Investigating potential treatments for the myasthenias
Project leader: Prof. David Beeson
Location: University of Oxford
Conditions: Myasthenia gravis and congenital myasthenic syndromes
Duration of project: 3 years (starting October 2009)
Total project cost: £91,950
Official title: Targeting ColQ as a cause of disease and as a novel therapy in myasthenic disorders
Prof Beeson will supervise this three year PhD studentship with the overall aim of investigating treatment and diagnostic approaches for the myasthenias, which include myasthenia gravis and congenital myasthenic syndromes. He will try to further understand the underlying causes of the myasthenias and investigate whether decreasing the levels of a protein called ColQ could be a practical approach for the treatment of these conditions.
Contents
- What are the researchers aiming to do?
- How will the outcomes of the research benefit patients?
- Background information
- Further information and links
What are the researchers aiming to do?
The inherited and acquired myasthenias, which include myasthenia gravis and the congenital myasthenic syndromes, have in common a problem with the signal that comes from the nerve and tells the muscle to contract.
The place where the nerve and muscle meet is called the neuromuscular junction and in order for the muscle to contract, the nerve must send a signal across the neuromuscular junction. The signal travels down the nerve and causes it to release a chemical signal called acetylcholine. The acetylcholine then binds to proteins on the muscle membrane called receptors which set in motion the chain of events that allows the muscle to contract. Once the muscle has contracted, the signal must be "switched off" allowing the muscle to relax. This is done by an enzyme called acetylcholinesterase which breaks down the acetylcholine that is left in the neuromuscular junction.
In order for this process to function properly, many different proteins play a role in making sure that the acetylcholine receptors and the acetylcholinesterase are correctly positioned at the neuromuscular junction. Mutations in the genes that carry the instructions for any of these proteins can cause one of the congenital myasthenic syndromes. In myasthenia gravis, it is antibodies attacking the proteins at the neuromuscular junction that are the cause of the problem. Both of these problems result in a weaker signal reaching the muscle leading to the muscle weakness and fatigue seen in these conditions.
Prof Beeson's work will follow two strands of research. The first part aims to look at myasthenia gravis. It is known that this is caused by antibodies attacking proteins in the neuromuscular junction, most commonly the acetylcholine receptors and a protein called MuSK. Clinicians can test for antibodies to these proteins in order to diagnose the patients. There are some patients, however, for whom antibodies cannot be found and it is thought this is because the antibodies are attacking other, as yet unknown, neuromuscular junction proteins. Prof Beeson wishes identify other proteins that might be involved in myasthenia gravis. To do this, he will label certain proteins with a fluorescent green marker in order to determine if antibodies from patients with myasthenia gravis will bind to them.
The second strand of work involves looking at treatment approaches for the myasthenias. Current treatments for both the congenital myasthenic syndromes and myasthenia gravis are often drug treatments aimed at inhibiting acetylcholinesterase so it can no longer break down the acetylcholine. This tends to become less effective over time and can have side effects. Prof Beeson will investigate other ways to inhibit acetylcholinesterase by altering the levels of a protein called ColQ. ColQ is needed to anchor acetylcholinesterase at the neuromuscular junction, so by decreasing the amount of ColQ, there would be a corresponding decrease in the amount of acetylcholinesterase present at the neuromuscular junction. This would allow an increase in the amount of acetylcholine so increasing the strength of the signal from the nerve to the muscle.
How will the outcomes of the research benefit patients?
If Prof Beeson identifies new proteins that are being attacked by antibodies in myasthenia gravis, this could provide the basis of additional diagnostic tests to be used in the clinic. This will give those patients for whom the antibodies cannot currently be identified a definite diagnosis. The second strand of this work, which involves the investigation of therapeutic approaches will give scientists an idea of whether decreasing the amount of ColQ at the neuromuscular junction might be a viable therapy that could be moved forward into the clinic.
By looking at alternate ways to decrease the activity of the acetylcholinesterase enzyme new therapies could be created which have potentially fewer side effects than current drug treatments. By targeting specific proteins at the neuromuscular junction more effective treatments may be produced
Background information
The myasthenias include both inherited and acquired conditions. The congenital myasthenic syndromes are inherited and are caused by genetic faults in the genes that carry the instructions for proteins in the neuromuscular junction.
Myasthenia gravis, however, is an acquired condition. This means that you are not born with the fault but develop the condition during your lifetime. In myasthenia gravis, the body attacks its own proteins, in this case the proteins of the neuromuscular junction.
So although the underlying cause of myasthenia gravis and the congenital myasthenic syndromes is different, the end result - a problem with the signal coming from the nerve to the muscle - is similar.
Further information and links
More information about myasthenia gravis.
Find out about other research we are funding.
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