In the July 12 issue of Science, researchers reported uncovering the "death pathway" that's likely switched on when neurons die from the disease.

They've also highlighted the key role of a specific molecule in the chemical cascade--one called AIF, for apoptosis inducing factor.

"We believe the AIF route is the major one in nerve cells, over other more well-known death pathways that turn on in other cells," says Center scientist Valina Dawson. "Knowing this lets us target our search in a new way, to look specifically for things that prevent AIF release."

In the study, cultures of animal brain cells exposed to a neurotoxin----one that simulates ALS's end stages in cells----dramatically resisted death when their AIF was blocked.

Scientists have long known that one of two separate cell pathways, called apoptosis and necrosis, brings about death of cells. Generally, things that trip the death process activate one path or the other, though both may be involved in later stages. Eventually, a point of no return is reached and the cell dies.

But in nerve cells and some other types, Dawson says, emphasis is on a third route. This pathway turns on when a cell is heavily stressed, as nerve cells are in ALS. Stress-initiated shifts in internal chemistry trigger the over-activation of a normally helpful repair enzyme called PARP-1. And overzealous PARP-1 brings about a rapid and dramatic drop in cell energy.

The team's work, under Dawson's direction, suggests that major drops in energy, in turn, cause release of AIF from the mitochondria, the cell bodies that produce it. Then AIF travels to the nucleus and triggers massive destruction of chromosomal material. Cells die quickly after that.

"Our ultimate goal," says Dawson, "is to see if we can find small molecules that block AIF release----a stage approaching the point of no return." She and team members have a separate project that screens unusually death-resistant cells, trying to find what unusual genes are turned on and what products they produce. The team has already found several molecules that block AIF and Center scientists are currently exploring their use.

"We really don't know how the molecules work yet," says Dawson, "but we're hoping they'll give us a new therapeutic opportunity.

Because AIF's move to the nucleus is so easily tracked, using colored molecular tags that can be spotted under the microscope, it becomes a clear and handy way to see if nerve cells are headed downhill.

A new automated system that reports on the state of hundreds of cells at a time will let the scientists in Dawson's lab screen potential AIF-blockers quickly and accurately. "We'll be able to test any number of drugs we couldn't have before," she says.

This research was funded by The Robert Packard Center for ALS Research at Johns Hopkins.

THE ROBERT PACKARD CENTER FOR ALS RESEARCH

The Robert Packard Center for ALS Research at Johns Hopkins is a collaborative effort by some of the best ALS and non-ALS scientists to aggressively and rapidly develop new treatments and find a cure for ALS, also know as Lou Gehrig's disease. It's the only institution of its kind dedicated solely to the disease. Research conducted by the Center is meant to translate from bench to bedside in an expedited time frame. Center scientists from institutions around the world have made some of the most important discoveries in ALS, leading to advances in understanding and treatment of the disease.

The nature of ALS shapes the Center's aggressive, results-oriented scientific approach. ALS is a devistating, progressive neuromuscular disease that causes complete paralysis and loss of function-including the ability to eat, speak, and breathe-and eventually, death. ALS progresses quickly and is not curable. Most patients die within five years of diagnosis.

To learn more about the Robert Packard Center for ALS Research at Johns Hopkins, including the latest information on ALS research and treatment, log on to www.alscenter.org.