The tyrosine phosphatases LAR and PTPRδ act as receptors of the nidogen-tetanus toxin complex

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 PTPR delta interact with the nidogen-TeNT complex, enabling its neuronal uptake. Binding of LAR and PTPR delta 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.Tetanus neurotoxin (TeNT) causes long-lasting spastic paralysis by blocking neurotransmission in the spinal cord and is a major health burden in developing countries. This work shows that the receptor-type protein tyrosine phosphatases LAR and PTPR delta act as receptors of TeNT, thereby mediating its uptake and delivery into the nervous system.LAR and PTPR delta bind to the extracellular matrix proteins nidogens, which function as TeNT co-receptors.Binding of LAR and PTPR delta to the nidogen-TeNT complex is mediated by their immunoglobulin and fibronectin III domains.These domains can be leveraged to inhibit TeNT entry into motor neurons in culture and protect mice from TeNT-induced paralysis.The function of LAR in neuronal uptake of the nidogen-TeNT complex is independent of its role in regulating TrkB receptor activity.LAR and PTPR delta mediate tetanus toxin uptake and delivery into the nervous system.