UCLA scientists have discovered that a sex gene responsible for
making embryos male and forming the testes is also produced by the
brain region targeted by Parkinson's disease. Published in the Feb.
21 edition of Current Biology, the new research may explain why more
men than women develop the degenerative disorder, which afflicts
roughly 1 million Americans.

"Men are 1.5 times more likely to develop Parkinson's disease than
women," said Dr. Eric Vilain, associate professor of human genetics
at the David Geffen School of Medicine at UCLA. "Our findings may
offer new clues to how the disorder affects men and women
differently, and shed light on why men are more susceptible to the
disease."

In 1990, British researchers identified SRY as the gene that
determines gender and makes embryos male. Located on the male sex
chromosome, SRY manufactures a protein that is secreted by cells in
the testes.

Now, in an unexpected discovery, Vilain's team became the first to
trace the SRY protein to a region of the brain called the substantia
nigra, which deteriorates in Parkinson's disease.

Parkinson's disease occurs when cells in the substantia nigra begin
to malfunction and die. These brain cells produce a neurotransmitter
called dopamine that communicates with the brain areas controlling
movement and coordination.

As the cells die off, they produce less dopamine. This slows the
delivery of messages from the brain to the rest of the body, leaving
the person unable to initiate or control their physical movements.
The condition eventually leads to paralysis.

"For the first time, we've discovered that the brain cells that
produce dopamine depend upon a sex-specific gene to function
properly," Vilain said. "We've also shown that SRY plays a central
role not just in the male genitals, but also in regulating the
brain."

Vilain's lab used a rat model to study the effect of SRY on the
brain. When the researchers lowered the level of SRY in the
substantia nigra, they saw a corresponding drop in an enzyme called
tyrosine hydroxylase (TH), which plays a key role in the brain's
production of dopamine.

In a surprise finding, the drop in TH occurred only in the male
rats. The female rats remained unaffected.

"When we reduced SRY levels in the rats' brains, the male animals
began experiencing the movement problems caused by insufficient
dopamine," Vilain said. "Low levels of SRY triggered Parkinson's
symptoms in the male rats, cutting their physical agility by half in
a week.

"Initially, the rat could walk 14 steps in 10 seconds," he
noted. "After we lowered the SRY levels in its brain, the rat could
only manage seven steps in the same amount of time."

Vilain believes that variations in SRY levels may be linked to the
onset of Parkinson's and could offer insights into who is at risk
for the disease.

"SRY may serve as a protective agent against Parkinson's," he
said. "Men who contract the disease may have lower levels of the
gene in the brain."

Because SRY is found only in males, Vilain thinks women must possess
another physiological mechanism that protects dopamine-producing
cells in the substantia nigra.

"We suspect that estrogens in women could play the same role as SRY
in protecting the female brain from Parkinson's disease," he
said. "Our lab is currently studying this hypothesis in an animal
model."

Sex differences in other dopamine-linked disorders, such as
schizophrenia or addiction, may also be explained by the SRY gene,
Vilain said.

"It's possible that dopamine-related disorders that reveal dramatic
differences in severity and rates in the genders could depend on the
SRY levels in the brain," he said.

Article Date: 22 Feb 2006