in the July 12 issue of the journal Science, Hopkins-led researchers

say they have identified in neurons a novel form of "programmed" cell death

unlike those already known -- apoptosis and necrosis.

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 s 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; Bowers and

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 Packard Center for ALS Research at s Hopkins, the

American Heart Association, and the Lou McIlhaney Scholar Award.

Under an agreement between The s 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.

- -JHMI- -

On the Web:

http://www.sciencemag.org

Media Contact: Joanna Downer

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