Molecular Mechanism of Action of Botulinal Neurotoxins and the Synaptic Remodeling They Induce In Vivo at the Skeletal Neuromuscular Junction

Meunier, Frédéric A.; Herreros, Judit; Schiavo, Giampietro; Poulain, Bernard; Molgó, Jordi

doi:10.1385/1-59259-132-9:305

Cited by 17 publications

(22 citation statements)

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“…This is the case for the clostridial NTs which are zincdependent proteases that cleave specific proteins inserted in synaptic vesicular membrane or presynaptic plasma membrane. TeNT and BoNT/B, D, F and G proteolyse VAMP (vesicle-associated membrane protein), leading to a blockade of neuroexocytosis (Meunier et al, 2002;Poulain et al, 2006). Interestingly, proteolytic activity of these NTs is higher with native VAMPs inserted into synaptic vesicle membranes than with soluble recombinant VAMPs.…”

Section: Lipids As Intracellular Receptors For Toxins or Associated Wmentioning

confidence: 99%

Bacterial protein toxins and lipids: role in toxin targeting and activity

Geny

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2006

Biology of the Cell

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All bacterial toxins, which globally are hydrophilic proteins, interact first with their target cells by recognizing a surface receptor, which is either a lipid or a lipid derivative, or another compound but in a lipid environment. Intracellular active toxins follow various trafficking pathways, the sorting of which is greatly dependent on the nature of the receptor, notably lipidic receptor or receptor embedded into a distinct environment such as lipid microdomains. Numerous other toxins act locally on cell membrane. Indeed, phospholipase activity is a common mechanism shared by several membrane‐damaging toxins. In addition, many toxins active intracellularly or on cell membrane modulate host cell phospholipid pathways. Unusually, a few bacterial toxins require a lipid post‐translational modification to be active. Thereby, lipids are obligate partners of bacterial toxins.

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Section: Lipids As Intracellular Receptors For Toxins or Associated Wmentioning

confidence: 99%

Bacterial protein toxins and lipids: role in toxin targeting and activity

Geny

Popoff

2006

Biology of the Cell

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“…The L chain translocates into the cytosol of motoneurons, where it gains access to substrate. L chains are zinc-dependent proteases that specifically cleave one of the three soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptors (SNARE), thus blocking evoked acetylcholine release at the skeletal neuromuscular junction (reviewed by Humeau et al, 2000;Meunier et al, 2002;Schiavo et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Expression of botulinum neurotoxins A and E, and associated non-toxin genes, during the transition phase and stability at high temperature: analysis by quantitative reverse transcription-PCR

2006

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Production of botulinum neurotoxin A (BoNT/A) and associated non-toxic proteins (ANTPs), which include a non-toxic non-haemagglutinin (NTNH/A) as well as haemagglutinins (HAs), was found previously to be dependent upon an RNA polymerase alternative sigma factor (BotR/A). Expression of the botR/A, bont/A and antp genes, monitored by reverse transcription and real-time PCR analysis, occurred concomitantly at the transition between the exponential and stationary growth phases of Clostridium botulinum A. The botR/A expression level was about 100-fold less than those of the bont/A and antp genes. Therefore, BotR/A is an alternative sigma factor controlling the botulinum A locus genes during the transition phase. The highest toxin concentration was released into the culture supernatant 12 h after maximum expression of the botR/A, bont/A and antp genes, without any apparent bacterial lysis. Toxin levels were then stable over 5 days in cultures at 37 6C, whereas a dramatic decrease in lethal activity was observed between 24 and 48 h in cultures at 44 6C. High temperature did inhibit transcription, since expression levels of the botR/A, bont/A and antp genes were similar in cultures at 37 and 44 6C. However, incubation at 44 6C triggered a calcium-dependent protease that degraded BoNT/A and NTNH/A, but not HAs. In C. botulinum E, which contains no gene related to botR, the bont/E and p47 genes were also expressed during the transition phase, and no protease activation at 44 6C was evident.

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“…Indeed, the peripheral dysautonomia and flaccid paralysis caused by BoNTs result from preferential inhibition of acetylcholine release. In the spinal cord or facial motor nuclei, TeNT-mediated blockade of glycine or GABA release disrupts the negative controls exerted by the inhibitory interneurons onto the motoneurons turning on excessive firing of the motoneurons and ensuing muscle contraction (review in [32,73,157,178]). …”

Section: Mode Of Action Of Clostridial Neurotoxinsmentioning

confidence: 99%

“…In vivo [220] and tissue-culture studies [221,222] have consistently shown that CGRP increases nicotinic ACh receptors messenger RNA (mRNA) and protein expression on the muscle cell surface, probably mediated by the intracellular cyclic adenosine monophosphate (cAMP) with a concomitant activation of protein kinase A (PKA). During BoNT/Ainduced synaptic remodeling, there is a large increase in CGRP immunoreactivity [178,[223][224][225][226]. This increase can be explained not only by the accumulation of large dense core vesicles containing CGRP in the nerve terminals following inhibition of the release machinery, but also from an upregulated synthesis of the neuropeptide in the motoneuron's soma [225,226].…”

Section: Bont-induced Muscle Paralysis Triggers Sprouting and Differementioning

confidence: 99%