VGLUT2 function in dopamine neuron vulnerability

Parkinsons disease (PD) is the second most common neurodegenerative disorder after Alzheimers disease. It affects approximately 1% in people older than 60 and around 4% in people older than 80 years of age. As a result of population aging the global burden of PD has more than doubled within the last 30 years, and it is expected that the number of patients suffering from PD will increase by another 40-50% over the next 20-30 years. The cardinal symptoms of PD include slowness of movement, muscle rigidity and a resting tremor, symptoms that usually present in a persons 50s to 60s, but patients also display numerous non-motor symptoms such as sleep disturbances, depression or cognitive deficits. The motor symptoms of PD are caused primarily by the decline of nerve cells producing the neurotransmitter dopamine (DA) though many other cell populations in the brain are also affected. Interestingly, not all DA-producing neurons are equally affected by degeneration, but some are more vulnerable than others. These differences in DA neuron susceptibility have been observed in human PD and animal models, but the mechanisms accounting for selective vulnerability remain unknown. We previously determined that a subset of DA neurons express a protein called VGLUT2 (vesicular glutamate transporter 2), which allows DA neurons to store and release the neurotransmitter glutamate. Hence, these neurons can store and release two transmitters, namely DA and glutamate. We also found that the expression of VGLUT2 in DA neurons is protective to cells under conditions of neuronal injury such as in animal models and human PD; however, if VGLUT2 levels in DA neurons become too high, VGLUT2 gains toxic properties and causes DA neurodegeneration. This suggests that DA neurons need to tightly balance VGLUT2 expression levels. Using a combination of mouse genetics, molecular, biochemical, physiological and human postmortem pathology approaches we will test how aging and sex affect VGLUT2 expression and DA neuron survival in PD; and we will determine molecular mechanisms how VGLUT2 can confer either protection or toxicity to DA neurons. Our main goal is to further our understanding of selective vulnerability and DA neurodegeneration during normal aging and in PD and to test whether VGLUT2 modifying gene therapies may alleviate PD pathology.