Department of Cell Biology and Physiology, University of New Mexico - Health Sciences Center, Albuquerque, New Mexico, USA.
J Neurochem. 2019 Feb;148(3):426-439. doi: 10.1111/jnc.14604. Epub 2018 Dec 3.
Glutathione peroxidase 4 (GPx4) is the only enzyme capable of reducing toxic lipid hydroperoxides in biological membranes to the corresponding alcohols using glutathione as the electron donor. GPx4 is the major inhibitor of ferroptosis, a non-apoptotic and iron-dependent programmed cell death pathway, which has been shown to occur in various neurological disorders with severe oxidative stress. In this study, we investigate whether GPx4 expression is altered in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). The results clearly show that mRNA expression for all three GPx4 isoforms (cytoplasmic, mitochondrial and nuclear) decline in multiple sclerosis gray matter and in the spinal cord of MOG peptide-induced EAE. The amount of GPx4 protein is also reduced in EAE, albeit not in all cells. Neuronal GPx4 immunostaining, mostly cytoplasmic, is lower in EAE spinal cords than in control spinal cords, while oligodendrocyte GPx4 immunostaining, mainly nuclear, is unaltered. Neither control nor EAE astrocytes and microglia cells show GPx4 labeling. In addition to GPx4, two other negative modulators of ferroptosis (γ-glutamylcysteine ligase and cysteine/glutamate antiporter), which are critical to maintain physiological levels of glutathione, are diminished in EAE. The decrease in the ability to eliminate hydroperoxides was also evidenced by the accumulation of lipid peroxidation products and the reduction in the proportion of the docosahexaenoic acid in non-myelin lipids. These findings, along with presence of abnormal neuronal mitochondria morphology, which includes an irregular matrix, disrupted outer membrane and reduced/absent cristae, are consistent with the occurrence of ferroptotic damage in inflammatory demyelinating disorders.
谷胱甘肽过氧化物酶 4（GPx4）是唯一能够利用谷胱甘肽作为电子供体将生物膜中有毒的脂质过氧化物还原为相应醇的酶。GPx4 是铁依赖性细胞程序性死亡途径（ferroptosis）的主要抑制剂，这种死亡途径是非凋亡性的，已经在具有严重氧化应激的各种神经紊乱中显现。在这项研究中，我们调查了谷胱甘肽过氧化物酶 4（GPx4）的表达是否在多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎（EAE）中发生改变。结果清楚地表明，在多发性硬化症灰质和髓鞘碱性蛋白诱导的 EAE 脊髓中，所有三种 GPx4 同工型（细胞质、线粒体和核）的 mRNA 表达均下降。EAE 中 GPx4 蛋白的含量也减少了，尽管不是在所有细胞中。EAE 脊髓中的神经元 GPx4 免疫染色，主要是细胞质，比对照脊髓中的染色少，而少突胶质细胞 GPx4 免疫染色，主要是核，不变。对照和 EAE 星形胶质细胞和小胶质细胞均无 GPx4 标记。除了 GPx4 之外，两种其他的铁死亡负调节剂（γ-谷氨酰半胱氨酸连接酶和半胱氨酸/谷氨酸反向转运体），它们对维持谷胱甘肽的生理水平至关重要，在 EAE 中也减少了。通过脂质过氧化产物的积累和二十二碳六烯酸在非髓鞘脂质中的比例减少，也证明了消除过氧化物的能力下降。这些发现，以及异常神经元线粒体形态的存在，包括不规则的基质、外膜破坏和嵴减少/缺失，与炎症性脱髓鞘疾病中发生的铁死亡损伤一致。
