Perturbation to Cholesterol at the Neuromuscular Junction Confers Botulinum Neurotoxin A Sensitivity to Neonatal Mice

作者：Thyagarajan Baskaran^*; Potian Joseph G; McArdle Joseph J; Baskaran Padmamalini

来源：Toxicological Sciences, 2017, 159(1): 179-188.

DOI：10.1093/toxsci/kfx127

• neonatal neuromuscular junction
• botulinum neurotoxin
• cholesterol-rich lipid microdomains
• synaptic vesicle protein
• methyl-beta-cyclodextrin

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) 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. However, cholesterol depletion using methyl-beta-cyclodextrin (MbCD) sensitized <P7 neonates to BoNT/A and facilitated BoNT/A uptake into NMPs obtained from < P7 neonates. Further, MbCD (10mM; 30min 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, in vitro, 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).

• 出版日期2017-9
• 单位rutgers