Brain Protein May Be Linked to Depression

[Guest guest]

http://news./s/ap/20060106/ap_on_he_me/depression_protein

Brain Protein May Be Linked to Depression By LAURAN

NEERGAARD, AP Medical Writer

2 hours, 47 minutes ago

WASHINGTON - 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 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.

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.

___

On the Net:

Government depression information:

http://www.nimh.nih.gov