Association-funded PhD student, Helena Chaytow (Royal Holloway, University of London), is using DNA to develop a targeted treatment for MND. Now entering her final year, we report on what she’s achieved so far and her future plans.
Helena’s research is looking at the chemical messenger ‘glutamate’. Glutamate is released by motor neurones in order to stimulate a nerve impulse from one motor neurone to the other, which is how the instruction to move our muscles travels from our brain to our limbs.
In order to pass the message on, glutamate needs to bind to the second nerve cell, and it does this by acting like a ‘lock and key’. Glutamate acts as a key, opening its specific lock (receptor) on the second nerve cell. This causes the nerve cell to open up and fill with several molecules including calcium, triggering the second nerve cell to pass on the nerve impulse (see image below).
However, too much glutamate can be toxic to motor neurones causing ‘excitotoxicity’. Excitotoxicity is one of the mechanisms believed to cause motor neurones to die in MND. An overload of glutamate can cause the motor neurone to be constantly ‘open’, leading to an excess build up of calcium within the cell. This build up of calcium eventually causes the motor neurones to die. Stopping this glutamate overload is key to Helena’s research.
Stopping excitoxicity (Helena’s project)
The glutamate receptor normally prevents calcium entry, enabling the cell to control this process. When cells make a receptor, the information coded in the DNA is put into an RNA molecule, which acts as a messenger carrying the information from the nucleus to the rest of the cell. The cell usually edits this RNA molecule before it is used to create the glutamate receptor. However, this RNA editing process appears to be disrupted in MND, and so the glutamate receptor becomes faulty and is unable to control the amount of calcium entering the cell, leading to cell death.
During the first two years of Helena’s research, she has been focussed on this RNA editing process, and how it can be improved in MND. One way is to improve the cell’s editing machinery. By manipulating the enzyme that carries out the RNA editing, the number of “edited” glutamate receptors could be increased. Helena has also been working on purposefully disrupting the RNA editing to observe any other effects in cells.
The way in which Helena has corrected this process is by using antisense oligonucleotides. This is a new type of therapy that is designed to bind directly to the faulty RNA target sequence and correct it. By correcting at this early stage, before the faulty glutamate receptor is produced, Helena hopes to reduce excitotoxicity from happening within the cell, and so reducing the calcium levels and stopping the motor neurone from dying.
Helena said: “The next steps in my project are to move my treatments from the cell lines that I’ve been working in to neuronal cells. I can then assess whether my antisense therapy can improve RNA editing enough to prevent neurones from dying.”
The ability to improve RNA editing gives this research a foundation to build on in order to develop a potential treatment for MND.
More about this research
Dr Philip Chen, Prof George Dickson and Dr Linda Popplewell, based at the Royal Holloway, University of London, were awarded £88,924 in 2012 for Helena’s three year PhD studentship.
This project aims to investigate whether small strands of DNA, known as ‘antisense oligonucleotides’ can be used to improve the efficiency of the RNA editing process, resulting in more properly formed glutamate receptor proteins and making the neurone more resistant to damage.