Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice.
Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice.
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DOI：
10.1038/s41598-021-92369-8
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发表时间：
2021-06-18
影响因子：
4.6
通讯作者：
Ran Q
中科院分区：
文献类型：
--
作者：
Chen L;Na R;Danae McLane K;Thompson CS;Gao J;Wang X;Ran Q
肌萎缩性侧索硬化症（ALS）患者运动神经元的退化和死亡与脂质过氧化增加有关。脂质过氧化是铁下垂的驱动因素，铁下垂是一种依赖铁的细胞死亡的氧化模式。然而，铁下垂在ALS运动神经元退行性变中的重要性尚不清楚。谷胱甘肽过氧化物酶4 （Glutathione peroxidase 4, Gpx4）是抑制铁下垂的关键酶，它通过减少细胞膜中的磷脂氢过氧化物来抑制铁下垂。为了评估增强对铁上吊的保护作用对运动神经元疾病的影响，我们将GPX4转基因小鼠与广泛使用的ALS小鼠模型SOD1G93A小鼠杂交，产生SOD1G93AGPX4双转基因小鼠。与对照SOD1G93A小鼠相比，雄性和雌性SOD1G93AGPX4小鼠的寿命均延长。SOD1G93AGPX4小鼠也表现出疾病发作延迟和运动功能增加，这与改善脊髓运动神经元变性和减少脂质过氧化有关。此外，SOD1G93A诱导的细胞毒性可以通过Gpx4过表达和铁下垂的化学抑制剂在体外得到改善。我们进一步发现，症状性SOD1G93A小鼠和散发性ALS患者脊髓组织的抗铁下垂防御系统可能由于Gpx4缺乏而受损。因此，我们的研究结果表明，铁下垂在ALS的运动神经元变性中起关键作用。
Degeneration and death of motor neurons in Amyotrophic Lateral Sclerosis (ALS) are associated with increased lipid peroxidation. Lipid peroxidation is the driver of ferroptosis, an iron-dependent oxidative mode of cell death. However, the importance of ferroptosis in motor neuron degeneration of ALS remains unclear. Glutathione peroxidase 4 (Gpx4) is a key enzyme in suppressing ferroptosis by reducing phospholipid hydroperoxides in membranes. To assess the effect of increased protection against ferroptosis on motor neuron disease, we generated SOD1G93AGPX4 double transgenic mice by cross-breeding GPX4 transgenic mice with SOD1G93A mice, a widely used ALS mouse model. Compared with control SOD1G93A mice, both male and female SOD1G93AGPX4 mice had extended lifespans. SOD1G93AGPX4 mice also showed delayed disease onset and increased motor function, which were correlated with ameliorated spinal motor neuron degeneration and reduced lipid peroxidation. Moreover, cell toxicity induced by SOD1G93A was ameliorated by Gpx4 overexpression and by chemical inhibitors of ferroptosis in vitro. We further found that the anti-ferroptosis defense system in spinal cord tissues of symptomatic SOD1G93A mice and sporadic ALS patients might be compromised due to deficiency of Gpx4. Thus, our results suggest that ferroptosis plays a key role in motor neuron degeneration of ALS.
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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
影响因子：
7.4
作者：
Perluigi, M;Poon, HF;Butterfield, DA
通讯作者：
Butterfield, DA
影响因子：
12.4
作者：
Foust, Kevin D.;Salazar, Desiree L.;Kaspar, Brian K.
通讯作者：
Kaspar, Brian K.
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M
影响因子：
4.8
作者：
Petrov D;Mansfield C;Moussy A;Hermine O
通讯作者：
Hermine O