Brain Protein May Be Linked to Depression

Scientists have discovered a protein that seems to play a crucial role in developing depression, a finding that may lead to new treatments for the often debilitating illness — and fundamental understanding of why it strikes.

Although problems with the mood-regulating brain chemical serotonin have long been linked to depression, scientists don't know what causes the disease that afflicts some 18 million Americans — or exactly what serotonin's role is.

The newly found protein, named p11, appears to regulate how brain cells respond to serotonin, researchers from Rockefeller University and Sweden's Karolinska Institute report Friday in the journal Science.

"We're all very excited about this discovery," said Nobel laureate Paul Greengard, a Rockefeller neuroscientist who led the research. "People have been looking for modulators of serotonin for a long time."

Said Oxford University pharmacologist Trevor Sharp, who reviewed the work: "This finding represents compelling evidence that p11 has a pivotal role in both the cause of depression and perhaps its successful treatment."

Most depression medications used today are members of the Prozac family that work by making more serotonin available to brain cells. They stem from a theory that depression patients might not have enough serotonin, a neurotransmitter, or chemical that carries signals between nerve cells.

Then scientists discovered the serotonin connection was more complicated, dependent on how well the neurotransmitter binds to receptors, or docking ports, on cell surfaces. Fourteen different serotonin receptors have been discovered.

The new research focuses on one of those receptors, dubbed the "1B" receptor, that seems to play a particularly big role in major depression.

Greengard and colleagues discovered that the p11 protein increases the numbers of these receptors on the surfaces of cells, mobilizing them so they're available for serotonin to do its job.

That led to a series of remarkable experiments, using mice as well as brain tissue saved from the autopsies of depressed patients, that found:

--Depressed people have substantially lower levels of p11 in their brain tissue than the non-depressed. So did a breed of mice, called "helpless" mice, that exhibit depression symptoms.

--Then the mice were given two older antidepressants — one known as a tricyclic, the other an MAO inhibitor — and electric shock therapy. Each treatment increased the amount of p11 in mice brains, even though each therapy is known to work in different ways.

--So the researchers bred mice that had no p11-producing gene. They acted depressed, and had fewer 1B receptors and less serotonin activity than regular mice. They also were less likely to improve with depression medication. Mice genetically altered to produce extra p11 acted in just the opposite way — no depression-like behavior, and their brain cells carried extra serotonin-signaling receptors.

"It's a very important finding," said Dr. Thomas Insel, director of the National Institute of Mental Health, which funded the research. "This gives us a new set of targets for drug development," but also "suggests a whole new area of investigation for trying to ... ultimately discover does this have anything to do with why some people get depressed and others don't."

The researchers don't yet know whether a genetic defect or some other factor is responsible for altering p11 levels.

"The p11 is upstream of the receptor, and now the question is what is upstream of the p11," Greengard said.

But Sharp noted that bouts of depression often are associated with serious stress, and that p11 is part of a protein family known to be sensitive to certain stress-related hormones.

Greengard's lab now is researching the potential for p11-related therapies.

But the discovery likely will aid research into other diseases that also depend on cell-based receptors.

"We're finding that other molecules control other receptors, so I think this may open up quite a major new area of approach to developing therapeutic drugs," Greengard said.