According to one study, levels of a protein involved in transporting brain signaling molecules in dopamine-producing neurons appear to be gender-specific – higher in female than in male animal models and human cells – and appear to protect against age-related neurodegeneration.
Given that older age and males are risk factors for Parkinson’s disease, these results provide insights into the underlying mechanisms of gender susceptibility to Parkinson’s and point to this protein – known as the vesicular glutamate transporter, or VGLUT – as a potential treatment target .
“We’re entering a Parkinson’s epidemic and we need to understand how to make our neurons more resilient,” said Dr. Zachary Freyberg, senior study’s lead author and assistant professor of psychiatry and cell biology at the University of Pittsburgh Schools of Health Sciences, said in a university news release.
“From flies to rodents to humans, we’ve found that VGLUT levels differentiate men from women during healthy aging,” Freyberg said, adding that preservation of this trait throughout the animal kingdom “suggests that we are familiar with deal with a basic piece of biology. “
The study, “The vesicular glutamate transporter modulates the gender differences in the susceptibility of dopamine neurons to age-related neurodegeneration, ”Was published in Aging Cell magazine.
Parkinson’s is characterized by the progressive loss of dopaminergic neurons, or nerve cells, that produce an important brain signaling molecule (neurotransmitter) called dopamine. While advancing age is the biggest risk factor for Parkinson’s, men are at higher risk than women of developing neurodegenerative diseases.
However, the molecular actors behind these gender and age-related differences in susceptibility to Parkinson’s remain largely unclear.
Freyberg and his team, together with colleagues from other US and Swiss institutions, found that changes in VGLUT levels can contribute to gender-specific differences in the susceptibility of dopaminergic neurons to age-related neurodegeneration.
VGLUT is a transporter protein primarily responsible for uploading glutamate, a neurotransmitter, into vesicles, which release their contents at the point of contact between neurons, thus promoting communication between nerve cells and nerve cells. Growing evidence also shows that VGLUT helps promote the packaging and release of other neurotransmitters, including dopamine.
In particular, previous studies have shown that this transporter is often found in a subpopulation of dopaminergic neurons that are known to be more resistant to degeneration.
Therefore, researchers assessed changes in VGLUT levels of dopaminergic neurons between sexes and with age in fruit flies (Drosophila melanogaster), a model that is often used to better understand neurodevelopmental disorders and neurodegenerative diseases in humans.
The results showed that VLGUT levels increased with age and were significantly higher in women than in men – with both the number of dopaminergic neurons and mobility decreasing significantly more with increasing age.
Blocking VLGUT production in dopaminergic neurons also increased the likelihood of cells dying, including in female mice, thereby minimizing gender differences in susceptibility to age-related loss of dopaminergic neurons.
This indicated that age-related increases in VGLUT “could be a potential compensation mechanism for decreased VGLUT [dopamine] Neurotransmission During Aging, ”the researchers wrote.
“We found that VGLUT expression increases with age and that flies become more prone to dopamine neuron degeneration when we do [suppress] VGLUT “, said Silas Buck, the first author of the study and doctoral student in Freyberg’s laboratory.
It is important that a connection between higher VGLUT levels and female sex was also observed in human and mouse dopaminergic neurons, “which indicates a highly conserved VGLUT-dependent mechanism that underlies these sex-dependent effects on DA [dopaminergic] Neural Susceptibility “to age-related neurodegeneration, the team added.
While increasing VGLUT levels in dopaminergic neurons seemed like a straightforward approach to increasing neuron resilience and survival, further analysis in mice found that VGLUT production needs to be fine-tuned as promoting extremely high levels of the Neurotransmitter transporters could not protect cells from neurodegeneration.
“Our data therefore suggest that DA neurons need a finely tuned balance of [VGLUT] Expression to increase resilience; Disturbance of this balance either over [suppression] or by high levels of [overproduction] Instead, it increases the susceptibility of DA neurons to insult, ”the researchers wrote.
“Our results show gender-specific differences in the susceptibility of DA neurons to age-related neurodegeneration,” the researchers concluded, adding that the increase in VGLUT with age “is neuroprotective and a critical factor in the greater resilience of DA neurons and the musculoskeletal system in women. “
Understanding how this mechanism works can help lengthen [dopaminergic] Neuron resilience and delaying aging, ”said Freyberg.
“VGLUT is an enticing new target that will not only help understand the basic biology of dopamine neuron survival, but ultimately also help develop 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 gender-specific VGLUT differences that could provide new therapeutic targets for reducing age and Parkinson’s dependence neurodegeneration .
Marta Figueiredo holds a Masters in Evolution and Developmental Biology and a PhD in Biomedical Sciences from the University of Lisbon, Portugal. Her research focuses on the role of multiple signaling pathways in embryonic development of the thymus and parathyroid glands.
Total posts: 208
Ana received her PhD in Immunology from the University of Lisbon and worked as a postdoctoral fellow at the Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She holds a BSc in Genetics from the University of Newcastle and a Masters in Biomolecular Archeology from the University of Manchester, England. After leaving the lab to pursue a career in science communication, she was director of science communication at iMM.