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

• DOI: 10.1016/j.celrep.2024.115178
• Publication Date: 2025-01-07T04:09:04Z
• Authors: Morgan G. Stykel; Shehani V. Siripala; Eric Soubeyrand; Carla L. Coackley; Ping Lu; Suelen Camargo; Sharanya Thevasenan; Gerardo Balderas ...; Raphaella W.L. So; Erica Stuart; Rachi Panchal; Elissavet-Kalliop...; Jeffery T. Joseph; Omid Haji-Ghassemi; Era Taoufik; Tariq A. Akhtar; Joel C. Watts; Scott D. Ryan
• Keywords: Phenocopy

Highlights•α-syn binds to and anchors G6PD synaptic vesicles•α-syn fibrilization inhibits function impairs redox homeostasis•Loss of phenocopies Parkinson's disease•Restoration activity rescues dopamine signaling in diseaseSummaryLoss dopaminergic neurons disease (PD) is preceded by loss (DA) accumulation proteinaceous aggregates. Linking these deficits critical restoring DA PD. Using murine human pluripotent stem cell (hPSC) models PD coupled with postmortem tissue, we show that α-syn micro-aggregates metabolic flux through the pentose phosphate pathway (PPP). This leads decreased nicotinamide adenine dinucleotide (NADP/H) glutathione (GSH) levels, resulting oxidation total levels. We find PPP enzyme vesicles via C terminus this interaction lost Furthermore, clinical mutations are associated diagnosis, deletion pathology. Finally, NADPH or GSH levels genetic pharmacological intervention blocks steady-state identifying as a target against PD.Graphical abstract