G6PD deficiency triggers dopamine loss and the initiation of Parkinson’s disease pathogenesis
Morgan G. Stykel,
Shehani V. Siripala,
Eric Soubeyrand,
Carla L. Coackley,
Ping Lu,
Suelen Camargo,
Sharanya Thevasenan,
Gerardo Balderas Figueroa,
Raphaella W.L. So,
Erica Stuart,
Rachi Panchal,
Elissavet-Kalliopi Akrioti,
Jeffery T. Joseph,
Omid Haji-Ghassemi,
Era Taoufik,
Tariq A. Akhtar,
Joel C. Watts,
Scott D. Ryan
Affiliations
Morgan G. Stykel
Department of Molecular and Cellular Biology, The University of Guelph, Guelph ON, Canada
Shehani V. Siripala
Department of Molecular and Cellular Biology, The University of Guelph, Guelph ON, Canada; Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada
Eric Soubeyrand
Department of Molecular and Cellular Biology, The University of Guelph, Guelph ON, Canada
Carla L. Coackley
Department of Molecular and Cellular Biology, The University of Guelph, Guelph ON, Canada
Ping Lu
Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada
Suelen Camargo
Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada
Sharanya Thevasenan
Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada
Gerardo Balderas Figueroa
Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada
Raphaella W.L. So
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada
Erica Stuart
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada
Rachi Panchal
Biological Sciences, Hellenic Pasteur Institute, Athens, Greece
Elissavet-Kalliopi Akrioti
Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
Jeffery T. Joseph
Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada
Omid Haji-Ghassemi
Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
Era Taoufik
Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
Tariq A. Akhtar
Department of Molecular and Cellular Biology, The University of Guelph, Guelph ON, Canada
Joel C. Watts
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada
Scott D. Ryan
Department of Molecular and Cellular Biology, The University of Guelph, Guelph ON, Canada; Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada; Corresponding author
Summary: Loss of dopaminergic neurons in Parkinson’s disease (PD) is preceded by loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates. Linking these deficits is critical to restoring DA signaling in PD. Using murine and human pluripotent stem cell (hPSC) models of PD coupled with human postmortem tissue, we show that accumulation of α-syn micro-aggregates impairs metabolic flux through the pentose phosphate pathway (PPP). This leads to decreased nicotinamide adenine dinucleotide phosphate (NADP/H) and glutathione (GSH) levels, resulting in DA oxidation and decreased total DA levels. We find that α-syn anchors the PPP enzyme G6PD to synaptic vesicles via the α-syn C terminus and that this interaction is lost in PD. Furthermore, G6PD clinical mutations are associated with PD diagnosis, and G6PD deletion phenocopies PD pathology. Finally, we show that restoring NADPH or GSH levels through genetic and pharmacological intervention blocks DA oxidation and rescues steady-state DA levels, identifying G6PD as a pharmacological target against PD.
