Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration
Author:
Buck Silas A.ORCID, Rubin Sophie A., Kunkhyen Tenzin, Treiber Christoph D.ORCID, Xue XiangningORCID, Fenno Lief E.ORCID, Mabry Samuel J.ORCID, Sundar Varun R., Yang Zilu, Shah Divia, Ketchesin Kyle D.ORCID, Becker-Krail Darius D.ORCID, Vasylieva IaroslavnaORCID, Smith Megan C., Weisel Florian J.ORCID, Wang Wenjia, Erickson-Oberg M. Quincy, O’Leary Emma I.ORCID, Aravind Eshan, Ramakrishnan CharuORCID, Kim Yoon Seok, Wu YanyingORCID, Quick MatthiasORCID, Coleman Jonathan A., MacDonald William A., Elbakri Rania, De Miranda Briana R.ORCID, Palladino Michael J., McCabe Brian D.ORCID, Fish Kenneth N.ORCID, Seney Marianne L., Rayport StephenORCID, Mingote SusanaORCID, Deisseroth KarlORCID, Hnasko Thomas S.ORCID, Awatramani RajeshwarORCID, Watson Alan M.ORCID, Waddell ScottORCID, Cheetham Claire E. J.ORCID, Logan Ryan W.ORCID, Freyberg ZacharyORCID
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.
Publisher
Cold Spring Harbor Laboratory
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