A group of researchers has discovered how the tetanus neurotoxin enters the nerve cells. Furthermore, they believe the pathway used by the toxins could potentially be used to deliver treatments to the nervous system for other neurological conditions such as motor neuron disease.
As well as being able to explain how the tetanus neurotoxin enters the nervous system, the scientists from University College London (UCL) in the UK have discovered why it is so toxic, even when encountered in small quantities.
A group of proteins called nidogens that coat the surfaces of the cells are directly involved. Tetanus neurotoxin sticks to these proteins and is “shuttled” inside the cells. Once inside, the neurotoxin then begins to spread and cause damage throughout the nervous system.
“The nidogen coating around nerve cells acts like fly paper, attracting tetanus neurotoxins to cluster around them,” says study author Kinga Bercsenyi. “This explains why tetanus neurotoxin is so poisonous even at low doses, as it largely concentrates around motor neuron terminals, which are surrounded by high levels of nidogens.”
Tetanus is a potentially life-threatening bacterial disease, characterized by muscular spasms and stiffness, particularly in the jaw and neck, which can interfere with breathing. It is caused by spores of Clostridium tetani bacteria entering the body through wounds and producing powerful toxins that impair the motor neurons.
For the study, published in Science and funded by the Medical Research Council, the researchers inhibited the interaction between tetanus neurotoxin and nidogens in mice. They found that in doing so, the neurotoxin was prevented from binding with neurons, and the mice were protected from spastic paralysis caused by tetanus.
Through exploiting nidogens in the same way that the bacteria do, the researchers hope that new methods can be developed with which to deliver drugs directly into the nervous system.
For senior author Prof. Giampietro Schiavo, successfully finding a way to transport treatment to motor neurons solves half the problem of treating neurological disorders. “Now that we understand how tetanus gets in, we hope to mimic the mechanism to deliver advanced therapies,” he says.
The approach is comparable to virotherapy, whereby modified viruses are used to transport drugs to particular areas of the body or to attack harmful cells.
Prof. Schiavo explains that utilizing a pre-existing pathway into motor neurons is important, as creating new routes into cells can cause damage, adding:
“Our discovery should complement virotherapy, as protein engineers could design molecular shuttles that bind to and enter motor neurons in the same way as tetanus. The qualities that make tetanus such a powerful neurotoxin could help us to develop targeted treatments for patients with some of the most debilitating and paralyzing conditions.”
This could be good news for patients with conditions such as motor neuron diseases – including amyotrophic lateral sclerosis (ALS) – and peripheral neuropathies. These conditions currently lack either cures or standard forms of treatment, but this could change following the new findings.
Equally, although an effective tetanus vaccine is available, no targeted treatments currently exist. According to the authors, their findings should pave the way for the development of therapeutics for the prevention of tetanus by targeting the protein-protein interaction.
“We have now shown that the matrix around neurons plays a major role in cell entry, offering a new route for delivering treatments,” concludes Prof. Schiavo. “This discovery will help us to develop better treatments for motor and sensory neurons that concentrate in the right place, making them more effective at lower doses and reducing side effects.”
Recently, Medical News Today reported on a study that found a form of hypertension medication is associated with a reduced risk of ALS.