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Botulinum Neurotoxin Light Chains Expressed by Defective Herpes Simplex Virus Type-1 Vectors Cleave SNARE Proteins and Inhibit CGRP Release in Rat Sensory Neurons

1
UMR U1179 INSERM/Université de Versailles Saint Quentin en Yvelines (UVSQ)—Paris Saclay, 78180 Montigny-le-Bretonneux, France
2
Neuro-Urology R. Poincaré Hospital AP-HP, 92380 Garches, France
3
Ipsen Innovation SAS, 91940 Les Ulis, France
4
Department of Chemical and Pharmaceutical Sciences (DipSCF), University of Ferrara, 44121 Ferrara, Italy
5
Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, Universidad Autonoma de Madrid (UAM), 28049 Cantoblanco, Madrid, Spain
6
Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, 20129 Milan, Italy
7
University Vita-Salute San Raffaele, 20129 Milan, Italy
8
Ipsen Bioinnovation Ltd., Abingdon, Oxon OX14 4RY, UK
*
Author to whom correspondence should be addressed.
Toxins 2019, 11(2), 123; https://doi.org/10.3390/toxins11020123
Received: 16 January 2019 / Revised: 7 February 2019 / Accepted: 15 February 2019 / Published: 19 February 2019
(This article belongs to the Section Bacterial Toxins)
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Abstract

A set of herpes simplex virus type 1 (HSV-1) amplicon vectors expressing the light chains (LC) of botulinum neurotoxins (BoNT) A, B, C, D, E and F was constructed. Their properties have been assessed in primary cultures of rat embryonic dorsal root ganglia (DRG) neurons, and in organotypic cultures of explanted DRG from adult rats. Following infection of primary cultures of rat embryonic DRG neurons, the different BoNT LC induced efficient cleavage of their corresponding target Soluble N-ethylmaleimide-sensitive-factor Attachment protein Receptor (SNARE) protein (VAMP, SNAP25, syntaxin). A similar effect was observed following infection by BoNT-A LC of organotypic cultures of adult rat DRG. To quantify and compare the functional activities of the different BoNT LC, the inhibition of calcitonin gene-related protein (CGRP) secretion was assessed in DRG neurons following infection by the different vectors. All BoNT-LC were able to inhibit CGRP secretion although to different levels. Vectors expressing BoNT-F LC displayed the highest inhibitory activity, while those expressing BoNT-D and -E LC induced a significantly lower CGRP release inhibition. Cleavage of SNARE proteins and inhibition of CGRP release could be detected in neuron cultures infected at less than one transducing unit (TU) per neuron, showing the extreme efficacy of these vectors. To our knowledge this is the first study investigating the impact of vector-expressed transgenic BoNT LC in sensory neurons. View Full-Text
Keywords: HSV-1 amplicon vectors; transgenic botulinum neurotoxins; light chains; sensory neurons; DRG; SNARE proteins HSV-1 amplicon vectors; transgenic botulinum neurotoxins; light chains; sensory neurons; DRG; SNARE proteins
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Joussain, C.; Le Coz, O.; Pichugin, A.; Marconi, P.; Lim, F.; Sicurella, M.; Salonia, A.; Montorsi, F.; Wandosell, F.; Foster, K.; Giuliano, F.; Epstein, A.L.; Aranda Muñoz, A. Botulinum Neurotoxin Light Chains Expressed by Defective Herpes Simplex Virus Type-1 Vectors Cleave SNARE Proteins and Inhibit CGRP Release in Rat Sensory Neurons. Toxins 2019, 11, 123.

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