Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
Department of Biochemistry, University of Oxford, Parks Road, Oxford, OX1 3QU, UK.
Mol Neurobiol. 2019 Mar;56(3):1558-1577. doi: 10.1007/s12035-018-1174-x. Epub 2018 Jun 15.
Glucose metabolism is essential for the brain: it not only provides the required energy for cellular function and communication but also participates in balancing the levels of oxidative stress in neurons. Defects in glucose metabolism have been described in neurodegenerative disease; however, it remains unclear how this fundamental process contributes to neuronal cell death in these disorders. Here, we investigated the molecular mechanisms driving the selective neurodegeneration in an ataxic mouse model lacking oxidation resistance 1 (Oxr1) and discovered an unexpected function for this protein as a regulator of the glycolytic enzyme, glucose-6-phosphate isomerase (GPI/Gpi1). Initially, we present a dysregulation of metabolites of glucose metabolism at the pre-symptomatic stage in the Oxr1 knockout cerebellum. We then demonstrate that Oxr1 and Gpi1 physically and functionally interact and that the level of Gpi1 oligomerisation is disrupted when Oxr1 is deleted in vivo. Furthermore, we show that Oxr1 modulates the additional and less well-understood roles of Gpi1 as a cytokine and neuroprotective factor. Overall, our data identify a new molecular function for Oxr1, establishing this protein as important player in neuronal survival, regulating both oxidative stress and glucose metabolism in the brain.
它不仅为细胞功能和通讯提供所需的能量，还参与平衡神经元中的氧化应激水平。在神经退行性疾病中已经描述了葡萄糖代谢的缺陷；然而，目前尚不清楚这个基本过程如何导致这些疾病中的神经元细胞死亡。在这里，我们研究了在缺乏氧化还原酶 1（Oxr1）的共济失调小鼠模型中驱动选择性神经退行性变的分子机制，并发现了这种蛋白质作为糖酵解酶葡萄糖-6-磷酸异构酶（GPI/Gpi1）调节剂的意外功能。最初，我们在 Oxr1 敲除小脑的前症状阶段呈现葡萄糖代谢代谢物的失调。然后，我们证明 Oxr1 和 Gpi1 物理和功能相互作用，并且当 Oxr1 在体内缺失时，Gpi1 寡聚化的水平被破坏。此外，我们表明 Oxr1 调节 Gpi1 作为细胞因子和神经保护因子的其他和不太为人了解的作用。总的来说，我们的数据确定了 Oxr1 的一个新的分子功能，将这种蛋白质确立为神经元存活的重要参与者，调节大脑中的氧化应激和葡萄糖代谢。
