Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
Cell Death Dis. 2013 Oct 10;4(10):e841. doi: 10.1038/cddis.2013.378.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of motor neurons, axon degeneration, and denervation of neuromuscular junctions (NMJ). Here we show that death receptor 6 (DR6) levels are elevated in spinal cords from post-mortem samples of human ALS and from SOD1(G93A) transgenic mice, and DR6 promotes motor neuron death through activation of the caspase 3 signaling pathway. Blocking DR6 with antagonist antibody 5D10 promotes motor neuron survival in vitro via activation of Akt phosphorylation and inhibition of the caspase 3 signaling pathway, after growth factor withdrawal, sodium arsenite treatment or co-culture with SOD1(G93A) astrocytes. Treatment of SOD1(G93A) mice at an asymptomatic stage starting on the age of 42 days with 5D10 protects NMJ from denervation, decreases gliosis, increases survival of motor neurons and CC1(+) oligodendrocytes in spinal cord, decreases phosphorylated neurofilament heavy chain (pNfH) levels in serum, and promotes motor functional improvement assessed by increased grip strength. The combined data provide clear evidence for neuroprotective effects of 5D10. Blocking DR6 function represents a new approach for the treatment of neurodegenerative disorders involving motor neuron death and axon degeneration, such as ALS.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是运动神经元死亡、轴突变性和运动神经元与肌纤维连接处（NMJ）失神经支配。在这里，我们发现，在人类 ALS 的死后样本和 SOD1(G93A)转基因小鼠的脊髓中，死亡受体 6 (DR6)水平升高，DR6 通过激活半胱天冬酶 3 信号通路促进运动神经元死亡。用拮抗剂抗体 5D10 阻断 DR6，在生长因子撤出、亚砷酸钠处理或与 SOD1(G93A)星形胶质细胞共培养后，通过激活 Akt 磷酸化和抑制半胱天冬酶 3 信号通路，促进体外运动神经元存活。从 42 天大的无症状阶段开始，用 5D10 治疗 SOD1(G93A)小鼠，可防止 NMJ 失神经支配，减少神经胶质增生，增加脊髓中运动神经元和 CC1(+)少突胶质细胞的存活，降低血清中磷酸化神经丝重链 (pNfH)水平，并通过增加握力评估促进运动功能改善。综合数据为 5D10 的神经保护作用提供了明确证据。阻断 DR6 功能代表了一种治疗涉及运动神经元死亡和轴突变性的神经退行性疾病（如 ALS）的新方法。
