Worms on the brain
I’m a PhD student working at the University of Manchester, in a lab which has received lots of support from Alzheimer’s Research UK over the years. I’m funded by the University, but we have also recently been awarded a grant from the charity to fund more work in our lab starting later this year.
My research uses a species of tiny microscopic worm to study a gene called C9ORF72, and the role it plays in dementia. Here’s a bit about how I do it!
What is C9ORF72, and what does it have to do with dementia?
In 2011, researchers discovered an error in a gene called C9ORF72 as a major cause of two debilitating diseases which can occur together in the same people, or run in the same family. The first is a type of dementia called frontotemporal dementia (or FTD), which causes a wide range of behavioural symptoms including changes in social conduct and loss of empathy for other people’s feelings. The second is motor neurone disease (or MND, also known as ALS or Lou Gehrig’s disease). MND is a truly devastating disease, causing progressive paralysis and shortening life-expectancy to just a few years from diagnosis. Some people with the C9ORF72 error develop either FTD or MND, whilst others develop symptoms of both diseases together.
The faulty C9ORF72 gene is by far the most common genetic cause of either FTD or MND that we know about to date, responsible for around 1 in 12 cases. So it’s really important to focus research on understanding exactly how having this version of the gene damages brain cells and causes dementia. Under the supervision of Prof Stuart Pickering-Brown at the University of Manchester, I’m trying to figure this out using a species of worm called C. elegans.
How can worms be used to study dementia?
C. elegans worms are only about 1mm long when fully grown, which is why we need a microscope to see them properly. These tiny invertebrate worms may seem a million miles away from human beings, but there’s a surprising amount of similarity in our genes and the way our cells work. In fact, for more than 75% of all the genes that we know cause disease in people, there is an equivalent gene in the worm. This makes C. elegans a really useful tool to study genetic disease.
We know that the faulty C9ORF72 gene stops brain cells from working properly, and that this leads to symptoms in those people affected. What we don’t know is exactly how this happens, and that’s where our worms come in. Luckily for us, the C. elegans worm has a gene which is very similar to human C9ORF72. By making changes to the C. elegans version of C9ORF72 and seeing what happens to the worms, we hope to better understand exactly how an error in C9ORF72 leads to the symptoms of FTD and MND in patients.
Of course we can’t look for typical FTD symptoms like loss of empathy or changes in social conduct in worms. However, we can look for symptoms reminiscent of MND. People with MND experience severe movement difficulties and a shortened life-expectancy. Both of these things are easy to spot in worms. So we can make changes to the C. elegans gene, and then see whether our worms develop problems similar to the symptoms of MND. Since FTD and MND can be caused by the same faulty gene, a worm that mimics aspects of MND would be a useful tool to study both diseases at once.
Could worms help us find new dementia drugs?
A major advantage of using C. elegans worms to study genetic diseases is that we can use them to very efficiently test new drugs which might be useful to treat the disease in people. If we are able to create a worm which mimics FTD or MND, we could use these worms to test different compounds on a large-scale, and look for any that reduce the symptoms of disease. So if we make changes to the C9ORF72 gene in C. elegans, and this causes movement problems reminiscent of MND, we can treat these worms with different drugs and see whether they start to move more normally again. This could mean we’ve found a drug that might be useful in the treatment of FTD and MND cases caused by the faulty C9ORF72 gene.
The process of testing drugs like this is much quicker in worms than in other animals like rats and mice, and much cheaper and easier to do. Our collaborators in Prof David Sattelle’s lab at University College London have developed an automated method to screen whole libraries of around 1000 drugs in a matter of just a few short months, to look for potential new therapies. Any promising drugs would need to be further tested in mice or other animals which are more biologically similar to people, but by carrying out the initial tests of hundreds of drugs in worms we can save a huge amount of time and hopefully be on the way to developing new treatments for dementia much more quickly.