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

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-01-28 Epub Date: 2025-01-07 DOI:10.1016/j.celrep.2024.115178

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

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引用次数: 0

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.

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G6PD缺乏症触发多巴胺丢失，启动帕金森病发病机制。

帕金森氏病（PD）中多巴胺能神经元的丧失先于突触多巴胺（DA）的丧失和蛋白质聚集体的积累。连接这些缺陷对于恢复PD中的DA信号至关重要。通过小鼠和人多能干细胞（hPSC）模型与人死后组织结合，我们发现α-syn微聚集体的积累会通过戊糖磷酸途径（PPP）损害代谢通量。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，导致DA氧化和总DA水平降低。我们发现α-syn通过α-syn C端将PPP酶G6PD锚定在突触囊泡上，而这种相互作用在PD中丢失。此外，G6PD临床突变与PD诊断相关，G6PD缺失表型与PD病理相关。最后，我们发现通过遗传和药物干预恢复NADPH或GSH水平可以阻断DA氧化并恢复稳态DA水平，从而确定G6PD是对抗PD的药理学靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.