Yang Kangqin, Liu Yang, Deng Wenhua, Gong Zhenxiang, Huang Lifang, Li Zehui, Zhang Min
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Neurology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, Shanxi, China.
J Neurochem. 2025 Jul;169(7):e70146. doi: 10.1111/jnc.70146.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons. The mechanisms underlying the selective degeneration of motor neurons in ALS remain poorly understood, underscoring the need for further investigation into the factors driving this process. In this study, we utilized ALS mouse models and an in vitro NSC34 motor neuron cell line expressing the SOD1 mutation to identify a novel pathogenic mechanism wherein astrocyte-secreted Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to Death Receptor 5 (DR5)on motor neurons, leading to caspase-8 activation and subsequent neuronal death. Blocking DR5 with neutralizing antibodies significantly attenuated TRAIL-induced motor neuron death. These findings provide the first evidence that TRAIL may serve as a potential therapeutic target in ALS, offering new insights into the mechanisms of motor neuron degeneration in this disease.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是上下运动神经元均发生退化。ALS中运动神经元选择性退化的潜在机制仍知之甚少，这突出表明需要进一步研究驱动这一过程的因素。在本研究中，我们利用ALS小鼠模型和表达SOD1突变的体外NSC34运动神经元细胞系，确定了一种新的致病机制，即星形胶质细胞分泌的肿瘤坏死因子相关凋亡诱导配体（TRAIL）与运动神经元上的死亡受体5（DR5）结合，导致半胱天冬酶-8激活及随后的神经元死亡。用中和抗体阻断DR5可显著减轻TRAIL诱导的运动神经元死亡。这些发现首次证明TRAIL可能是ALS的一个潜在治疗靶点，为该疾病中运动神经元退化的机制提供了新的见解。
