Ferroptosis Mediates Cuprizone-Induced Loss of Oligodendrocytes and Demyelination
Ferroptosis Mediates Cuprizone-Induced Loss of Oligodendrocytes and Demyelination
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DOI：
10.1523/jneurosci.1749-20.2020
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发表时间：
2020-11-25
影响因子：
5.3
通讯作者：
David, Samuel
中科院分区：
文献类型：
--
作者：
Jhelum, Priya;Santos-Nogueira, Eva;David, Samuel
多发性硬化(MS)是一种慢性中枢神经系统脱髓鞘疾病。铜络合剂(CZ)是一种铜络合剂，被广泛用于研究中枢神经系统的脱髓鞘和再髓鞘形成，但在MS的背景下，导致少突胶质细胞(OL)细胞丢失和脱髓鞘的机制尚不清楚。由于含铜酶在铁稳态和控制氧化应激中发挥重要作用，我们研究了螯合铜是否会导致参与铁稳态的分子被破坏，从而触发铁介导的OL丢失。我们发现，在饮食中给予小鼠(雄性)CZ会在2天后导致胼胝体中OL的迅速丧失，并伴随着铁下垂的几个标记物的表达，铁下垂是一种相对较新的铁介导的细胞死亡形式。在铁性下垂中，铁介导的自由基在谷胱甘肽不足的情况下触发脂质过氧化，并降低修复脂质损伤的能力。使用铁下垂的小分子抑制剂进一步证实了这一点，该抑制剂可以防止CZ诱导的OL丢失和脱髓鞘，为CZ诱导的神经毒性中铜-铁联系提供了明确的证据。这项工作对多发性硬化症和中枢神经系统损伤等疾病具有更广泛的影响。
Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS. Cuprizone (CZ), a copper chelator, is widely used to study demyelination and remyelination in the CNS, in the context of MS. However, the mechanisms underlying oligodendrocyte (OL) cell loss and demyelination are not known. As copper-containing enzymes play important roles in iron homeostasis and controlling oxidative stress, we examined whether chelating copper leads to disruption of molecules involved in iron homeostasis that can trigger iron-mediated OL loss. We show that giving mice (male) CZ in the diet induces rapid loss of OL in the corpus callosum by 2 d, accompanied by expression of several markers for ferroptosis, a relatively newly described form of iron-mediated cell death. In ferroptosis, iron-mediated free radicals trigger lipid peroxidation under conditions of glutathione insufficiency, and a reduced capacity to repair lipid damage. This was further confirmed using a small-molecule inhibitor of ferroptosis that prevents CZ-induced loss of OL and demyelination, providing clear evidence of a copper-iron connection in CZ-induced neurotoxicity. This work has wider implications for disorders, such as multiple sclerosis and CNS injury.