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.

中文翻译：

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酪氨酸磷酸酶 LAR 和 PTPRδ 充当巢菌-破伤风毒素复合物的受体。


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引起痉挛性瘫痪。 TeNT 与神经肌肉接头结合，导致其内化到运动神经元中，并随后转胞吞到中间神经元中。虽然细胞外基质蛋白巢蛋白对于 TeNT 结合至关重要，但其受体复合物的分子组成仍不清楚。在这里，我们证明受体型蛋白酪氨酸磷酸酶 LAR 和 PTPRδ 与 nidogen-TeNT 复合物相互作用，使其神经元摄取。 LAR 和 PTPRδ 与毒素复合物的结合是由它们的免疫球蛋白和纤连蛋白 III 结构域介导的，我们利用它们来抑制 TeNT 进入运动神经元并保护小鼠免受 TeNT 诱导的麻痹。 LAR 的这种功能与其调节 TrkB 受体活性的作用无关，TrkB 受体活性增强 TeNT 的轴突转运。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运输途径。我们的研究为开发预防破伤风的疗法和剖析控制生理配体靶向神经系统长距离轴突运输的机制提供了潜在的新途径。