We now know how Botox enters neurons and paralyses muscles

Molecular imaging shows that botulinum neurotoxin uses three receptors to enter neurons. The finding could help develop drugs to stop the toxin from infecting cells.

We finally know how Botox infiltrates neurons. The finding could aid efforts to develop an antidote for the molecule’s neurotoxic effects, which can result in paralysis or even death.

Illustration of Clostridium botulinum, bacteria that produce botulinum neurotoxin

Botox uses a type of botulinum neurotoxin, a highly poisonous substance produced by bacteria. The toxin disrupts communication between neurons, leading to muscle paralysis. In small, therapeutic doses this can ease muscle spasms, treat migraines or, more famously, reduce wrinkles. However, at high doses, the molecule causes botulism, a potentially fatal disease with few treatments.

Frederic Meunier at the University of Queensland in Australia and his colleagues analysed how botulinum neurotoxin type A enters neurons using a technique called single-molecule imaging. This allowed them to capture the movement of molecules labelled with fluorescent dye.

The researchers placed the toxin into a dish with neurons from rats. They trained one camera on the neurotoxin and another on receptors in the neuron membranes, also marked with different-coloured dyes.

Previously, it was believed only two receptors, called polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2), were key to the toxin’s entry into cells. But as they tracked SV2’s response to the toxin, they saw it was moving in tandem with another receptor known as synaptotagmin 1 (Syt1).

“We basically started to think, ‘oh, that’s bizarre’,” says Meunier. The researchers genetically modified the rat neurons to prevent Syt1 from binding with SV2 and repeated the experiment. If you inhibit the binding between these two receptors, the toxin cannot enter the cell anymore, says Meunier.

The same was true when they genetically modified neurons to lack PSG, indicating all three receptors are needed for botulinum neurotoxin type A to infiltrate cells. Future drugs that block the three receptors from binding together could stop the toxin from infecting neurons, says Meunier.

“By understanding more about the mechanism of cell entry, we are one step closer to preventing cell entry and preventing botulism,” says Sabine Pellett at the University of Wisconsin-Madison.

Journal reference:

The EMBO Journal DOI: 10.15252/embj.2022112095

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