Illustration of Clostridium botulinum, a bacterium that produces botulinum neurotoxin
Shutterstock/Mzhenchenko
We finally know how Botox invades neurons. The discovery could aid efforts to develop antidotes to the neurotoxic effects of this molecule, which can lead to paralysis and death.
Botox uses a type of botulinum neurotoxin, a highly toxic substance produced by bacteria. This toxin interferes with communication between neurons, causing muscle paralysis. Small therapeutic doses can relieve muscle spasms, treat migraines and, more famously, reduce wrinkles. However, at high doses, the molecule causes botulism, a potentially fatal disease with few treatments.
Frederick Meunier of the University of Queensland, Australia, and his colleagues used a technique called single-molecule imaging to analyze how the botulinum toxin type A enters neurons. This made it possible to capture the movement of molecules labeled with fluorescent dyes.
The researchers put the toxin in dishes containing rat neurons. They trained one camera on neurotoxins and another on receptors on neuronal membranes, also marked with different colored dyes.
Previously, only two receptors, called polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2), were thought to be key to toxin entry into cells. However, when we tracked SV2’s response to toxins, we found that SV2 works in conjunction with another receptor known as synaptotagmin 1 (Syt1).
“We basically started thinking, ‘Oh, that’s weird,'” says Meunier. The researchers genetically modified rat neurons to prevent Syt1 from binding to SV2 and repeated the experiment. Blocking the binding of these two receptors prevents the toxin from entering the cell, says Meunier.
The same was true when neurons were genetically modified to lack PSG, showing that all three receptors were required for botulinum type A neurotoxin to infiltrate cells. In the future, drugs could be developed that block the binding of the three receptors, preventing the toxin from infecting neurons, Meunier said.
“By better understanding the mechanisms of cell entry, we are one step closer to blocking cell entry and preventing botulism,” says Sabine Perrett of the University of Wisconsin-Madison.
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