Summary: Researchers have cracked the mystery behind how the Botulinum neurotoxin type-A, also known as Botox, infiltrates neurons. The toxin utilizes a small complex formed by a receptor called Synaptotagmin 1, along with two other clostridial neurotoxin receptors, to enter synaptic vesicles in neurons.
This infiltration interrupts nerve-to-muscle communication, leading to paralysis. The findings, which provide a complete picture of Botox’s method of operation, will aid in identifying new therapeutic targets for botulism treatment.
- Researchers discovered that a receptor called Synaptotagmin 1, in collaboration with two other receptors, helps Botox enter neurons.
- Once inside the neurons, Botox disrupts communication between nerves and muscle cells, causing paralysis.
- The study’s insights could lead to the identification of new therapeutic targets to treat botulism.
Source: University of Queensland
Researchers from The University of Queensland have determined how Botox—a drug made from a deadly biological substance—enters brain cells.
Professor Frederic Meunier and Dr. Merja Joensuu at UQ’s Queensland Brain Institute have discovered the specific molecular mechanism by which the highly deadly Botulinum neurotoxin type-A, more widely known as Botox, enters neurons.
The research is published in The EMBO Journal.
“We used super-resolution microscopy to show that a receptor called Synaptotagmin 1 binds to two other previously known clostridial neurotoxin receptors to form a tiny complex that sits on the plasma membrane of neurons,” Professor Meunier said.
“The toxin hijacks this complex and enters the synaptic vesicles which store neurotransmitters critical to communication between neurons.
“Botox then interrupts the communication between nerves and muscle cells, causing paralysis.”
The discovery means new therapeutic targets can be identified to develop effective treatments for botulism—a rare but potentially fatal bacterial infection.
“Now we know how this complex allows the toxin internalization, we can block interactions between any two of the three receptors to stop the deadly toxins from getting into neurons,” Professor Meunier said.
The injectable drug Botox was originally developed to treat people with the eye condition strabismus, but was quickly found to alleviate migraine, chronic pain, and spasticity disorders.
Now, it’s regularly used in plastic surgeries and is commonly known as a cosmetic treatment to smooth wrinkles.
Dr. Joensuu said just how the neurotoxin worked to relax muscles has previously been difficult to track.
“Clostridial neurotoxins are among the most potent protein toxins known to humans,” Dr. Joensuu said.
“We now have a full picture of how these toxins are internalized to intoxicate neurons at therapeutically relevant concentrations.”
About this neuroscience research news
Author: Frederic Meunier
Source: University of Queensland
Contact: Frederic Meunier – University of Queensland
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Presynaptic targeting of botulinum neurotoxin type A requires a tripartite PSG‐Syt1 ‐ SV2 plasma membrane nanocluster for synaptic vesicle entry” by Frederic Meunier et al. EBMO Journal
Presynaptic targeting of botulinum neurotoxin type A requires a tripartite PSG‐Syt1 ‐ SV2 plasma membrane nanocluster for synaptic vesicle entry
The unique nerve terminal targeting of botulinum neurotoxin type A (BoNT/A) is due to its capacity to bind two receptors on the neuronal plasma membrane: polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Whether and how PSGs and SV2 may coordinate other proteins for BoNT/A recruitment and internalization remains unknown.
Here, we demonstrate that the targeted endocytosis of BoNT/A into synaptic vesicles (SVs) requires a tripartite surface nanocluster. Live-cell super-resolution imaging and electron microscopy of catalytically inactivated BoNT/A wildtype and receptor-binding-deficient mutants in cultured hippocampal neurons demonstrated that BoNT/A must bind coincidentally to a PSG and SV2 to target synaptic vesicles.
We reveal that BoNT/A simultaneously interacts with a preassembled PSG-synaptotagmin-1 (Syt1) complex and SV2 on the neuronal plasma membrane, facilitating Syt1-SV2 nanoclustering that controls endocytic sorting of the toxin into synaptic vesicles.
Syt1 CRISPRi knockdown suppressed BoNT/A- and BoNT/E-induced neurointoxication as quantified by SNAP-25 cleavage, suggesting that this tripartite nanocluster may be a unifying entry point for selected botulinum neurotoxins that hijack this for synaptic vesicle targeting.