Surana, Sunaina;
Villarroel Campos, David;
Rhymes, Ellie R;
Kalyukina, Maria;
Panzi, Chiara;
Novoselov, Sergey S;
Fabris, Federico;
... Schiavo, Giampietro; + view all
(2024)
The tyrosine phosphatases LAR and PTPRδ act as receptors of the nidogen-tetanus toxin complex.
The EMBO Journal
10.1038/s44318-024-00164-8.
(In press).
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Abstract
Tetanus neurotoxin (TeNT) causes spastic paralysis by inhibiting neurotransmission in spinal inhibitory interneurons. It binds to the neuromuscular junction, leading to its internalisation into motor neurons and subsequent transcytosis into interneurons. Whilst 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 PTPRD interact with the nidogen-TeNT complex, enabling its neuronal uptake. Binding of LAR and PTPRD 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. Importantly, this paves the way 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.
| Type: | Article |
|---|---|
| Title: | The tyrosine phosphatases LAR and PTPRδ act as receptors of the nidogen-tetanus toxin complex |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s44318-024-00164-8 |
| Publisher version: | https://doi.org/10.1038/s44318-024-00164-8 |
| Language: | English |
| Additional information: | © 2024 The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible. |
| Keywords: | LAR, Neuromuscular Junction, Nidogen, PTPRD, Tetanus neurotoxin |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10194345 |
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