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 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 disease.
Parkinson 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," which plays a key role in the brain's production of dopamine.
In a surprise finding, the drop in tyrosine hydroxylase 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.
The study was co-authored by Marie-Francoise Chesselet, UCLA chair of neurobiology; and Paul Micevych, UCLA professor of neurobiology; and Vincent Harley, associate professor of human molecular genetics at Prince Henry's Institute of Medical Research, Australia.
The National Institute of Child Health and Human Development and the American Parkinson Disease Association supported the research.
Parkinson disease is a chronic movement disorder that worsens over time. While 15 percent of people with Parkinson's are diagnosed before age 40, prevalence increases with age. The cause of Parkinson's is unknown, and there is no cure. However, medication and surgery can help manage the symptoms.