‘Death fold’ proteins can make cells self-destruct. Scientists want to control them : Shots

In Alzheimer's disease, brain cells die too early. In cancer, dangerous cells do not die quickly enough.

That's because both diseases change the way cells decide when to end their lives, a process called programmed cell death.

“Cell death sounds painful, but it is important for our health,” says Douglas Greenwho studied this process for decades at St. Jude Children's Research Hospital in Memphis, Tennessee.

For example, making nerve cells live longer could help people with Alzheimer's disease, Parkinson's disease or ALS (Lou Gehrig's disease), he says, and speeding up the death of tumor cells could help people with cancer.

So researchers have looked for disease treatments that “alter or modulate a cell's propensity to die,” Green says.

One of these researchers is Randal Hafmann at the Stowers Institute for Medical Research in Kansas City, Missouri.

He studied immune cells that self-destruct when exposed to molecules that pose a threat to the body.

“They have to somehow acknowledge that [threat] in this huge variety of other complex molecules,” he says, “and then kill themselves within minutes.”

They do this in much the same way that a soldier might throw himself on a grenade to save the lives of others.

Huffman's team focused on special proteins inside cells that may trigger this process.

When these proteins recognize molecules associated with a virus or some other pathogen, he says, “they explode.”

The proteins crumple and begin to combine with other crumpled proteins, forming a structure called “death fold“polymer. This starts a polymerization chain reaction that ultimately kills the cell.

Hafmann's team knew that this process required enormous amounts of energy. But they couldn't find the source.

Then they thought about Process discovered in reusable hand warmers — which produce heat as they change from a liquid state to a crystalline solid.

Users start a chain reaction by bending a metal disc inside the heating pad. The mechanical action causes the formation of several tiny crystals, which quickly grow into much larger crystals.

“It releases all this energy,” Hafmann says. “This is exactly what we thought was happening with these proteins.”

His team provides proof supporting this explanation in the journal electronic life.

It was a little unsettling for Hufmann to think that so many cells had these self-destruct buttons waiting to be pressed.

“It seemed like a really terrible way to live,” he says, “to be at risk of spontaneous death every moment of a cell’s life.”

Of course, death is what you want for a cancer cell or a cell infected with a virus. But Halfmann suspects that this trigger system unnecessarily kills brain cells in diseases such as Alzheimer's.

He notes that the hallmark of Alzheimer's disease is a misfolded protein called amyloid.

“This amyloid, for reasons we don’t fully understand, ends up killing neurons,” he says.

This may be because misfolded amyloid proteins, much like death fold proteins, appear to replicate and form crystal-like structures.

So Hafmann began looking for ways to keep brain cells alive by making it harder for these crystals to form. He hopes to use an approach similar to adding antifreeze to water to prevent it from freezing.

Biotech firms are also trying to stop this process, but at a different stage – by interrupting the various communication pathways involved in cell death.

Several companies are “working furiously” to block one particular path, Greene said. This pathway involves some of the same death fold proteins that Hafmann's lab is studying.

This pathway leads to inflammation as well as neuronal death in Alzheimer's disease and other neurodegenerative diseases.

Biotech companies are betting on products known as antisense drugs that can stop a cell from making certain proteins, including fold proteins, Green said.

If they're right, he says, these efforts “will cure a lot of diseases that we associate with aging and inflammation.”

They will do this in part by changing how cells make life and death decisions.