Long-distance retrograde effects of botulinum neurotoxin A.
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.
Antonucci
Flavia
F
Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, 56100 Pisa, Italy.
Rossi
Chiara
C
Gianfranceschi
Laura
L
Rossetto
Ornella
O
Caleo
Matteo
M
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality; D008032:Limbic System / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000008:administration & dosage* / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D013997:Time Factors; D014738:Vibrissae / Q000294:innervation; D014795:Visual Pathways / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D050825:Synaptosomal-Associated Protein 25; D019274:Botulinum Toxins, Type A