GPX4 deficiency-dependent phospholipid peroxidation drives motor deficits of ALS

• DOI: 10.1016/j.jare.2022.02.016
• Publication Date: 2022-03-05T01:09:11Z
• Authors: Long-Fang Tu; Tian-Ze Zhang; Yang-Fan Zhou; Qing-Qing Zhou; Hai-Biao Gong; Lei Liang; Lin-Na Hai; Nan-Xin You; Yang Su; Yong-Jun Chen; Xu-Kai Mo; Chang-Zheng Shi; Liang-Ping Luo; Wan-Yang Sun; Wen-Jun Duan; Hiroshi Kurihara; Yi-Fang Li; Rong-Rong He
• Keywords: GPX4

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, mechanisms underlying exact role of ALS-associated neural degeneration are not definitively established. Oxidative stress-generated phospholipid peroxides known to have extensive physiological pathological consequences tissues. Here, we discovered deficiency glutathione peroxidase 4 (GPX4), an essential antioxidant peroxidase, led accumulation resulted cords ALS mice. Mutant human SOD1G93A transgenic mice were intrathecally injected with neuron-targeted adeno-associated virus (AAV) expressing GPX4 (GPX4-AAV) or peroxidation inhibitor, ferrostatin-1. The results showed impaired performance induced toxicity lumbar spine substantially alleviated ferrostatin-1 treatment AAV-mediated delivery. In addition, denervation neuron-muscle junction atrophy rescued overexpression, suggesting for maintenance function. comparison, conditional knockdown Gpx4 Gpx4fl/fl triggered obvious increase occurrence ALS-like phenotype. Altogether, our findings underscore importance maintaining redox homeostasis cord presents as attractive therapeutic target treatment.