VGLUT2 Protein May Protect Neurons From Disease-related Degeneration

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A protein involved in the transport of brain signaling molecules may confer protection against neurodegeneration in Parkinson’s disease, a study shows.

This transport protein, called vesicular glutamate transporter 2 (VGLUT2), is associated with greater resilience to the toxic effects of alpha-synuclein clumps in dopamine-producing neurons, preventing their death. Dopamine is a major brain signaling molecule (neurotransmitter), and dopamine-producing, or dopaminergic, neurons are the cells progressively lost in people with Parkinson’s.

Data also showed that surviving dopaminergic neurons in patients were more likely to be positive for VGLUT2.

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These findings augment previous research showing that VGLUT2 protects against age-related neurodegeneration, including in Parkinson’s, and suggest that it may be a potential therapeutic target for the disease, the researchers noted.

The study, “Dopamine neurons exhibit emergent glutamatergic identity in Parkinson’s disease,” was published in the journal Brain.

Parkinson’s is characterized by the gradual loss of dopaminergic neurons in the substantia nigra, a brain region that controls voluntary movement. Dopamine deficiency causes the disease’s hallmark motor symptoms.

Also, as the disease progresses, the drop in dopamine levels affects other neurotransmitters, including glutamate, the brain’s major excitatory neurotransmitter.

Dopaminergic neuron death is thought to be triggered mainly by the toxic buildup of alpha-synuclein, a protein abundant in the brain that’s believed to help regulate nerve cell function and communication.

However, not all dopaminergic neurons are “equally vulnerable and a better understanding of the cell-type specific properties relating to selective [neurodegeneration] is needed,” the researchers wrote.

Vesicular glutamate transporters — including three functionally similar proteins (VGLUT1, VGLUT2, and VGLUT3) — are mainly responsible for uploading glutamate into vesicles that release their content at the point of contact between neurons, thereby promoting nerve cell communication.

VGLUTs have also been shown to facilitate the packaging and release of other neurotransmitters, including dopamine.

Previous studies highlighted that VGLUT2 is commonly found in a subpopulation of dopaminergic neurons known to be more resistant to age-related and Parkinson’s-related neurodegeneration.

Also, evidence suggests that surviving dopaminergic neurons can increase VGLUT2 levels “as part of a compensatory response to acute toxic insult,” while VGLUT2 suppression in dopaminergic neurons was shown to increase their vulnerability to neurotoxins, the researchers wrote.

While these data suggest that VGLUT2 contributes to these cells’ resilience against neurodegeneration, there is limited evidence on its role when cells are exposed to Parkinson’s-related toxic insults.

To address this, a team of researchers in the U.S. analyzed the survival of VGLUT2-positive and VGLUT2-negative dopaminergic neurons when exposed to neurotoxins and to toxic alpha-synuclein accumulation in mice.

Results showed that brain injection of neurotoxins known to promote dopaminergic neuron death resulted in a significant loss of VGLUT2-negative dopaminergic neurons, while the number of those positive for VGLUT2 was unchanged.

Similar responses were observed at three and six months after injecting the mice’s brain with toxic forms of alpha-synuclein, and VGLUT2 levels were found also to be increased in VGLUT2-positive dopaminergic neurons.

In another model of alpha-synuclein-related stress, the induced production of an alpha-synuclein mutated form associated with familial Parkinson’s did not result in dopaminergic neuron death after three months, but the number of neurons positive for VGLUT2 was significantly increased.

These findings suggest that VGLUT2-positive dopaminergic neurons are more resilient to degeneration and that VGLUT2 production is increased in response to alpha-synuclein-related stress.

To assess whether this was also true in Parkinson’s, the team analyzed the substantia nigra of deceased Parkinson’s patients and age-matched people without a neurodegenerative condition related to alpha-synuclein (used as controls).

Similar to what was found in mice, VGLUT2-negative dopaminergic neurons were significantly reduced in Parkinson’s patients relative to controls, while no difference was detected in terms of neurons positive for VGLUT2.

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In addition, while Parkinson’s patients showed significantly fewer dopaminergic neurons in substantia nigra than controls, they had a significantly higher proportion of VGLUT2-positive dopaminergic neurons.

These results “provide a direct link between VGLUT2 [levels] and DA [dopaminergic] neuron resilience in human Parkinson’s disease,” in which the increased transport of glutamate, and potentially of dopamine, “may be part of a neuroprotective response in Parkinson’s disease,” the researchers wrote.

Given that VGLUT2 levels were previously shown to be finely tuned — with both drops and raises resulting in toxic effects to dopaminergic neurons — “therapeutic strategies that [boost] VGLUT2 function … without increasing [its levels] may prove fruitful in preventing DA neuron loss in Parkinson’s disease,” they added.