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Gene May Explain Men's Raised Risk for Parkinson's
(HealthDay News)
by By E.J. Mundell
HealthDay Reporter
Updated: Feb 20th 2006

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MONDAY, Feb. 20 (HealthDay News) -- For years, it's been a puzzle: Why are men 50 percent more likely than women to develop Parkinson's disease?

Researchers now say that a gene long associated with fetal gender is also crucial to a Parkinson's-linked area of the male brain.

The gene, called Sry, appears to help neurons residing in the brain's substantia nigra -- a locus for motor control -- secrete the neurochemical dopamine. In Parkinson's disease, these neurons gradually die off, lowering dopamine levels and causing the gradual loss of motor function that's a hallmark of the illness.

Before this study, scientists studying Parkinson's had little to go on when it came to understanding why this neuronal death and dysfunction occurs.

That may no longer be the case.

"We now have a starting point with this one gene that we know for sure works directly upon the neurons that secrete dopamine," said senior researcher Dr. Eric Vilain, an associate professor of human genetics at the University of California, Los Angeles' David Geffen School of Medicine.

His team's findings are published in the Feb. 21 issue of Current Biology.

Experts at the Parkinson's Disease Foundation estimate that more than 1 million Americans, most of them over 50 years old, suffer from the degenerative neurological illness. Parkinson's disease often starts with a slight tremor of one arm, leg or hand, then moves to the rest of the body, causing constant trembling, head shaking and difficulty in walking, among other symptoms. While dopamine replacement can help slow or ease symptoms, there is currently no cure for Parkinson's disease.

In fact, very little is known about the root causes of this disease, or why men are more likely to be affected.

Vilain explained that he was a member of a team that originally identified Sry in 1990. In the developing fetus, "this gene makes the gonads, which start out as undifferentiated, turn into either testicles or ovaries, thus making the fetus male or female," he said.

In studies in mice a few years ago, Vilain said he noticed unexpected Sry activity in the rodents' brains. Intrigued, he reviewed the literature and found that experts elsewhere had noticed the same thing. None of them had been able to pinpoint the neurological locus of this activity, however.

"So, in this rat study, we have looked closer," he said. "We found that the gene is expressed in the substantia nigra. It's a real surprise, because this part of the brain has nothing to do with gender identity."

Instead, the substantia nigra is all about dopamine-mediated control of motor function -- the messages brain cells send to the nervous system and (ultimately) muscles to spur and direct movement.

Sry appears to affect only the substantia nigra in the male rat brain, however. In fact, when the UCLA team lowered Sry activity in males' brains, the animals began to exhibit the impaired movement characteristic of Parkinson's disease.

"This means that the mechanisms by which neurons in the substantia nigra function are dependent on a gene in males and on something else, as yet unknown, in females," Vilain said.

Although the finding itself doesn't answer the nagging question of why men are more at risk for Parkinson's, it does offer some suggestions. "Maybe females have another way to make these dopamine-secreting neurons work nicely -- estrogens, for example," Vilain said. "It's just a hypothesis, but maybe Sry compensates for the lack of estrogens [in men]."

Unfortunately, for some men, this gene-based compensation may not be enough, he added, rendering them more vulnerable to neuronal dysfunction and Parkinson's.

One expert said the finding is exciting, but needs to be replicated in human studies.

"Clearly, this animal study should lead to human investigation," said Paul Sanberg, director of the University of South Florida's Center for Aging and Brain Repair in Tampa.

Sanberg noted, however, that "rat studies have been predictive of how to develop treatments for Parkinson's disease. This allows one to start studying this gene in post-mortem Parkinson's brains, to see if it's related."

In fact, Vilain said his team is already doing just that -- comparing Sry levels in the brains of people who died of Parkinson's to samples from individuals who died of other causes.

Vilain stressed this research is still in the discovery stage, and much of it remains speculative.

And while it's tempting to think about a gene-based "fix" for Parkinson's, "treatments are a long way off," he said.

Still, the Los Angeles researcher said he was "excited" by the discovery -- the first time that a gene has been found to have gender-specific activity in the brain.

Vilain also noted that other brain areas contain dopamine-secreting neurons.

"These areas have functions other than motor behavior," he said. "They can affect some psychiatric disorders like schizophrenia, for example. It's pure speculation right now, but that's another area we'd like to explore."

More information

For more on Parkinson's disease, head to the Parkinson's Disease Foundation.