One of the enduring mysteries of Parkinson’s disease is why it disproportionately affects men. The debilitating neurodegenerative disorder is observed far more often in men than in women—perhaps twice as often—and generally begins at an earlier age in men.

Recent findings from Pitt scientists suggest a potential explanation, opening new possibilities for understanding and treating Parkinson’s and other aging-related brain disorders.

In a paper published in Aging Cell, Zachary Freyberg, assistant professor of psychiatry and cell biology, and Silas Buck, PhD candidate in Pitt’s Center for Neuroscience, examine the role that vesicular glutamate transporters (VGLUT) play in neurodegeneration.

VGLUT is a protein that helps move glutamate, a chemical that plays a vital role in maintaining normal brain function.

The team found VGLUT in greater abundance in females. To explore a possible link between VGLUT and females’ greater resilience to aging-related neurodegeneration, researchers used genetic tools to remove VGLUT from female Drosophila flies. With just a 60- to 90-day lifespan, the flies are handy for observing the effects of aging.

Monitoring the male and female flies as they aged, researchers found something incredible.

“Females ordinarily were protected” from losing dopamine neurons and locomotion, says Freyberg. But with VGLUT removed, these measures deteriorated in the females at the same rate they did in males, an outcome he describes as “shocking.”

The research offers hope, Freyberg says, that VGLUT could be an important target for future therapies treating Parkinson’s and other aging-related brain disorders. More broadly, the findings contribute to an ongoing effort in the scientific community to factor sex differences into understanding the human body and the diseases that challenge it.

“By understanding what makes men and women different biologically, we can find the factors that provide women greater survival benefits and apply them to more vulnerable men and women,” says Buck. “And everyone benefits.”

Freyberg described his investigations in flies to a colleague, Thomas Hnasko of the University of California, San Diego (a coauthor on the Aging Cell paper), and was surprised to learn that Hnasko had observed the same phenomenon in work with rodents.

To determine whether VGLUT was at work in humans, as well, the team worked with Pitt’s NIH-sponsored NeuroBioBank and David Lewis, Jill Glausier and Kenneth Fish. Examining postmortem brains, they found that VGLUT was, indeed, in greater abundance in females than it was in males.

Though encouraged by the findings, the team says there is still much work to be done in deepening our understanding of VGLUT.

“It’s still possible that it’s not VGLUT driving these differences, that it’s just a marker of something else,” says Buck.

Freyberg adds, “The next step is to understand what controls VGLUT expression itself. What is it about VGLUT that increases survival?”

Buck will focus on the protein over the remainder of his PhD studies, trying to unlock the mechanism of how VGLUT offers protection against aging-related degeneration.

What makes Parkinson’s disease so devastating, Freyberg says, is that existing therapies address only its symptoms.

“But nothing stops the pathology,” he says. “So if you can prevent the cells from dying in the first place, you can slow the progression or even stop it. That’s something that’s absolutely new and important, and that will help everyone. And then that becomes a game-changer.”