RESUMO
Parkinson's disease (PD) targets some dopamine (DA) neurons more than others. Sex differences offer insights, with females more protected from DA neurodegeneration. The mammalian vesicular glutamate transporter VGLUT2 and Drosophila ortholog dVGLUT have been implicated as modulators of DA neuron resilience. However, the mechanisms by which VGLUT2/dVGLUT protects DA neurons remain unknown. We discovered DA neuron dVGLUT knockdown increased mitochondrial reactive oxygen species in a sexually dimorphic manner in response to depolarization or paraquat-induced stress, males being especially affected. DA neuron dVGLUT also reduced ATP biosynthetic burden during depolarization. RNA sequencing of VGLUT+ DA neurons in mice and flies identified candidate genes that we functionally screened to further dissect VGLUT-mediated DA neuron resilience across PD models. We discovered transcription factors modulating dVGLUT-dependent DA neuroprotection and identified dj-1ß as a regulator of sex-specific DA neuron dVGLUT expression. Overall, VGLUT protects DA neurons from PD-associated degeneration by maintaining mitochondrial health.
RESUMO
Growing evidence has established that a subset of dopamine (DA) neurons co-release glutamate and express vesicular glutamate transporter 2 (VGLUT2). VGLUT2 expression in DA neurons plays a key role in selective vulnerability to DA neurodegeneration in Parkinson's disease (PD). In this review, we summarize recent findings on impacts of VGLUT2 expression and glutamate co-release from DA neurons on selective DA neuron vulnerability. We present evidence that DA neuron VGLUT2 expression may be neuroprotective, boosting DA neuron resilience in the context of ongoing neurodegenerative processes in PD. We highlight genetic and pesticide models of PD that have provided mechanistic insights into selective DA neuron vulnerability. Finally, we discuss potential neuroprotective mechanisms, focusing on roles of VGLUT2 and glutamate in promoting mitochondrial health and diminishing oxidative stress and excitotoxicity. Elucidating these mechanisms may ultimately lead to more effective treatments to boost DA neuron resilience that can slow or even prevent DA neurodegeneration.