Botulinum Neurotoxin A Impairs Neurotransmission Following Retrograde Transynaptic Transport

Restani, Laura; Novelli, Elena; Bottari, David; Leone, Paola; Barone, Ilaria; Galli‐Resta, Lucia; Strettoi, Enrica; Caleo, Matteo

doi:10.1111/j.1600-0854.2012.01369.x

Cited by 80 publications

(82 citation statements)

References 52 publications

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“…In present study we examined whether BoNT/A's enzymatic activity in the TNC is located in primary sensory In present experiments we did not observe any truncated SNAP-25 remaining after ganglionic denervation, thus, our results do not support possible transcytosis to second order synapses in the TNC. However, transcytosis of BoNT/A in rats was demonstrated after both anterograde and retrograde axonal transport in the optic system [52,53]. Recently, a decrease of spontaneous and evoked inhibitory glycinergic potentials in isolated rat lumbar substantia gelatinosa neurons following peripheral BoNT/A injection was reported [1].…”

Section: Enzymatic Activity Of Bont/a In Tnc Occurs In Central Afferementioning

confidence: 99%

Botulinum toxin type A selectivity for certain types of pain is associated with capsaicin-sensitive neurons

Matak

Rossetto

Lacković

2014

Pain

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Section: Enzymatic Activity Of Bont/a In Tnc Occurs In Central Afferementioning

confidence: 99%

Botulinum toxin type A selectivity for certain types of pain is associated with capsaicin-sensitive neurons

Matak

Rossetto

Lacković

2014

Pain

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“…In addition, BoNT/A2 is more potent than BoNT/A1 in cultured primary neurons (24,28). Retrograde movement of BoNT/A1 has been observed in mice (29)(30)(31) and cultured neurons (32), but BoNT/A2 trafficking has not been examined. Thus, to identify potential differences between BoNT/A1 and BoNT/A2, entry of H C A1 and H C A2 into neurons was studied.…”

mentioning

confidence: 99%

Entry of Botulinum Neurotoxin Subtypes A1 and A2 into Neurons

et al. 2017

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Botulinum neurotoxins (BoNTs) are the most toxic proteins for humans but also are common therapies for neurological diseases. BoNTs are dichain toxins, comprising an N-terminal catalytic domain (LC) disulfide bond linked to a C-terminal heavy chain (HC) which includes a translocation domain (H N ) and a receptor binding domain (H C ). Recently, the BoNT serotype A (BoNT/A) subtypes A1 and A2 were reported to possess similar potencies but different rates of cellular intoxication and pathology in a mouse model of botulism. The current study measured H C A1 and H C A2 entry into rat primary neurons and cultured Neuro2A cells. We found that there were two sequential steps during the association of BoNT/A with neurons. The initial step was ganglioside dependent, while the subsequent step involved association with synaptic vesicles. H C A1 and H C A2 entered the same population of synaptic vesicles and entered cells at similar rates. The primary difference was that H C A2 had a higher degree of receptor occupancy for cells and neurons than HcA1. Thus, H C A2 and H C A1 share receptors and entry pathway but differ in their affinity for receptor. The initial interaction of H C A1 and H C A2 with neurons may contribute to the unique pathologies of BoNT/A1 and BoNT/A2 in mouse models.KEYWORDS botulinum toxin, gangliosides, synaptic vesicles, synaptic vesicle protein 2, TIRF microscopy, clostridial neurotoxins, Clostridium botulinum, toxins B otulinum neurotoxins (BoNTs) are AB exotoxins secreted by several species of the genus Clostridium. BoNTs are single-chain 150-kDa proteins cleaved by either bacterial or host proteases to a dichain comprising a 50-kDa light chain (LC) and a 100-kDa heavy chain (HC) linked by an interchain disulfide bond. The HC includes a translocation domain (H N ) and receptor binding domain (H C ) (1). The H C includes an N-terminal subdomain (H CN ) of limited known function and a C-terminal subdomain (H CC ) that confers neuron specificity by binding dual neuron-specific receptors. There are seven BoNT serotypes (A to G) (2). BoNT serotype A (BoNT/A) binds a ganglioside and synaptic vesicle glycoprotein 2 (SV2) (3-6), which allows rapid toxin entry via synaptic vesicles. Acidification of the synaptic vesicle lumen triggers H N to form a channel to facilitate LC translocation into the cytosol. Intracellular LC cleaves a SNARE (soluble N-ethylmaleimide-sensitive factor [NSF] attachment protein receptor) protein (7-12). SNARE protein cleavage inhibits exocytosis of cholinergic synaptic vesicles at neuromuscular junctions. BoNT LCs are long-lived proteases, sustaining paralysis in humans for several months depending on the serotype (2), which led to the licensing of BoNT/A and BoNT/B for human therapies (13,14).BoNT serotypes include subtypes neutralized by serotype-specific antisera (15-17). Informatics has classified eight BoNT/A subtypes (A1 to A8), which vary by ϳ10 to 15% in amino acid identity (15,16,(18)(19)(20)(21). While BoNT/A1 and BoNT/A2 cleave SNAP25 with similar kinetics (22-2...

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“…As such, the intracellular fate of BoNTs might not be restricted to synapses, but rather involve long-range traffic similar to TeNT. In agreement, several research groups have demonstrated that BoNT/A is retrogradely transported in different neuronal types, including hippocampal, tectal, and motor neurons [113,114], and undergoes transcytosis in the visual system [115,116]. Additionally, FGFR3 was identified as a new protein receptor for BoNT/A in resting conditions [117].…”

Section: Bont Receptorsmentioning

confidence: 73%