LUHMES Dopaminergic Neurons Are Uniquely Susceptible to Ferroptosis.
LUHMES Dopaminergic Neurons Are Uniquely Susceptible to Ferroptosis.
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DOI：
10.1007/s12640-022-00538-y
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发表时间：
2022-10
影响因子：
3.7
通讯作者：
Gerhold, David
中科院分区：
文献类型：
--
作者：
Tong, Zhi-Bin;Kim, Hyunhee;El Touny, Lara;Simeonov, Anton;Gerhold, David
铁凋亡是一种由脂质氧化引起的坏死性细胞死亡，可能是帕金森病神经变性的原因。我们评估了三种神经元细胞系是否对铁凋亡的杀伤敏感。铁凋亡诱导剂erastin在亚微摩尔浓度下杀死LUHMES神经元，而来自SH-SY 5 Y细胞或神经干细胞的神经元细胞的敏感性至少低50倍。LUHMES分化的神经元同样对RSL 3或ML 210的杀伤敏感，RSL 3或ML 210是谷胱甘肽过氧化物酶4酶（GPX 4）的抑制剂，其消耗GSH来解毒脂质过氧化物。另外的测定显示，erastin、RSL 3和ML 210增加脂质过氧化物水平，并且LUHMES神经元受到ferrostatin-1的保护免于过氧化物积累和细胞死亡。通过评价五种金属螯合剂对erastin和RSL 3细胞毒性的影响来评估铁的可能作用。LUHMES神经元通过三种螯合剂2，3-二巯基-1-丙磺酸（DMPS）、去铁酮（DFX）和去铁酮（DFP）保护免受RSL 3的影响。总的来说，这些结果表明，LUHMES神经元的脆弱性，通过化学治疗，破坏谷胱甘肽合成，脂质过氧化物解毒，或铁代谢铁凋亡。同样的脆弱性可能发生在中枢神经系统神经元中，据报道，中枢神经系统神经元产生低水平的GSH和金属硫蛋白，限制了它们中和氧化应激和有毒金属的能力。这些结果提出了一个理由和方法来寻找环境毒物，可能利用这些漏洞，促进神经退行性疾病。
Ferroptosis is a necrotic cell death caused by lipid oxidation that may be responsible for neural degeneration in Parkinson’s disease. We assessed whether three neuronal cell lines are sensitive to killing by ferroptosis. Ferroptosis inducer erastin killed LUHMES neurons at sub-micromolar concentrations, whereas neuronal cells derived from SH-SY5Y cells or neural stem cells were at least fifty-fold less sensitive. LUHMES differentiated neurons were likewise sensitive to killing by RSL3 or ML210, inhibitors of the glutathione peroxidase 4 enzyme (GPX4) that consumes GSH to detoxify lipid peroxides. Additional assays showed that erastin, RSL3, and ML210 increased lipid peroxide levels, and that LUHMES neurons were protected from both peroxide accumulation and cell death by ferrostatin-1. A possible role of iron was assessed by evaluating the effects of five metal chelators on cytotoxicity of erastin and RSL3. LUHMES neurons were protected from RSL3 by three of the chelators, 2,3-Dimercapto-1-propanesulfonic acid (DMPS), Deferoxiprone (DFX) and Deferriprone (DFP). Collectively, these results demonstrate the vulnerability of LUHMES neurons to ferroptosis by chemical treatments that disrupt glutathione synthesis, lipid peroxide detoxification, or iron metabolism. The same vulnerabilities may occur in CNS neurons, which reportedly generate low levels of GSH and metallothioneins, limiting their ability to neutralize oxidative stresses and toxic metals. These results suggest a rationale and methods to search for environmental toxicants that may exploit these vulnerabilities and promote neurodegenerative diseases.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
DOI：
10.1016/j.jtemb.2014.12.012
发表时间：
2015-01-01
影响因子：
3.5
作者：
Ward, Roberta J.;Dexter, David T.;Crichton, Robert R.
通讯作者：
Crichton, Robert R.
超生汀在多种疾病模型中抑制氧化脂质损伤和细胞死亡。
影响因子：
15
作者：
Skouta R;Dixon SJ;Wang J;Dunn DE;Orman M;Shimada K;Rosenberg PA;Lo DC;Weinberg JM;Linkermann A;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
3.3
作者：
Tong, Zhi-Bin;Hogberg, Helena;Kuo, David;Sakamuru, Srilatha;Xia, Menghang;Smirnova, Lena;Hartung, Thomas;Gerhold, David
通讯作者：
Gerhold, David
影响因子：
6.2
作者：
Miyazaki, Ikuko;Asanuma, Masato;Kita, Taizo
通讯作者：
Kita, Taizo