Tetanus toxin C-fragment protects against excitotoxic spinal motoneuron degeneration in vivo

Abstract

The tetanus toxin C-fragment is a non-toxic peptide that can be transported from peripheral axons into spinal motoneurons. In in vitro experiments it has been shown that this peptide activates signaling pathways associated with Trk receptors, leading to cellular survival. Because motoneuron degeneration is the main pathological hallmark in motoneuron diseases, and excitotoxicity is an important mechanism of neuronal death in this type of disorders, in this work we tested whether the tetanus toxin C-fragment is able to protect MN in the spinal cord in vivo. For this purpose, we administered the peptide to rats subjected to excitotoxic motoneuron degeneration induced by the chronic infusion of AMPA in the rat lumbar spinal cord, a well-established model developed in our laboratory. Because the intraspinal infusion of the fragment was only weakly effective, whereas the i.m. administration was remarkably neuroprotective, and because the i.m. injection of an inhibitor of Trk receptors diminished the protection, we conclude that such effects require a retrograde signaling from the neuromuscular junction to the spinal motoneurons. The protection after a simple peripheral route of administration of the fragment suggests a potential therapeutic use of this peptide to target spinal MNs exposed to excitotoxic conditions in vivo.

Neuronal and astroglial monocarboxylate transporters play key but distinct roles in hippocampus-dependent learning and memory formation

“…Brains were removed, postfixed for 24 h at 4 °C, and transferred successively to 10, 20 and 30 % sucrose (24 h each). Immunohistochemistry was performed as previously described (Netzahualcoyotzi and Tapia, 2018), on freely floating fixed tissue sections. Antibodies used are listed in Supplementary Table 4.…”

A modular RNA delivery system comprising spherical nucleic acids built on endosome-escaping polymeric nanoparticles

“…The C-terminal fragment of the heavy chain (TTC) retains the ability to bind neuronal membranes: binding is followed by internalization and retrograde axonal transport with nal accumulation in the motor neuron. 52,53 We reacted TTC (which contains cysteine residues) with maleimide-DNA to form conjugates that hybridize with the PSNA corona (ESI Fig. 1 †).…”

“…DNA oligonucleotides conjugated to the PMPC terminus form internal and external coronae which can be used for sequence-specific loading of DNA-or RNA-tagged molecules, for instance siRNA duplexes or targeting moieties such as tetanus toxin fragment C (structure 1DFQ). 52,53,61 Unbound cargoes can also be encapsulated in the lumen. (b) PMPC 25 -PDPA 72 vesicles escape the endosomal pathway via pH-driven osmotic shock.…”

Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus Neurotoxin

“…In view of the established view of the mechanism [ 30 , 36 , 37 ], we address the hypothesis that TeNT might mimic NTR-ligands and present preliminary experimental results. In 2020 a seminal work presented a synoptic report concerning newer findings of the mechanistic aspects of cell uptake of tetanus neurotoxins [ 38 ].…”