Summary: Researchers have cracked the mystery of how 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 the synaptic vesicles of neurons.
This infiltration interrupts nerve-muscle communication, leading to paralysis. The results, which provide a complete picture of how Botox works, will help identify new therapeutic targets for the treatment of botulism.
Highlights:
- Researchers have found that a receptor called Synaptotagmin 1, in conjunction with two other receptors, helps Botox enter neurons.
- Once inside neurons, Botox disrupts communication between nerves and muscle cells, causing paralysis.
- Insights from 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 the Queensland Brain Institute at UQ have discovered the specific molecular mechanism by which the highly deadly botulinum neurotoxin type A, better known as Botox, enters neurons.
The research is published in The EMBO newspaper.
“We used super-resolution microscopy to show that a receptor called Synaptotagmin 1 binds to two other known clostridial neurotoxin receptors to form a tiny complex that sits on the plasma membrane of neurons,” Prof. Meunier said.
“The toxin hijacks this complex and enters synaptic vesicles which store neurotransmitters essential for communication between neurons.
“The Botox then interrupts the communication between nerves and muscle cells, causing paralysis.”
This discovery means that new therapeutic targets can be identified to develop effective treatments for botulism, a rare but potentially fatal bacterial infection.
“Now that we know how this complex enables toxin internalization, we can block interactions between two of the three receptors to prevent deadly toxins from entering neurons,” Professor Meunier said.
The injectable drug Botox was originally developed to treat people with strabismus, but was soon found to relieve migraine, chronic pain and spasticity disorders.
Now it is regularly used in plastic surgeries and is commonly referred to as a cosmetic treatment to smooth out wrinkles.
Dr Joensuu said how the neurotoxin works to relax muscles has previously been difficult to track.
“Clostridian neurotoxins are among the most potent protein toxins known to man,” 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: Frédéric Meunier – University of Queensland
Picture: Image is credited to Neuroscience News
Original research: Free access.
“Presynaptic targeting of botulinum neurotoxin type A requires a PSG‐Syt1‐SV2 tripartite plasma membrane nanocluster for synaptic vesicle entry” by Frederic Meunier et al. EPO Journal
Abstract
Presynaptic targeting of botulinum neurotoxin type A requires a PSG-Syt1-SV2 tripartite plasma membrane nanocluster for synaptic vesicle entry
The unique nerve terminal targeting of botulinum neurotoxin type A (BoNT/A) is due to its ability to bind to two receptors on the neuronal plasma membrane: polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). . It is unclear if and how PSG and SV2 can coordinate other proteins for the recruitment and internalization of BoNT/A.
Here, we demonstrate that the targeted endocytosis of BoNT/A in synaptic vesicles (SV) requires a tripartite surface nanocluster. Live-cell super-resolution imaging and electron microscopy of wild-type catalysis-inactivated BoNT/A and receptor-deficient mutants in cultured hippocampal neurons demonstrated that BoNT/A must coincidentally bind to a PSG and an SV2 to target synaptic vesicles.
We reveal that BoNT/A simultaneously interacts with a preassembled PSG-synaptotagmin-1 (Syt1) and SV2 complex on the neuronal plasma membrane, facilitating Syt1-SV2 nanoclustering that controls endocytic sorting of the toxin into synaptic vesicles.
Knockout of Syt1 CRISPRi abolished 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 certain botulinum neurotoxins that hijack this to targeting synaptic vesicles.