Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration

Silas A Buck; Sophie A Rubin; Tenzin Kunkhyen; Christoph D Treiber; Xiangning Xue; Lief E Fenno; Samuel J Mabry; Varun R Sundar; Zilu Yang; Divia Shah; Kyle D Ketchesin; Darius D Becker-Krail; Iaroslavna Vasylieva; Megan C Smith; Florian J Weisel; Wenjia Wang; M Quincy Erickson-Oberg; Emma I O'Leary; Eshan Aravind; Charu Ramakrishnan; Yoon Seok Kim; Yanying Wu; Matthias Quick; Jonathan A Coleman; William A MacDonald; Rania Elbakri; Briana R De Miranda; Michael J Palladino; Brian D McCabe; Kenneth N Fish; Marianne L Seney; Stephen Rayport; Susana Mingote; Karl Deisseroth; Thomas S Hnasko; Rajeshwar Awatramani; Alan M Watson; Scott Waddell; Claire E J Cheetham; Ryan W Logan; Zachary Freyberg

doi:10.1101/2023.10.02.560584

Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration

bioRxiv [Preprint]. 2023 Oct 3:2023.10.02.560584. doi: 10.1101/2023.10.02.560584.

Authors

Silas A Buck^{1

2}, Sophie A Rubin¹, Tenzin Kunkhyen³, Christoph D Treiber⁴, Xiangning Xue⁵, Lief E Fenno⁶, Samuel J Mabry¹, Varun R Sundar¹, Zilu Yang¹, Divia Shah¹, Kyle D Ketchesin^{1

2}, Darius D Becker-Krail^{1

2}, Iaroslavna Vasylieva^{7

8}, Megan C Smith^{7

8}, Florian J Weisel⁹, Wenjia Wang⁵, M Quincy Erickson-Oberg^{1

2}, Emma I O'Leary^{1

2}, Eshan Aravind¹, Charu Ramakrishnan¹⁰, Yoon Seok Kim¹⁰, Yanying Wu⁴, Matthias Quick^{11

12}, Jonathan A Coleman¹³, William A MacDonald¹⁴, Rania Elbakri¹⁴, Briana R De Miranda¹⁵, Michael J Palladino^{16

17}, Brian D McCabe¹⁸, Kenneth N Fish¹, Marianne L Seney¹, Stephen Rayport^{11

12}, Susana Mingote^{11

12

19}, Karl Deisseroth^{10

20}, Thomas S Hnasko^{21

22}, Rajeshwar Awatramani²³, Alan M Watson^{7

8}, Scott Waddell⁴, Claire E J Cheetham³, Ryan W Logan^{24

25}, Zachary Freyberg^{1

7}

Affiliations

¹ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
² Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA.
³ Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁴ Centre for Neural Circuits & Behaviour, University of Oxford, Oxford OX1 3TA, UK.
⁵ Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15232, USA.
⁶ Departments of Psychiatry and Neuroscience, The University of Texas at Austin, Austin, TX 78712, USA.
⁷ Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁸ Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁹ Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
¹⁰ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
¹¹ Department of Psychiatry, Columbia University, New York, NY 10032, USA.
¹² Department of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA.
¹³ Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
¹⁴ Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15224, USA.
¹⁵ Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
¹⁶ Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
¹⁷ Pittsburgh Institute of Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15260, USA.
¹⁸ Brain Mind Institute, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
¹⁹ Neuroscience Initiative, Advanced Science Research Center, Graduate Center of The City University of New York, New York, NY 10031, USA.
²⁰ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
²¹ Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
²² Research Service, VA San Diego Healthcare System, San Diego, CA 92161, USA.
²³ Department of Neurology, Northwestern University, Chicago, IL 60611, USA.
²⁴ Department of Psychiatry, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
²⁵ Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.

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 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.

Keywords: Drosophila; Parkinson’s disease; RNAseq; VGLUT2; dVGLUT; dopamine; glutamate; neurodegeneration; paraquat.

Publication types

Preprint

Abstract

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