Abstract
Botulinum neurotoxin type A (BoNT/A) is a metalloprotease that blocks synaptic transmission via the cleavage of SNAP-25 (synaptosomal-associated protein of 25 kDa). BoNT/A is successfully used in clinical neurology for the treatment of several neuromuscular pathologies and pain syndromes. Despite its widespread use, relatively little is known on BoNT/A intracellular trafficking in neurons. Using the visual pathway as a model system, here we show that catalytically active BoNT/A is capable of undergoing anterograde axonal transport and transcytosis. Following BoNT/A injection into the rat eye, significant levels of BoNT/A-cleaved SNAP-25 appeared in the retinorecipient layers of the superior colliculus (SC). Anterograde propagation of BoNT/A effects required axonal transport, ruling out a systemic spread of the toxin. Cleaved SNAP-25 was present in presynaptic structures of the tectum, but retinal terminals were devoid of the immunoreactivity, indicative of transcytosis. Experiments based on sequential administration of BoNT/A and BoNT/E showed a persistent catalytic activity of BoNT/A in tectal cells following its injection into the retina. Our findings demonstrate that catalytically active BoNT/A is anterogradely transported from the eye to the SC and transcytosed to tectal synapses. These data are important for a more complete understanding of the mechanisms of action of BoNT/A.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biological Transport / drug effects
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Botulinum Toxins / administration & dosage
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Botulinum Toxins / pharmacokinetics*
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Botulinum Toxins, Type A / pharmacology*
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CD11b Antigen / metabolism
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Dose-Response Relationship, Drug
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Excitatory Amino Acid Agonists / toxicity
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Functional Laterality / drug effects
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Glial Fibrillary Acidic Protein / metabolism
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Injections, Intraocular / methods
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Kainic Acid / toxicity
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Nerve Tissue Proteins / drug effects
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Nerve Tissue Proteins / metabolism*
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Neurotoxins / pharmacology*
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Phosphopyruvate Hydratase / metabolism
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Rats
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Rats, Long-Evans
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Superior Colliculi / drug effects
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Superior Colliculi / metabolism
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Synaptosomal-Associated Protein 25 / drug effects
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Synaptosomal-Associated Protein 25 / metabolism
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Time Factors
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Transcytosis / drug effects*
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Vesicular Glutamate Transport Protein 1 / metabolism
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Vesicular Glutamate Transport Protein 2 / metabolism
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Visual Pathways / drug effects*
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Visual Pathways / injuries
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Visual Pathways / metabolism
Substances
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CD11b Antigen
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Excitatory Amino Acid Agonists
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Glial Fibrillary Acidic Protein
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Nerve Tissue Proteins
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Neurotoxins
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Slc17a6 protein, rat
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Slc17a7 protein, rat
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Snap25 protein, rat
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Synaptosomal-Associated Protein 25
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Vesicular Glutamate Transport Protein 1
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Vesicular Glutamate Transport Protein 2
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Botulinum Toxins
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Botulinum Toxins, Type A
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Phosphopyruvate Hydratase
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Kainic Acid
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botulinum toxin type E