Abstract：
Tetanus neurotoxin (TeNT) causes spastic paralysis by inhibiting neurotransmission in spinal inhibitory interneurons. TeNT binds to the neuromuscular junction, leading to its internalisation into motor neurons and subsequent transcytosis into interneurons. While the extracellular matrix proteins nidogens are essential for TeNT binding, the molecular composition of its receptor complex remains unclear. Here, we show that the receptor-type protein tyrosine phosphatases LAR and PTPRδ interact with the nidogen-TeNT complex, enabling its neuronal uptake. Binding of LAR and PTPRδ to the toxin complex is mediated by their immunoglobulin and fibronectin III domains, which we harnessed to inhibit TeNT entry into motor neurons and protect mice from TeNT-induced paralysis. This function of LAR is independent of its role in regulating TrkB receptor activity, which augments axonal transport of TeNT. These findings reveal a multi-subunit receptor complex for TeNT and demonstrate a novel trafficking route for extracellular matrix proteins. Our study offers potential new avenues for developing therapeutics to prevent tetanus and dissecting the mechanisms controlling the targeting of physiological ligands to long-distance axonal transport in the nervous system.
摘要：
破伤风神经毒素（TeNT）通过抑制脊髓抑制性中间神经元的神经传递而引起痉挛性瘫痪。TeNT与神经肌肉接头结合,导致其内化为运动神经元，随后转胞吞为中间神经元。虽然细胞外基质蛋白nidogen是TeNT结合所必需的，其受体复合物的分子组成尚不清楚.这里,我们显示受体型蛋白酪氨酸磷酸酶LAR和PTPRδ与nidogen-TeNT复合物相互作用，使其神经元吸收。LAR和PTPRδ与毒素复合物的结合由其免疫球蛋白和纤连蛋白III结构域介导，我们利用它来抑制TeNT进入运动神经元并保护小鼠免受TeNT诱导的瘫痪。LAR的这种功能独立于其在调节TrkB受体活性中的作用。这增加了TeNT的轴突运输。这些发现揭示了TeNT的多亚基受体复合物，并证明了细胞外基质蛋白的新型运输途径。我们的研究为开发预防破伤风的疗法和解剖控制生理配体靶向神经系统中长距离轴突运输的机制提供了潜在的新途径。
