Stykel Morgan G, Siripala Shehani V, Soubeyrand Eric, Coackley Carla L, Lu Ping, Camargo Suelen, Thevasenan Sharanya, Figueroa Gerardo Balderas, So Raphaella W L, Stuart Erica, Panchal Rachi, Akrioti Elissavet-Kalliopi, Joseph Jeffery T, Haji-Ghassemi Omid, Taoufik Era, Akhtar Tariq A, Watts Joel C, Ryan Scott D
Department of Molecular and Cellular Biology, The University of Guelph, Guelph ON, Canada.
Department of Molecular and Cellular Biology, The University of Guelph, Guelph ON, Canada; Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada.
Cell Rep. 2025 Jan 28;44(1):115178. doi: 10.1016/j.celrep.2024.115178. Epub 2025 Jan 7.
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.
帕金森病（PD）中多巴胺能神经元的丧失之前会出现突触多巴胺（DA）的丧失和蛋白质聚集体的积累。将这些缺陷联系起来对于恢复PD中的DA信号传导至关重要。利用PD的小鼠和人类多能干细胞（hPSC）模型以及人类尸检组织，我们发现α-突触核蛋白微聚集体的积累会损害通过磷酸戊糖途径（PPP）的代谢通量。这导致烟酰胺腺嘌呤二核苷酸磷酸（NADP/H）和谷胱甘肽（GSH）水平降低，从而导致DA氧化和总DA水平降低。我们发现α-突触核蛋白通过α-突触核蛋白C末端将PPP酶G6PD锚定到突触小泡上，并且这种相互作用在PD中丧失。此外，G6PD临床突变与PD诊断相关，并且G6PD缺失模拟了PD病理。最后，我们表明通过基因和药物干预恢复NADPH或GSH水平可阻断DA氧化并挽救稳态DA水平，将G6PD确定为抗PD的药物靶点。
