Wu You, Li Jiahuan, Zhai Wenya, Liu Wenye, Wu Hao, Liu Hong, Min Junxia, Wang Fudi, Liu Jing-Xia
College of Fisheries, Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Huazhong Agricultural University, Wuhan 430070, China.
State Key Laboratory of Agricultural Microbiology, College of Animal Science & Technology and College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; Hubei Hongshan Laboratory, Wuhan 430070, China.
Neurobiol Dis. 2025 Sep;213:107027. doi: 10.1016/j.nbd.2025.107027. Epub 2025 Jul 11.
ATP7A genetic mutations lead to Menkes disease (MD), a hereditary neurodegenerative disorder develops significant metabolic abnormalities including copper deficiency and hypomyelination, and even death before 3 years old. However, the underlying mechanisms remain poorly understood. In this study, a dysfunction in axons as evidenced by the shortened axons, reduced branching in each axon, thinner spinal myelin sheaths, and a significant decrease in neuronal membrane potential, was manifested in the central nervous system (CNS) of atp7a larvae. Atp7a is indispensable for the axonal survival in a cell-autonomous manner by fine-tuning copper homeostasis. The transcriptomics analysis identified a significant enrichment of ferroptosis among the differentially expressed genes (DEGs). Iron overload, GPX4 degradation, and lipid peroxidation, the fundamental characteristics of ferroptosis, were evident during atp7a ablation. More importantly, administration of ferroptosis inhibitor Fer-1 or iron chelator DFO, substantially suppressed ferroptosis and largely ameliorated axonal and myelin defects in atp7a larvae. Whereas, larvae exposed to ferroptosis inducer RSL3, and engineered larvae developing ferroptosis, phenocopied the myelin and axonal extension defects observed in atp7a mutants. Taken together, this study highlights the critical importance of atp7a in supporting axonal and myelin development during zebrafish embryogenesis by tightly restraining ferroptosis. This study will shed some light on the theoretical basis and therapeutic targets underlying ATP7A dysfunction induced neurodegenerative diseases.
ATP7A基因突变导致门克斯病（MD），这是一种遗传性神经退行性疾病，会出现包括铜缺乏和髓鞘形成不良在内的显著代谢异常，甚至在3岁前死亡。然而，其潜在机制仍知之甚少。在本研究中，atp7a幼虫的中枢神经系统（CNS）出现了轴突功能障碍，表现为轴突缩短、每个轴突的分支减少、脊髓髓鞘变薄以及神经元膜电位显著降低。Atp7a通过微调铜稳态以细胞自主方式对轴突存活不可或缺。转录组学分析确定在差异表达基因（DEGs）中显著富集了铁死亡。铁过载、GPX4降解和脂质过氧化，这些铁死亡的基本特征，在atp7a基因敲除期间很明显。更重要的是，给予铁死亡抑制剂Fer-1或铁螯合剂DFO，可显著抑制铁死亡，并在很大程度上改善atp7a幼虫的轴突和髓鞘缺陷。而暴露于铁死亡诱导剂RSL3的幼虫以及发生铁死亡的工程幼虫，表现出了在atp7a突变体中观察到的髓鞘和轴突延伸缺陷。综上所述，本研究强调了atp7a在斑马鱼胚胎发育过程中通过严格抑制铁死亡来支持轴突和髓鞘发育的关键重要性。这项研究将为ATP7A功能障碍所致神经退行性疾病的理论基础和治疗靶点提供一些启示。
