Protein linked to sex differences in age-related loss of dopaminergic neurons – sciencedaily

It is not every day that scientists encounter a phenomenon so fundamental that it is observed through fruit flies, rodents and humans.

In an article published today in Aging cell, neuroscientists from the University of Pittsburgh’s Schools of Health Sciences have found that a single protein – a glutamate transporter on the membrane of vesicles that carry dopamine into neurons – is essential for regulating sex differences in the body. vulnerability of the brain to age-related loss of neurons. .

The protein – named VGLUT – was more abundant in dopaminergic neurons in female fruit flies, rodents, and humans than in males, corresponding to women’s greater resilience to neuron loss and mobility impairments. age-related, the researchers found. Excitingly, the genetic reduction in VGLUT levels in female flies decreased their protection against aging-associated neurodegeneration, suggesting that VGLUT may be a new target for prolonging the resilience of dopaminergic neurons and delaying the onset of symptoms of aging. in the brain.

“From flies to rodents to humans, we’ve found that VGLUT levels distinguish males from females during healthy aging,” said senior author Zachary Freyberg, MD, Ph.D., professor. assistant of psychiatry and cell biology at Pitt. “The fact that this marker of dopaminergic neuron survival is conserved throughout the animal kingdom suggests that we are examining a fundamental element of biology. Understanding how this mechanism works can help prolong the resilience of dopaminergic neurons and delay aging.

Neurodegenerative disorders such as Parkinson’s disease are more likely to develop with age. Parkinson’s disease – a slow but relentless loss of dopaminergic neurons in the brain that impairs the ability to move or speak – is known to primarily affect men. But while biological differences between the sexes, which result from a combination of hormonal, genetic and environmental influences, seem to explain why women are protected from the early stages of Parkinson’s disease, the engine and regulator of these protections was , so far unknown.

Using a combination of biochemical and genetic techniques, as well as behavioral studies where the locomotion of the flies was monitored over a 24-hour period, the researchers found that the age-related benefits granted to females wore off as levels of VGLUT gene expression were significantly reduced in dopamine. neurons.

“We have found that VGLUT expression increases with age and that flies become more vulnerable to degeneration of dopaminergic neurons when we knock down VGLUT,” said lead author Silas Buck, PhD. candidate at the Pitt Center for Neuroscience. “We also found that VGLUT expression is higher in women than in men, suggesting that VGLUT may play a role in regulating sex differences in vulnerability to neurodegeneration in Parkinson’s disease and other neurological disorders where women are more resilient than men. “

As rates of Parkinson’s disease rise rapidly – the number of people affected by the disease worldwide is expected to reach 20 million by 2040 – scientists at Pitt hope to deepen the role of VGLUT in neuroprotection in humans.

“We are entering an epidemic of Parkinson’s disease and we need to figure out how to make our neurons more resilient,” Freyberg said. “VGLUT is an exciting new target that is essential not only for understanding the fundamental biology at the heart of dopaminergic neuron survival, but also for developing new therapies.”

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