Center Scientist Eyes Key Step in Cells’ ‘Death March’

Valina Dawson finds a new pathway.

A current hot spot in als research centers on something long ignored as a source of trouble in the disease: the mitochondria. The plentiful, often jellybean-shaped cell bodies are dubbed the cell’s powerhouses because they generate most of its energy.

But mitochondria have a darker side: They can unleash a cascade of reactions that destroy the surrounding cell. That capability, plus recent evidence from the AIDS clinic that mitochondria gone awry from a particular drug can result in motor neuron damage, has Center researchers keen to study their role.

Now, work by neuroscientist Valina Dawson has gone well beyond enthusiasm. It’s potentially provided a large general target, along with a small specific one, for a new approach to therapy. Reporting in Science last July, Dawson and her team laid out a series of painstaking studies that identified a new “death pathway,” the one most likely switched on when neurons die from ALS.

Scientists have long known that one of two separate cell routes, called apoptosis and necrosis, bring about death of cells. Generally, whatever trips the death process activates one path or the other, though in later stages, both may kick in. Eventually a point of no return is reached and the cell dies.

But in nerve cells, Dawson says, emphasis is on a third path that turns on when a cell is heavily stressed, as nerve cells are in ALS. Stress indirectly triggers over-activity of a normally helpful repair enzyme called PARP-1. Because the enzyme consumes cell energy as it works, overzealous PARP-1 brings about a rapid, dramatic drop in cell energy reserves.

Dawson’s study suggests the massive fall in energy, in turn, prompts release of a key molecule from mitochondria. Called AIF (for apoptosis inducing factor), the newly released molecule moves to the cell’s nucleus, where it triggers wholesale destruction of chromosomes. Cells die quickly after that.

“Our ultimate goal,” says Dawson, “is to find small molecules that block AIF release—that stage approaching the point of no return.”

In a separate project, her team screens cells unusually resistant to cell neuro-poisons, to see what atypical genes are turned on and what products they produce. Several of those products, they’ve already found, block AIF. They’re the topic of intense study at the Center.

Also, because AIF’s move to the nucleus can be tracked, it offers a way to check nerve cells’ downhill slide. An automated system that scans hundreds of cells at a time lets Dawson’s team screen potential AIF-blockers quickly and accurately. “We’ll be able to test any number of drugs we couldn’t before,” she says.

Next > Accentuate the Positive
Some Center scientists, eying a cure, seek the cause of ALS. Others study how it damages cells. But a third group’s work may lessen immediate misery: They’re learning the basics of damage control and repair.