Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration

Abstract

SummaryParkinson’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 andDrosophilaortholog 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-1β as a regulator of sex-specific DA neuron dVGLUT expression. Overall, VGLUT protects DA neurons from PD-associated degeneration by maintaining mitochondrial health.

Salience signaling and stimulus scaling of ventral tegmental area glutamate neuron subtypes

“…To target VGluT2+VGaT- neurons (nonGABA glutamate neurons), VGluT2::Cre/VGaT::Flp mice were injected in VTA with AAVs encoding GCaMP6m dependent on the expression of Cre and the absence of Flp (AAV8-nEF-Con/Foff-GCaMP6m) (Root et al, 2020). To target VGluT2+/TH+ neurons (glutamate dopamine neurons), VGluT2::Cre/TH::Flp mice were injected in VTA with AAVs encoding GCaMP6m dependent on the expression of Cre and Flp (AAV8-nEF-Con/Fon-GCaMP6m) (Chuhma et al, 2018; Poulin et al, 2018; Mingote et al, 2019; Buck et al, 2023). All mice were implanted with optic fibers dorsal to VTA and food-restricted to promote consumption of reward ( Figure 1 ).…”

Aging disrupts the coordination between mRNA and protein expression in mouse and human midbrain

“…These data suggest that DA and glutamate may be released from different sites within the axons of these neurons, consistent with previous findings 42, 56, 57, 78, 79 . However, we cannot rule out that additional projections from TH + /VGLUT2 + cells which project to extra-striatal sites ( e.g ., frontal cortex and hippocampus) 47, 52, 80 may have greater co-localization of TH and VGLUT2.…”