Neurotrophic Properties of C-Terminal Domain of the Heavy Chain of Tetanus Toxin on Motor Neuron Disease.

Mireia Herrando-Grabulosa,Kevin Talbot,Caty Casas,José Aguilera

doi:10.3390/toxins12100666

Abstract

The carboxyl-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) exerts a neuroprotective effect in neurodegenerative diseases via the activation of signaling pathways related to neurotrophins, and also through inhibiting apoptotic cell death. Here, we demonstrate that Hc-TeTx preserves motoneurons from chronic excitotoxicity in an in vitro model of amyotrophic lateral sclerosis. Furthermore, we found that PI3-K/Akt pathway, but not p21ras/MAPK pathway, is involved in their beneficial effects under chronic excitotoxicity. Moreover, we corroborate the capacity of the Hc-TeTx to be transported retrogradely into the spinal motor neurons and also its capacity to bind to the motoneuron-like cell line NSC-34. These findings suggest a possible therapeutic tool to improve motoneuron preservation in neurodegenerative diseases such as amyotrophic lateral sclerosis.

Highlights

Motor neuron diseases (MNDs) are a group of neurodegenerative diseases which, despite having different etiologies and clinical patterns, demonstrate that spinal motoneurons (MNs) are selectively vulnerable
The different fractions obtained during the process of purification of the heavy chain of tetanus toxin (Hc-TeTx) protein were treated under reducing conditions and resolved in an electrophoretic gel by loading the same volume of each sample (15 μL)
The preservation of MNs from cell death is a relevant goal in MNDs

Summary

Introduction

Motor neuron diseases (MNDs) are a group of neurodegenerative diseases which, despite having different etiologies and clinical patterns, demonstrate that spinal motoneurons (MNs) are selectively vulnerable. The most common form of MND in adults, amyotrophic lateral sclerosis (ALS), is characterized by combined degeneration of upper and lower MNs, leading to progressive weakness and death from respiratory failure a median of 30 months from symptom onset [1]. Most ALS cases are apparently sporadic (sALS), though about 10% show familial inheritance (fALS), and specific disease-determining mutations can be identified in up to 15% cases overall, with more than 50 genes involved. ALS is currently incurable, with available therapies such as riluzole and edaravone only having a trivial impact on disease progression [2,3]. Precision medicine based on approaches to therapy in ALS is urgently needed [4].

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