GPX4 deficiency-dependent phospholipid peroxidation drives motor deficits of ALS.
GPX4 deficiency-dependent phospholipid peroxidation drives motor deficits of ALS.
复制标题
GPX4 缺乏依赖性磷脂过氧化导致 ALS 运动缺陷
DOI：
10.1016/j.jare.2022.02.016
复制
发表时间：
2023-01
影响因子：
10.7
通讯作者：
He, Rong-Rong
中科院分区：
文献类型：
--
作者：
Tu, Long-Fang;Zhang, Tian-Ze;Zhou, Yang -Fan;Zhou, Qing-Qing;Gong, Hai-Biao;Liang, Lei;Hai, Lin-Na;You, Nan-Xin;Su, Yang;Chen, Yong-Jun;Mo, Xu-Kai;Shi, Chang-Zheng;Luo, Liang-Ping;Sun, Wan-Yang;Duan, Wen -Jun;Kurihara, Hiroshi;Li, Yi-Fang;He, Rong-Rong
ALS小鼠模型脊髓磷脂过氧化水平升高。抗磷脂过氧化治疗可减少ALS小鼠的脊髓运动神经元损失。GPX 4在ALS小鼠和患者的腰髓中表达减少。Gpx 4的敲低导致脊髓运动神经元的损失和异常的神经肌肉连接。鞘内注射GPX 4-AAV使GPX 4过表达可使ALS的病理现象得到改善。肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，其特征是氧化应激，引发大脑和脊髓中的运动神经元损失。然而，氧化应激在ALS相关神经退行性变中的确切作用机制尚未明确确立。已知氧化应激产生的磷脂过氧化物对组织具有广泛的生理和病理后果。在这里，我们发现谷胱甘肽过氧化物酶4（GPX 4），一种重要的抗氧化剂过氧化物酶的缺乏，导致磷脂过氧化物的积累，并导致ALS小鼠脊髓运动神经元的损失。向突变型人SOD 1G 93 A转基因小鼠鞘内注射表达GPX 4的神经元靶向腺相关病毒（腺相关病毒）（GPX 4-腺相关病毒）或磷脂过氧化抑制剂ferrostatin-1。结果显示，腰椎中由SOD 1G 93 A毒性诱导的受损的运动表现和神经损失通过ferostatin-1治疗和AAV介导的GPX 4递送而显著减轻。此外，神经GPX 4过表达可挽救ALS小鼠神经元-肌肉接头的失神经支配和脊髓萎缩，表明GPX 4对运动神经的维持和功能至关重要。相比之下，Gpx 4 fl/fl小鼠脊髓中Gpx 4的条件性敲低引发了磷脂过氧化物的明显增加和ALS样运动表型的发生。总之，我们的研究结果强调了GPX 4在维持脊髓磷脂氧化还原稳态中的重要性，并将GPX 4作为ALS治疗的有吸引力的治疗靶点。
The level of phospholipid peroxidation in spinal cord is increased in ALS mouse model. Anti-phospholipid peroxidation treatment reduces spinal motor neuron loss in ALS mice. The expressions of GPX4 are decreased in lumbar spinal cords of ALS mice and patients. Knockdown of Gpx4 results in loss of spinal motor neurons and abnormal neuromuscular connections. Intrathecal injection of GPX4-AAV to overexpress GPX4 alleviates the pathological phenomenon of ALS. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by oxidative stress that triggers motor neurons loss in the brain and spinal cord. However, the mechanisms underlying the exact role of oxidative stress in ALS-associated neural degeneration are not definitively established. Oxidative stress-generated phospholipid peroxides are known to have extensive physiological and pathological consequences to tissues. Here, we discovered that the deficiency of glutathione peroxidase 4 (GPX4), an essential antioxidant peroxidase, led to the accumulation of phospholipid peroxides and resulted in a loss of motor neurons in spinal cords of ALS mice. Mutant human SOD1G93A transgenic mice were intrathecally injected with neuron-targeted adeno-associated virus (AAV) expressing GPX4 (GPX4-AAV) or phospholipid peroxidation inhibitor, ferrostatin-1. The results showed that impaired motor performance and neural loss induced by SOD1G93A toxicity in the lumbar spine were substantially alleviated by ferrostatin-1 treatment and AAV-mediated GPX4 delivery. In addition, the denervation of neuron-muscle junction and spinal atrophy in ALS mice were rescued by neural GPX4 overexpression, suggesting that GPX4 is essential for the motor neural maintenance and function. In comparison, conditional knockdown of Gpx4 in the spinal cords of Gpx4fl/fl mice triggered an obvious increase of phospholipid peroxides and the occurrence of ALS-like motor phenotype. Altogether, our findings underscore the importance of GPX4 in maintaining phospholipid redox homeostasis in the spinal cord and presents GPX4 as an attractive therapeutic target for ALS treatment.
登录
查看更多内容
影响因子：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
通讯作者：
Bayır H
影响因子：
4.4
作者：
Gurney, ME
通讯作者：
Gurney, ME
影响因子：
16.6
作者：
Arthur KC;Calvo A;Price TR;Geiger JT;Chiò A;Traynor BJ
通讯作者：
Traynor BJ
影响因子：
12.7
作者：
Gautam, Mukesh;Jara, Javier H.;Ozdinler, P. Hande
通讯作者：
Ozdinler, P. Hande
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