Novel roles of VGLUT in sex differences in dopamine neuron vulnerability to environmental toxicant-induced neurodegeneration

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PROJECT SUMMARY Exposure to environmental toxicants including pesticides causes dopamine (DA) neuron loss in the substantia nigra (SN) and raises risk for developing Parkinson’s disease (PD). Toxicant exposure studies show sexually dimorphic DA neuron resilience, such that females lose fewer DA neurons than males. This sex difference is relevant since PD in women is less prevalent and has a later age of symptomatic onset. However, the mechanisms for these sex differences in DA neuron resilience to toxicants remain poorly understood. We have leveraged the respective advantages of fly and rodent models of DA neurodegeneration to provide new insights into toxicants’ effects on selective DA neuron resilience, which we have translated to human postmortem brain tissue from PD patients. We identified the vesicular glutamate transporter VGLUT2 in mammals and its Drosophila ortholog dVGLUT as modulators of sex differences in DA neuron resilience. We find: 1) dVGLUT/VGLUT2+ DA neurons are likelier to survive insults versus DA neurons that do not express the transporter; 2) Conditional dVGLUT/VGLUT2 knockout in DA neurons increases vulnerability to insults; and 3) dVGLUT/VGLUT2 expression is upregulated in surviving DA neurons in response to PD-linked insults including aging, misfolded a-synuclein, and neurotoxins. Furthermore, we discovered females express more dVGLUT/VGLUT2 in DA neurons compared to males – a finding conserved across flies, rodents and humans that may explain the sex differences in PD. Yet, whether sex differences in DA neuron VGLUT2 expression contribute to resilience to environmental toxicants like rotenone and paraquat remains unknown. Thus, we hypothesize DA neuron dVGLUT/VGLUT2 expression is part of a conserved, sexually dimorphic neuroprotective response to DA neuron injury by environmental toxicants in PD. To test our hypothesis, we developed comparative approaches across flies, rodents and postmortem human brain, along with new genetic and imaging tools, to determine whether VGLUT2 modulates sex differences in DA neuron resilience to the pesticide rotenone (Aim 1). We will also determine the mechanisms for dVGLUT- and VGLUT2-mediated resilience to pesticides in males and females (Aim 2). Lastly, we will determine DA neuron VGLUT2 expression in brains of male and female PD patients, including in brains of subjects with known exposure to the pesticide heptachlor (Aim 3). Identifying VGLUT2’s roles in sex differences in DA neuron resilience as a result of environmental toxicant exposure may provide new insights into PD. Moreover, determining the mechanisms of increased DA neuron resilience in females can be transferred to males to boost DA neuron survival in PD. This may ultimately lead to new, effective treatments to either slow or stop PD neurodegeneration in both men and women.