title: Evidence for anterograde transport and transcytosis of botulinum neurotoxin A (BoNT/A).
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.
authors: CNR Neuroscience Institute, 56100 Pisa, Italy.
authors: Laura
authors: L
authors: Restani
authors: Flavia
authors: F
authors: Antonucci
authors: Laura
authors: L
authors: Gianfranceschi
authors: Chiara
authors: C
authors: Rossi
authors: Ornella
authors: O
authors: Rossetto
authors: Matteo
authors: M
authors: Caleo
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001905:Botulinum Toxins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019274:Botulinum Toxins, Type A / Q000494:pharmacology*; D039481:CD11b Antigen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D007839:Functional Laterality / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D056965:Injections, Intraocular / Q000379:methods; D007608:Kainic Acid / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D013477:Superior Colliculi / Q000187:drug effects / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D057900:Transcytosis / Q000187:drug effects*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism; D014795:Visual Pathways / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; C493475:Slc17a6 protein, rat; C493466:Slc17a7 protein, rat; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A; D010751:Phosphopyruvate Hydratase; D007608:Kainic Acid; C096326:botulinum toxin type E