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Featured ArticleArticles, Development/Plasticity/Repair

Long-Distance Retrograde Effects of Botulinum Neurotoxin A

Flavia Antonucci, Chiara Rossi, Laura Gianfranceschi, Ornella Rossetto and Matteo Caleo
Journal of Neuroscience 2 April 2008, 28 (14) 3689-3696; https://doi.org/10.1523/JNEUROSCI.0375-08.2008
Flavia Antonucci
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Chiara Rossi
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Laura Gianfranceschi
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Ornella Rossetto
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Matteo Caleo
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Abstract

Botulinum neurotoxins (designated BoNT/A–BoNT/G) are bacterial enzymes that block neurotransmitter release by cleaving essential components of the vesicle fusion machinery. BoNT/A, which cleaves SNAP-25 (synaptosomal-associated protein of 25 kDa), is extensively exploited in clinical medicine to treat neuromuscular pathologies, facial wrinkles, and various types of pain. It is widely assumed that BoNT/A remains at the synaptic terminal and its effects are confined to the injection site. Here we demonstrate that catalytically active BoNT/A is retrogradely transported by central neurons and motoneurons and is then transcytosed to afferent synapses, in which it cleaves SNAP-25. SNAP-25 cleavage by BoNT/A was observed in the contralateral hemisphere after unilateral BoNT/A delivery to the hippocampus. Appearance of cleaved SNAP-25 resulted in blockade of hippocampal activity in the untreated hemisphere. Injections of BoNT/A into the optic tectum led to the appearance of BoNT/A-truncated SNAP-25 in synaptic terminals within the retina. Cleaved SNAP-25 also appeared in the facial nucleus after injection of the toxin into rat whisker muscles. Experiments excluded passive spread of the toxin and demonstrated axonal migration and neuronal transcytosis of BoNT/A. These findings reveal a novel pathway of BoNT/A trafficking in neurons and have important implications for the clinical uses of this neurotoxin.

  • synaptic transmission
  • SNAP-25
  • retrograde axonal transport
  • transcytosis
  • hippocampus
  • visual system
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The Journal of Neuroscience: 28 (14)
Journal of Neuroscience
Vol. 28, Issue 14
2 Apr 2008
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Long-Distance Retrograde Effects of Botulinum Neurotoxin A
Flavia Antonucci, Chiara Rossi, Laura Gianfranceschi, Ornella Rossetto, Matteo Caleo
Journal of Neuroscience 2 April 2008, 28 (14) 3689-3696; DOI: 10.1523/JNEUROSCI.0375-08.2008

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Long-Distance Retrograde Effects of Botulinum Neurotoxin A
Flavia Antonucci, Chiara Rossi, Laura Gianfranceschi, Ornella Rossetto, Matteo Caleo
Journal of Neuroscience 2 April 2008, 28 (14) 3689-3696; DOI: 10.1523/JNEUROSCI.0375-08.2008
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  • Is botulinum toxin really moving into the CNS like tetanus toxin?
    K. Roger Aoki
    Published on: 19 April 2008
  • Published on: (19 April 2008)
    Page navigation anchor for Is botulinum toxin really moving into the CNS like tetanus toxin?
    Is botulinum toxin really moving into the CNS like tetanus toxin?
    • K. Roger Aoki, Vice President, Neurotoxins
    • Other Contributors:
      • Mitchell F. Brin, Sr. VP & Botox CSO and Scott M. Whitcup, Executive VP, Head R&D

    The authors claim to provide the first evidence for a mechanism by which botulinum toxin type A (BoNT/A) can access the CNS after peripheral administration (i.e., similar to tetanus toxin). Their data is limited and inconsistent with the literature (Lalli et al, 2003. Trends Microbiol. 11(9):431-437; Tang-Liu et al, 2003. Toxicon 42:461-469). This difference may be explained by several factors (high dose of a research to...

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    The authors claim to provide the first evidence for a mechanism by which botulinum toxin type A (BoNT/A) can access the CNS after peripheral administration (i.e., similar to tetanus toxin). Their data is limited and inconsistent with the literature (Lalli et al, 2003. Trends Microbiol. 11(9):431-437; Tang-Liu et al, 2003. Toxicon 42:461-469). This difference may be explained by several factors (high dose of a research toxin, unreported antibody specificity and lack of reported controls for nonspecific protein transport and detection methodology). The authors administered BoNT/A into a single site of the rat whisker pad (135 pg, ~450 pg/kg). Patients treated with BOTOX® (vs BoNT/A) for facial indications typically receive ~ 20 units (~3 pg/kg) administered into multiple muscles, which is ~150 fold lower than the dose used by the authors. The high dose administered to rats by the authors complicates interpretation of their data by triggering non-specific uptake and overloading the protein transport system of the neuron. The authors published data with an incompletely characterized antibody (sera or purified? controls to differentiate between cleaved/uncleaved SNAP25?) to represent toxin activity in the brain. Their experimental results relied on the appearance of the epitope resulting from cleavage of BoNT/A’s substrate, SNAP25, by western blot (WB) or immunohistochemical (IHC) localization of excised tissues. However, their conclusion of “positive” signal from their uncharacterized antibody as enzymatic activity of BoNT/A in the tissue (WB & IHC) is problematic. Readers should not draw the conclusion that these preliminary non-clinical results are relevant to clinical applications.

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    Competing Interests: None declared.

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