Motorneurone Disease (MND), which is also known as ALS and Lou Gehrig's Disease, is caused by the death of the motor nerves that convey movement instructions from the nervous system to muscles. We don't understand why this happens, but up to 10% of cases appear to be genetic. Now Babraham Institute researcher Jemeen Sreedharan has genetically engineered into a mouse the same genetic change that causes MND in humans. His animals are now providing us with new insights into the pathological process that underlies MND, as he explains to Chris Smith...
Jameen - Motorneurone disease is an incurable condition; and although we've been very good at actually finding genes that cause the disease over the past 10 years or so we don't know how they cause disease. So what we decided to do was to try and make models of disease. People have been doing this for some time now but they've been doing it usually by making an assumption which is that too much of a protein or too little bit of protein is bad. But we dont know if that's the case or not. So we decided to make a model that more accurately reflects what's going on in the human.
Chris - And in a human patient who has motor neurone disease, what do they present with? How would they know they have the disease? How would a person observing them know they had the disease?
Jameen - It varies a lot from person to person. MND is a disease that can affect such a large part of the body: any part of the brain, the motor system in the brain, or in the spinal cord. So it could affect the motor nerves that supply the legs or the arms or the hands or the tongue or swallowing.
Chris - And this is caused by the loss of nerve cells that communicates messages from the nervous system into muscles? For some reason, those cells are selectively vulnerable and we don't know why?
Jameen - Yeah there's a circuit, so the nerves in the in the brain the upper motorneurons go down into the brainstem or into the spinal cord and from there into the periphery where they supply the muscles; so those circuits are affected specifically in motor neurone disease although we're now understanding there are other nerves that also kind of connect between those nerves that are also important.
Chris - So the model that you set out to make - and when we say "model" this is basically making something like a mouse, for example, that develops something which recapitulates - we hope - what a human would suffer with? How have you gone about doing that, and why should your approach be better than what's come before?
Jameen - Other approaches are very useful, but what we've done is to try and not make an assumption about what we think causes disease. We know that these mutations are linked to disease, but how they cause disease we don't know.
Chris - When you say mutations what mutations are they?
Jemeen - Yeah. So we focused on a protein called TDP-43. This is a protein that's central to almost everybody with motor neurone disease, in that it accumulates in the brains of patients with MND. A handful of patients have mutations in the gene that encodes that protein - just one small change in most cases - and we made that one small change in the mouse, because the mouse has the same gene as the human.
Chris - So you engineer into a mouse the same change that a handful - but a reasonable handful - of people who have human motor neurone disease have; that means the mouse brain and tissues in the mouse also carry that change; do the mice go on to develop changes a bit like a person with MND then?
Jameen - Yes they do. But what we found was rather than getting a predominantly motor problem - with paralysis - they get mostly a cognitive problem. So we've looked very closely with a scientist called Tim Bussey at Cambridge University who is a psychologist - using some very sophisticated technology - to find out what kind of cognitive problems they have. And what they have in the cognitive realm matches what we see in patients with motor neurone disease and that overlaps with frontotemporal dementia.
Chris - How do you account for the difference, then, because the human takes five or six decades to get motor neurone disease; a mouse only lives for a couple of years, if it's very very lucky, yet you're saying you've got mice which are already manifesting changes when they carry this human mutation. Is that is that an artifact of the fact that it's gone into a mouse, or is it that something else is going on and the human brain is coping better with a mutation?
Jameen - I think it's partly the fact that we're we've got a mouse model. This is not a human, and the human brain is significantly bigger than a mouse brain. I think one possibility is that the plasticity of the human brain is able to compensate for abnormalities and therefore individuals don't actually seem to have cognitive problems. Some patients do actually have quite florid cognitive problems, and they manifest with striking behavioral changes. In our mouse model, what we've also found is that some mice get sick and others don't, which is another interesting phenomenon. So as well as the differences between the mouse and the human brain, perhaps explaining why we have a difference in the kind of observations we're making; I think the fact that the mouse doesn't live for seventy years may explain why they don't actually seem to get motorneurone disease; if they did that maybe they would.
Chris - How would this then explain what you think is going on in a person who has motor neurone disease; they carry this mutation, or or, if they don't carry that mutation and they're going to get motor neurone disease something else makes something change in cells in the same way as that mutation might. But how does that lead ultimately, then, to the loss of nerve cells and specifically the loss of the motor nerve cells? What do you think.
Jameen - Yeah this is a very important question. I mean, the protein that we're working on, TDP 43, is present everywhere. It's in the skin; it's in the eyes; it's in the liver, kidneys and it's also in the brain; and the brain is unusual in that it doesn't divide; the cells don't divide. So I think one of the problems with the brain is that it can't compensate over the course of time quite as well as other organs in the body, for example higher levels of the protein or the consequences of that higher level of protein. So the brain is particularly vulnerable; motorneurones are perhaps particularly vulnerable because of their size, and the fact that they form a very intricate network with the periphery; but also, for reasons that we don't fully understand, motor neurons have differences in gene expression compared to other neurons. They have vulnerabilities that I don't think we fully understand yet.
Chris - Do you think then that one possible model could be that theres a whole slew of nerve cells which are being affected in the brain when they have this mutation present or similar changes that produce similar biochemistry caused by some other genetic cause perhaps, but whatever the cause, you've got cells which are destined to die, and that in some way feeds back on the behaviour of the motor neurones so that they then are rendered say electrically unstable or they're more likely to get too carried away and die because of say over-excitement because of the loss of another cell. Because we've all pinned this, for years, on "it's a loss of motor neurons" - but are they dying because other cells have died first?
Jameen - Absolutely. I mean this is something that we've found in our mouse model. So what we've found is that although the brain appears to look superficially normal when we look at it with special stains for the nerve cells, when we look at what we call transcriptomic data - when we look at the genetic expression data - we find subtle changes in a gene that's expressed in specific interneurons. So these are neurons that are not motor neurons but they link motor neuron to other neurons, and what they do is normally dampen down the activity of motor neuron. So what we think is that the loss of these neurons may be contributing to eventually the death of motor neurons. We don't see that in a mouse yet because they don't live long enough, but the lack of dampening activity could result in what we call excitotoxicity.
Chris - If you can pin this on a protein, then, does that mean that you may have a new druggable target for motor neurone disease?
Jameen - I think we do. The single most important finding from the study is that the protein has lost the ability to control itself. Normally, through a homeostatic mechanism that isnt fully understood, it regulates its own expression. In this model, what we see is that it's slightly higher than normal, and it shouldn't be. If those mechanisms are conserved in human systems - and that's what we're looking at now using human stem cells - then we have a target. It's not going to be straightforward, because this is a protein that can't be too high and can't be too low. So we need to find a way of tinkering with the mechanism that causes the protein to balance itself very intimately without causing damage...
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