Transporter Protein May Underlie Sex Differences in Parkinson’s Risk

Levels of a protein involved in the transport of brain signaling molecules in dopamine-producing neurons appear to be sex specific — higher in female than in male animal models and human cells — and to protect against age-related neurodegeneration, a study reported.

Given that older age and male sex are risk factors for Parkinson’s disease, these findings provide insights into the underlying mechanisms of sex-based vulnerability to Parkinson’s, and point to this protein — called vesicular glutamate transporter or VGLUT — as a potential treatment target.

“We are entering an epidemic of Parkinson’s disease, and we need to understand how to make our neurons more resilient,” Zachary Freyberg, MD, PhD, the study’s senior author and an assistant professor of psychiatry and cell biology at the University of Pittsburgh Schools of the Health Sciences, said in a university press release.

“From flies to rodents to human beings, we found that VGLUT levels distinguish males from females during healthy aging,” Freyberg said, adding this feature’s preservation across the animal kingdom “suggests that we are looking at a fundamental piece of biology.”

The study, “Vesicular glutamate transporter modulates sex differences in dopamine neuron vulnerability to age‐related neurodegeneration,” was published in the journal Aging Cell.

Parkinson’s is characterized by the progressive loss of dopaminergic neurons, or nerve cells that produce a major brain signaling molecule (neurotransmitter) called dopamine. While advancing age is the greatest risk factor Parkinson’s, men are also at higher risk than women of developing the neurodegenerative disease.

However, the molecular players behind these sex- and age-related differences in Parkinson’s susceptibility remain largely unclear.

Freyberg and his team, along with colleagues at other U.S. and Swiss institutions, discovered that changes in VGLUT levels may contribute to sex differences in dopaminergic neurons’ vulnerability to age-related neurodegeneration.

VGLUT is a transporter protein mainly responsible for uploading glutamate, a neurotransmitter, into vesicles that release their content at the point of contact between neurons, in this way promoting nerve cell-to-nerve cell communication. Increasing evidence also shows that VGLUT helps to promote the packaging and release of other neurotransmitters, including dopamine.

Notably, previous studies highlighted that this transporter is commonly found in a subpopulation of dopaminergic neurons known to be more resistant to degeneration.

As such, the researchers evaluated changes in dopaminergic neuron VGLUT levels between sexes and with age in fruit flies (Drosophila melanogaster), a model widely used to better understand human neurodevelopmental and neurodegenerative disorders.

Results showed that VLGUT levels rose with age and were significantly higher in females than in males — with significantly greater reductions seen in both dopaminergic neuron numbers and mobility with aging.

Blocking VLGUT production in dopaminergic neurons also made the cells more likely to die, including in female mice, minimizing sex-based differences in susceptibility to age-related dopaminergic neuron loss.

This suggested that age-dependent increases in VGLUT may be “a potential compensatory mechanism for diminished [dopamine] neurotransmission during aging,” the researchers wrote.

“We found that VGLUT expression increases with age, and that flies become more vulnerable to dopamine neuron degeneration when we [suppress] VGLUT,” said Silas Buck, the study’s first author and a PhD student with Freyberg’s lab.

Importantly, an association between higher levels of VGLUT and female sex was also observed among human and mouse dopaminergic neurons, “suggesting a highly conserved VGLUT‐dependent mechanism underlying these sex‐dependent effects on DA [dopaminergic] neuron vulnerability” to age-related neurodegeneration, the team added.

While raising VGLUT levels in dopaminergic neurons appeared to be a straightforward approach to boost neurons’ resilience and survival, further analysis in mice found VGLUT production must be finely tuned, as promoting extremely high levels of the neurotransmitter transporter failed to protect cells against neurodegeneration.

“Our data therefore suggest that DA neurons require a finely tuned balance of [VGLUT] expression to boost resilience; disrupting this balance either via [suppression] or through high levels of [overproduction] instead increases DA neuron vulnerability to insults,” the researchers wrote.

“Our findings demonstrate sex differences in DA neuron vulnerability to age‐related neurodegeneration,” the researchers concluded, adding that increasing VGLUT with age “is neuroprotective and a critical factor for the greater DA neuron and locomotor resilience in females.”

An understanding of how this mechanism works “can help prolong [dopaminergic] neuron resilience and delay aging,” Freyberg said.

“VGLUT is a tantalizing new target that is key to not only understanding the fundamental biology at the core of dopamine neurons’ survival, but ultimately for developing new therapeutics,” he added.

The researchers now plan to define the regulatory mechanisms of VGLUT levels in dopamine-producing neurons and the role of additional factors, including sex hormones, in these sex-based VGLUT differences, which may provide new therapeutic targets to lessen age- and Parkinson’s-dependent neurodegeneration.