Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration.

ABSTRACT: 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

SUBMITTER: Buck SA 

PROVIDER: S-EPMC10592912 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature