Two Feet on the Membrane: Uptake of Clostridial Neurotoxins

Rummel, Andreas

doi:10.1007/82_2016_48

Cited by 46 publications

(62 citation statements)

References 189 publications

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“…Sequence analysis and structural alignment show that the ganglioside-binding site (GBS) motif ‘E…H…SXWY…G’, which is highly conserved in BoNT/A, B, E (residue H is replaced by a K), F, and G (residue E is replaced by a Q) [34], is strictly conserved in H C HA (E1195, H1245, S1256, W1258, Y1259, and G1271) (Figure 2A, green stars). Interestingly, our sequence alignment shows that the H CC of BoNT/HA is most similar to BoNT/A8 (~95%).…”

Section: Resultsmentioning

confidence: 99%

Crystal Structure of the Receptor-Binding Domain of Botulinum Neurotoxin Type HA, Also Known as Type FA or H

Yao

Lam

Perry

et al. 2017

Toxins

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Botulinum neurotoxins (BoNTs), which have been exploited as cosmetics and muscle-disorder treatment medicines for decades, are well known for their extreme neurotoxicity to humans. They pose a potential bioterrorism threat because they cause botulism, a flaccid muscular paralysis-associated disease that requires immediate antitoxin treatment and intensive care over a long period of time. In addition to the existing seven established BoNT serotypes (BoNT/A–G), a new mosaic toxin type termed BoNT/HA (aka type FA or H) was reported recently. Sequence analyses indicate that the receptor-binding domain (HC) of BoNT/HA is ~84% identical to that of BoNT/A1. However, BoNT/HA responds differently to some potent BoNT/A-neutralizing antibodies (e.g., CR2) that target the HC. Therefore, it raises a serious concern as to whether BoNT/HA poses a new threat to our biosecurity. In this study, we report the first high-resolution crystal structure of BoNT/HA-HC at 1.8 Å. Sequence and structure analyses reveal that BoNT/HA and BoNT/A1 are different regarding their binding to cell-surface receptors including both polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Furthermore, the new structure also provides explanations for the ~540-fold decreased affinity of antibody CR2 towards BoNT/HA compared to BoNT/A1. Taken together, these new findings advance our understanding of the structure and function of this newly identified toxin at the molecular level, and pave the way for the future development of more effective countermeasures.

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Section: Resultsmentioning

confidence: 99%

Crystal Structure of the Receptor-Binding Domain of Botulinum Neurotoxin Type HA, Also Known as Type FA or H

Yao

Lam

Perry

et al. 2017

Toxins

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“…However, earlier mice studies confirmed that TeNT effects were not affected by prior immunization in mice [13]. It is possible that the exceptional high affinity to the neuronal membrane of TeNT and a resulting rapid binding to motor neurons [32][33][34] results in a lower probability for a binding to circulating TeNT antibodies. It has furthermore been speculated that antibodies may neutralize only that minor proportion of TeNT, that get into the bloodstream, thus preventing generalized symptoms [13].…”

Section: Discussionmentioning

confidence: 98%

Therapeutic effects of Tetanus neurotoxin in spinal cord injury: a case series on four dogs

Hesse¹,

Kutschenko

Bryl³

et al. 2020

Spinal Cord Ser Cases

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Study design Case series on four dogs. Objectives To determine the alleviation of motor symptoms in spinal cord injury (SCI) by tetanus neurotoxin (TeNT). Setting Different Berlin veterinary clinics, Germany. Methods We report on the effect of intramuscular injections of low-dose TeNT into paretic hind limb muscles 2-157 weeks after SCI due to lumbar disc herniation in a clinical case series on four dogs. All dogs underwent unsuccessful or incomplete surgical decompression prior to TeNT treatment. TeNT was injected on a compassionate basis. Stance, gait ability and the diameter of the rectus femoris muscle were assessed as parameters. Results All four dogs improved their stance and three of these dogs improved in gait at 4 and 6 weeks after TeNT injections without evidence of side effects or spreading of TeNT effects. At the same time, the size of the rectus femoris muscle diameter increased considerably as compared with baseline (baseline: 100%; 4 weeks: 148.7% ± 10.9%; 6 weeks: 137.1% ± 7.9%). Conclusions Facilitation of α-motor neurons by TeNT injections into paretic hind limb muscles of four dogs improved standing and/or gait abilities and partly reversed muscle atrophy after SCI. The absence of generalized or painful muscle spasms supports the safety of low-dose TeNT. Therefore, TeNT might evolve as a promising therapeutic option for muscle paresis of central origin, e.g. in individuals with SCI, stroke or multiple sclerosis.

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“…After entering the general circulation, TeNT and BoNTs bind with high affinity to the presynaptic membrane of the motor neuron at the neuromuscular junction (NMJ) where they are rapidly internalised (Montal, 2010;Rummel, 2016) ( Figure 1A). BoNTs mainly remain at the NMJ and inhibit the release of the excitatory neurotransmitter acetylcholine (Figure 1), blocking muscle excitation-contraction coupling and thus causing a flaccid paralysis.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…The differences in clinical symptoms arise from preferential site of action in different neurons (Montal, 2010;Rummel, 2016) (Figure 1).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

The travel diaries of tetanus and botulinum neurotoxins

Surana

Tosolini

Meyer

et al. 2018

Toxicon

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Tetanus (TeNT) and botulinum (BoNT) neurotoxins, the causative agents of tetanus and botulism, respectively, are the most potent toxic molecules known to mankind. This extreme potency is attributed to: i) their specificity for essential components of the neurotransmitter release machinery present at vertebrate synapses, and ii) their high-affinity targeting to motor neurons by binding to polysialogangliosides and protein receptors. Comprising the clostridial neurotoxin family, TeNT and BoNTs engage distinct surface receptors and intracellular sorting pathways in neurons. BoNTs bind to the intraluminal domain of specific synaptic vesicle proteins that are exposed to the extracellular milieu upon exocytosis, and are taken up by synaptic vesicle recycling. A sizeable proportion of BoNT molecules remain at the neuromuscular junction, where their protease moiety is released into the cytoplasm, blocking synaptic transmission and causing flaccid paralysis. In contrast, TeNT undergoes binding to specific components of the basal membrane at the neuromuscular junction, is endocytosed into motor neurons and sorted to axonal signalling endosomes. Following this, TeNT is transported to the soma of motor neurons located in the spinal cord or brainstem, and then transcytosed to inhibitory interneurons, where it blocks synaptic transmission. TeNT-induced impairment of inhibitory input leads to hyperactivity of motor neurons, causing spastic paralysis, which is the hallmark of tetanus. This review examines the molecular mechanisms leading to the entry, sorting and intracellular trafficking of TeNT and BoNTs.

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Two Feet on the Membrane: Uptake of Clostridial Neurotoxins

Cited by 46 publications

References 189 publications

Crystal Structure of the Receptor-Binding Domain of Botulinum Neurotoxin Type HA, Also Known as Type FA or H

Crystal Structure of the Receptor-Binding Domain of Botulinum Neurotoxin Type HA, Also Known as Type FA or H

Therapeutic effects of Tetanus neurotoxin in spinal cord injury: a case series on four dogs

The travel diaries of tetanus and botulinum neurotoxins

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