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  • Title: Perturbation to Cholesterol at the Neuromuscular Junction Confers Botulinum Neurotoxin A Sensitivity to Neonatal Mice.
    Author: Thyagarajan B, Potian JG, McArdle JJ, Baskaran P.
    Journal: Toxicol Sci; 2017 Sep 01; 159(1):179-188. PubMed ID: 28645175.
    Abstract:
    Botulinum neurotoxin A (BoNT/A) cleaves SNAP25 at the motor nerve terminals and inhibits stimulus evoked acetylcholine release. This causes skeletal muscle paralysis. However, younger neonatal mice (<P7; <7-days old) are resistant to the neuroparalytic effects of BoNT/A. That is, invivo injection of BoNT/A at the innervations of Extensor digitorum longus muscle in the hindlimbs inhibited the toe spread reflex within 24 hours following BoNT/A injection in adult mouse and in older (>P7) mice. However, neonatal mice younger than 7 days-age remained unaffected by BoNT/A injection. Also, BoNT/A inhibited stimulus evoked acetylcholine release and stimulus-evoked twitch tension of diaphragm nerve muscle preparations (NMPs) of adult mouse and >P7 neonates but not that of <P7. Moreover, NMPs of <P7 showed decreased uptake of fluorescent BoNT/A compared to >P7. However, cholesterol depletion using methyl-β-cyclodextrin (MβCD) sensitized <P7 neonates to BoNT/A and facilitated BoNT/A uptake into NMPs obtained from <P7 neonates. Further, MβCD (10 mM; 30 min pretreatment) increased the interaction between synaptic vesicle protein 2 and BoNT/A. Also, cholesterol depletion increased the miniature endplate current in adult NMPs. Interestingly, cholesterol replenishment, invitro, delayed the onset of inhibitory effect of BoNT/A. Collectively, our data suggest that cholesterol rich lipid microdomains are involved in BoNT/A uptake mechanisms during development. Our data demonstrate that cholesterol depletion sensitized neonatal mice (<P7) to BoNT/A while replenishing cholesterol delayed the onset of inhibitory actin of BoNT/A. This suggests that membrane cholesterol modulates neurotoxin sensitivity at the neuromuscular junction (NMJ).
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