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

doi:10.1016/j.celrep.2024.115178

G6PD deficiency triggers dopamine loss and the initiation of Parkinson's disease pathogenesis

Cell Rep. 2025 Jan 7;44(1):115178. doi: 10.1016/j.celrep.2024.115178. Online ahead of print.

Authors

Morgan G Stykel¹, Shehani V Siripala², Eric Soubeyrand¹, Carla L Coackley¹, Ping Lu³, Suelen Camargo³, Sharanya Thevasenan³, Gerardo Balderas Figueroa³, Raphaella W L So⁴, Erica Stuart⁴, Rachi Panchal⁵, Elissavet-Kalliopi Akrioti⁶, Jeffery T Joseph⁷, Omid Haji-Ghassemi⁸, Era Taoufik⁶, Tariq A Akhtar¹, Joel C Watts⁴, Scott D Ryan⁹

Affiliations

¹ Department of Molecular and Cellular Biology, The University of Guelph, Guelph ON, Canada.
² Department of Molecular and Cellular Biology, The University of Guelph, Guelph ON, Canada; Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada.
³ Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada.
⁴ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
⁵ Biological Sciences, Hellenic Pasteur Institute, Athens, Greece.
⁶ Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece.
⁷ Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada.
⁸ Department of Biological Sciences, University of Calgary, Calgary, AB, Canada.
⁹ Department of Molecular and Cellular Biology, The University of Guelph, Guelph ON, Canada; Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada. Electronic address: [email protected].

PMID: 39772392
DOI: 10.1016/j.celrep.2024.115178

Abstract

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.

Keywords: CP: Neuroscience; G6PD; Parkinson's disease; alpha-synuclein; dopamine; hiPSC; oxidative stress.