Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved. To elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). We utilised the SOD1G37R mouse model of ALS and a CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo. We found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from human cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Further, we show the molecular correlation between ferroptosis and neurotoxic astrocytes evident in human ALS-affected spinal cord is recapitulated in the SOD1G37R mouse model where treatment with a CNS-permeant ferroptosis inhibitor, CuII(atsm), ameliorated these markers and was neuroprotective. By showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.

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小胶质细胞铁死亡应激导致非细胞自主神经元死亡

铁死亡是一种受调节的细胞死亡形式，其特征是脂质过氧化作为终点并且需要铁。尽管铁死亡可以预防癌症和感染，但它也与中枢神经系统（CNS）退行性疾病中神经元死亡有关。铁死亡在导致神经元死亡中的确切作用尚未完全解决。为了阐明铁死亡在神经元死亡中的作用，我们利用了涉及小胶质细胞、星形胶质细胞和神经元的共培养和条件培养基转移实验。我们通过评估致命性、瘫痪性肌萎缩侧索硬化症 (ALS) 神经退行性疾病病例中的人类中枢神经系统组织，证实了我们的细胞培养结果的临床意义。我们利用 ALS 的 SOD1G37R 小鼠模型和 CNS 渗透性铁死亡抑制剂来验证体内药理学意义。我们发现，选择性影响小胶质细胞的亚致死性铁死亡应激会引发炎症级联反应，导致非细胞自主神经元死亡。这一级联反应的核心是将星形胶质细胞转变为神经毒性状态。我们发现，人类 ALS 病例的脊髓组织表现出铁死亡的特征，包括原子、分子和生化特征。此外，我们还发现，人类受 ALS 影响的脊髓中明显的铁死亡和神经毒性星形胶质细胞之间的分子相关性在 SOD1G37R 小鼠模型中得到了重现，其中中枢神经系统渗透性铁死亡抑制剂 CuII(atsm) 的治疗改善了这些标记物，并且具有神经保护作用。通过表明小胶质细胞对亚致死铁死亡应激的反应最终导致非细胞自主神经元死亡，我们的结果表明小胶质细胞铁死亡应激是神经退行性疾病中神经元死亡的一个可纠正的原因。由于铁死亡目前主要被认为是一种内在的细胞死亡现象，这些结果为铁死亡在疾病中引入了全新的病理生理学作用。