What is motor neurone disease?

In his early 20s, Professor Hawking was diagnosed with a rare neurological condition called motor neurone disease (MND). He was unusually young to have developed the condition, which usually affects people in their 60s and 70s and is often fatal within a few years. Yet, despite his diagnosis, Stephen Hawking managed to survive and cope with the disease to reach the age of 76. Georgia Mills spoke with Jemeen Sreedharan, who studies Motor neurone disease at the Kings College London and the Babraham Institute in Cambridge...

Georgia - Can you tell us what is motor neurone disease?

Jemeen - Motor neurone disease is a destructive degenerative disease of the brain and the spinal cord. It affects predominantly the motor nerves, which is why it causes paralysis; people are unable to breath or to move and to swallow, so it’s quite a debilitating disease and there’s no cure at the moment.

Georgia - Do we have any idea what causes it?

Jemeen - In about 10% of cases there are genes that we know of that cause the disease. At the moment we’re trying to work out how these genes actually cause damage to nerve cells. In the other 90%, it’s not very clear what causes the disease. Patients tend to be completely normal, with no previous family history, no previous ill health.

Georgia - What happens? The motor neurone nerves are affected, so what actually happens to someone with this condition?

Jemeen - Those nerves supply muscles that are important for swallowing, speech, for breathing and for movement; so all of those processes can suffer as a consequence, and different people will have different symptoms. If it affects the muscles of the legs - difficulty walking, and muscles of the hands - difficulty turning handles or turning keys, for example. If it affects the bulbar muscles, as we call it, it can cause problems speaking and swallowing. Patients can often have problems thinking, changes in their behaviour and changes in their language as well. Although, in general, one of the most striking things about MND is that patients feel, and they can see, and they still have bowel and bladder function and yet, for some reason, it’s just the motor nerves that seem to die.

Georgia - Do we know what’s killing them?

Jemeen - Yeah, this is a very important question. One of the things that we might think about is the size of a motor nerve. If you think of an individual whose maybe two metres tall, a motor nerve maybe a metre in length. It’s one of the largest cells in the body, the upper motor neurone has to go from the brain down to the spinal cord, and then from the spinal cord out to the big toe, so that’s a very big cell. And you’ve got to somehow maintain that cell for your entire lifetime and that’s not an easy thing to do.

Georgia - I see. So the cables within you that you need to be intact, if they break, that’s it?

Jemeen - Yeah. They can regenerate so, if you were to sustain an injury to your arm, for example, nerves can grow back. In the case of motor neurone disease, they don’t grow back quite so well.

Georgia - You mentioned there’s no cure. Is there any way to treat this?

Jemeen - There’s one drug that’s being use at the moment in the UK called riluzole and most of our patients take that drug. There are other drugs in development around the world that are licensed in other countries. They have a relatively small effect on the disease progress so, at the moment, we’re working very hard to try and develop therapies that are really effective and are going to slow down the disease process in a more effective way.

Georgia - This disease is something you look into in your lab, so how are you investigating it?

Jemeen - We use a number of different tools. Most recently we have done a fly model - drosophila. And recently we’ve done a mouse model and this is a brand new model of motor neurone disease, and it gets dementia which is quite interesting because we know that, in humans, MND and frontotemporal dementia overlap quite a lot. That's something that’s relatively underappreciated but it’s something we recognise now.

The mouse is completely different to other mouse models in that we haven’t tried to make the animal deliberately very sick, which is the general approach. What we’ve done is replicate the human condition. We’ve made a 1 in 3 billion genetic change, which makes it look like a human basically, because the mouse has the same protein as we have. And we’ve found in the brains of these animals that they have changes in certain kinds of nerves cells that you wouldn’t normally have thought would be linked with motor neurone disease.

Georgia - When scientists examine diseases, what they often do is give this disease to a mouse - we call it a model, and what you’ve done is make it much more similar to how it expressed in humans rather than how it is in mice? So what has this told you?

Jemeen - What it’s told us, the most important thing is that the protein normally through very intricate homeostatic mechanisms regulates an expression. In this mouse we see that these protein levels are actually higher than normal. We haven’t tried to increase the protein level but the mutation results in the protein losing its ability to regulate and that causes a whole chain reaction. Because what it normally does is it regulates other genes’ expression and all of that has gone wrong and what we find is that the more of this protein that you have, the more other gene expressions can go wrong. One of those genes happens to be a gene that encodes “tal”  which is a protein that’s linked in Alzheimer’s disease which has never been discovered before.

Georgia - It sounds like you’re putting pieces of the jigsaw together here, does this mean now we know that protein goes wrong we can target it with a drug?

Jemeen - What we’re trying to do now is to work out whether this is relevant to humans, but we think it is. The reason is that this protein is highly conserved which means that it’s exactly the same pretty much as in humans. We’re trying to work with human stem cells now to confirm that finding and, if that’s the case, then it’s something that we can target.

It’s complicated because the protein TDP 43: too much of it is bad; too little of it is bad as well so we can’t just find ways of reducing the expression. We have to be very careful about how we balance that level of expression and we have to try and do that specifically within the nervous system. The protein is present all over the body but it seems to be the brain and spinal cord that are particularly vulnerable.