Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, NYU Medical School, New York, United States.
Center for Motor Neuron Biology and Disease and Departments of Pathology and Cell Biology and Neurology, Columbia University, New York, United States.
Elife. 2018 Feb 20;7:e34375. doi: 10.7554/eLife.34375.
In amyotrophic lateral sclerosis (ALS) and animal models of ALS, including mice, disassembly of the neuromuscular synapse precedes motor neuron loss and is sufficient to cause a decline in motor function that culminates in lethal respiratory paralysis. We treated mice with an agonist antibody to MuSK, a receptor tyrosine kinase essential for maintaining neuromuscular synapses, to determine whether increasing muscle retrograde signaling would slow nerve terminal detachment from muscle. The agonist antibody, delivered after disease onset, slowed muscle denervation, promoting motor neuron survival, improving motor system output, and extending the lifespan of mice. These findings suggest a novel therapeutic strategy for ALS, using an antibody format with clinical precedence, which targets a pathway essential for maintaining attachment of nerve terminals to muscle.
在肌萎缩侧索硬化症（ALS）和 ALS 的动物模型中，包括小鼠，运动神经元丧失之前神经肌肉突触的解体足以导致运动功能下降，最终导致致命的呼吸性瘫痪。我们用一种针对 MuSK 的激动性抗体治疗小鼠，MuSK 是一种受体酪氨酸激酶，对于维持神经肌肉突触是必需的，以确定增加肌肉逆行信号是否会减缓神经末梢从肌肉上脱离。在疾病发作后给予激动性抗体可减缓肌肉去神经支配，促进运动神经元存活，改善运动系统输出，并延长小鼠的寿命。这些发现为 ALS 提供了一种新的治疗策略，使用具有临床前例的抗体形式，针对维持神经末梢与肌肉连接的必需途径。
