Resume: Researchers have cracked the mystery behind how the Botulinum neurotoxin type-A, also known as Botox, infiltrates neurons. The toxin uses 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 how Botox works, will help identify new therapeutic targets for the treatment of botulism.
Key Facts:
- Researchers found that a receptor called Synaptotagmin 1, in conjunction with two other receptors, helps Botox enter neurons.
- Once inside the neurons, Botox disrupts communication between nerves and muscle cells, causing paralysis.
- The insights of the study could lead to the identification of new therapeutic targets to treat botulism.
Source: University of Queensland
Researchers at 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 of UQ’s Queensland Brain Institute have discovered the specific molecular mechanism by which the highly lethal Botulinum neurotoxin type-A, known as Botox, enters neurons.
The research has been 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 small complex that sits on the plasma membrane of neurons,” said Professor Meunier.
“The toxin hijacks this complex and enters the synaptic vesicles that store neurotransmitters essential for communication between neurons.
“Botox then interrupts 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 deadly bacterial infection.
“Now that we know how this complex facilitates toxin internalization, we can block interactions between two of the three receptors to prevent the deadly toxins from entering neurons,” said Professor Meunier.
The injectable drug Botox was originally developed to treat people with the eye condition strabismus, but was soon found to relieve migraines, chronic pain and spasticity.
Now it is regularly used in plastic surgery and is widely known as a cosmetic treatment to smooth out wrinkles.
Dr. Joensuu said it used to be difficult to figure out how the neurotoxin worked to relax muscles.
“Clostridial neurotoxins are among the most potent protein toxins known to man,” said Dr. Joensuu.
“We now have a complete picture of how these toxins are internalized to stun neurons at therapeutically relevant concentrations.”
About this neuroscience research news
Author: Frederick 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 entry into synaptic vesicles” by Frederic Meunier et al. EBMO journal
Abstract
Presynaptic targeting of botulinum neurotoxin type A requires a tripartite PSG-Syt1 – SV2 plasma membrane nanocluster for entry into synaptic vesicles
The unique nerve terminal targeting of botulinum neurotoxin type A (BoNT/A) is due to its ability to bind two receptors on the neuronal plasma membrane: polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Whether and how PSGs and SV2 can coordinate other proteins for BoNT/A recruitment and internalization remains unknown.
Here we show that the targeted endocytosis of BoNT/A in synaptic vesicles (SVs) requires a tripartite surface nanocluster. Live-cell super-resolution imaging and electron microscopy of catalytically inactivated BoNT/A wild-type and receptor-binding-deficient mutants in cultured hippocampal neurons showed that BoNT/A must coincidentally bind to a PSG and SV2 to target synaptic vesicles.
We reveal that BoNT/A interacts simultaneously with a preassembled PSG synaptotagmin-1 (Syt1) complex and SV2 at the neuronal plasma membrane, facilitating Syt1-SV2 nanoclustering that controls the 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 represent a unifying entry point for selected botulinum neurotoxins that hijack it for targeting synaptic vesicles.