Proteolytic ectodomain shedding of muscle-specific tyrosine kinase in myasthenia gravis
Proteolytic ectodomain shedding of muscle-specific tyrosine kinase in myasthenia gravis
复制标题
DOI：
10.1016/j.expneurol.2022.114300
复制
发表时间：
2022-12
影响因子：
5.3
通讯作者：
S. Mori;Shigeaki Suzuki;T. Konishi;N. Kawaguchi;M. Kishi;S. Kuwabara;Kei Ishizuchi;Heying Zhou;F. Shibasaki;H. Tsumoto;Takuya Omura;Y. Miura;S. Mori;M. Higashihara;S. Murayama;K. Shigemoto
中科院分区：
文献类型：
--
作者：
S. Mori;Shigeaki Suzuki;T. Konishi;N. Kawaguchi;M. Kishi;S. Kuwabara;Kei Ishizuchi;Heying Zhou;F. Shibasaki;H. Tsumoto;Takuya Omura;Y. Miura;S. Mori;M. Higashihara;S. Murayama;K. Shigemoto
神经肌肉接头 (NMJ) 处肌肉特异性酪氨酸激酶 (MuSK) 蛋白的自身抗体比其他 MG 亚型更容易导致难治性全身性重症肌无力 (MG)，并伴有呼吸困难。然而，MuSK（一种在骨骼肌 NMJ 上局部表达的膜蛋白）作为自身抗原提供给免疫系统的机制仍不清楚。在这里，我们在小鼠和人血清中发现了 MuSK，在运动神经去神经支配小鼠和 MG 模型小鼠中，MuSK 的含量显着增加。通过液相色谱-串联质谱 (LC-MS/MS) 进行的肽分析证实了人和小鼠血清中都存在 MuSK。此外，一些重症肌无力患者血清中 MuSK 的含量显着高于健康对照。我们的结果表明，MuSK 蛋白从肌肉分泌到血流中是由神经肌肉接头故障引发的胞外域脱落引起的。这些结果可以解释为什么 MuSK-MG 难以治疗，并且由于与 Ab 诱导的 NMJ 神经肌肉传递破坏相关的去神经支配，导致一些患者快速肌肉萎缩。这些发现为新的 MG 治疗铺平了道路，并且 MuSK 可以在临床前研究、临床诊断、治疗和药物发现中用作其他神经肌肉疾病的生物标志物。
Autoantibodies to muscle-specific tyrosine kinase (MuSK) proteins at the neuromuscular junction (NMJ) cause refractory generalized myasthenia gravis (MG) with dyspnea more frequently than other MG subtypes. However, the mechanisms via which MuSK, a membrane protein locally expressed on the NMJ of skeletal muscle, is supplied to the immune system as an autoantigen remains unknown. Here, we identified MuSK in both mouse and human serum, with the amount of MuSK dramatically increasing in mice with motor nerve denervation and in MG model mice. Peptide analysis by liquid chromatography-tandem-mass spectrometry (LC-MS/MS) confirmed the presence of MuSK in both human and mouse serum. Furthermore, some patients with MG have significantly higher amounts of MuSK in serum than healthy controls. Our results indicated that the secretion of MuSK proteins from muscles into the bloodstream was induced by ectodomain shedding triggered by neuromuscular junction failure. The results may explain why MuSK-MG is refractory to treatments and causes rapid muscle atrophy in some patients due to the denervation associated with Ab-induced disruption of neuromuscular transmission at the NMJ. Such discoveries pave the way for new MG treatments, and MuSK may be used as a biomarker for other neuromuscular diseases in preclinical studies, clinical diagnostics, therapeutics, and drug discovery.