Dr Ed Wild, University College London
Chris - Now, one of the most important neurological diseases on the block at the moment is one called Huntingtonís disease. It affects about 8 in every 100,000 people here in the UK. Itís a genetic disorder and people tend to get the disease symptoms by the time they're aged about 40 or 50. And it has impacts on peopleís ability to move correctly. It can also impair the way in which the brain functions, in thelater stage especially, and people are currently trying to work out why the disease occurs, why people get the symptoms they do and whether we can actually reverse or at least arrest the process. And one of the scientists whoís working on Huntingtonís disease is Dr. Ed Wald and heís based at University College Londonís Institute of Neurology and heís also interested on how the disease affects the functioning of the immune system, and what role that might play in the disease. Heís with us now. Hello, Ed.
Ed - Hi, Chris.
Chris - Welcome to The Naked Scientists. First of all, can you just explain a little bit about what we understand of the background of the genetics of Huntington's disease?
Ed - Yes, sure I will. Weíre quite lucky in Huntington's disease research because the genetics is quite well worked out and weíve known what the gene is that causes Huntington's disease since 1993, after a massive international research collaboration to look for it. And that in many ways, puts us at a bit of an advantage over other brain disease like Alzheimer's which weíll be hearing about later on, motor neuron disease, Parkinsonís disease where there are genes that are known to influence the disease. But in Huntington's disease, we know exactly what gene causes it. It has two names. One is the Huntington gene and the other is IT15 which stood for Interesting Transcript-15 which is perhaps the genetic understatement of the Ď90s. And this is a gene that encodes for a protein called Huntingtin. So the gene is the recipe for this Huntingtin protein. Weíve known about this now for 16 years. We know a lot of things that a Huntingtin protein does but itís still a very mysterious protein. Itís a very big protein and itís one thatís very difficult to work with.
Chris - Do we understand at all about why it is that it causes the very discreet symptoms it does? I mentioned some of them. People with Huntington's first of all tend to notice that their movements go a bit array and then they start to get other symptoms as well and this takes up to 40 years before it manifests itself. So why is that and why are there these very discreet changes to peopleís movements and behaviour?
Ed - Well, what we do know about HD is that the bit of the brain thatís affected earliest, at least as far as we can tell, looking at it under microscopes or with brain scans, is the basal ganglia. And those are the sort of deep grey matter structures down in the brain that have very important stop-go and coordinating functions for movements. And so, one of the characteristic features of Huntington's is a phenomenon called Chorea which is from the Greek word for dancing. Thatís where we get the word choreography from. And thatís because patients with HD almost invariably get these unusual dancing like movements, involuntary movements of the arms and legs, and face. On top of that though, they get problems with voluntary movements. They lose their voluntary movements, a bit like what you see in Parkinsonís disease.
Chris - Is this because they're actually physically losing brain cells? And if so, whatís going on in the cells that are dying? Why are they dying?
Ed - Well, thatís the million dollar question for HD families. We know lots of things are going on, but at the moment, thereís no clear consensus on what the most important function of the Huntington protein is, that makes the cells die. What weíre certain about though is that the cells are unhappy or dysfunctional for many years before they die. And thatís good news because it means if we can reverse that dysfunction, we could potentially prevent patients who we know have the mutation from going on to develop the disease. But exactly, you know, what the processes are that are going on in the cells, we know that there are lots of them. But, exactly what the balance of problems is, is unclear at the moment.
Chris - Interestingly, not all brain cells seem to be vulnerable to the same extent though, do they? So do we know why some cells seem to perish and others are less affected?
Ed - No. thatís a really important question and as I say, we know that the cells of the basal ganglia, the striatum are selectively involved early on. Whatís weird though is that those arenít necessarily the cells where, under the microscope, you see the most accumulation of the abnormal Huntingtin protein thatís seen throughout the brain, but the striatum doesnít seem to display a lot of that. And there are various theories as to why this might be. Probably, the most popular theory is that those cells receive a lot of inputs from other areas of brain. So those are incredibly busy cells, very metabolically active cells and they're connected to a lot of other cells, and it may well be that thereís a phenomenon called excitotoxicity going on where the cells get too many inputs. And that tips them over into the balance of not being able to cope because they were unhappy already because of having the abnormal protein floating around. But thereís another theory which is that Ė and this goes to the heart of the mutation that causes HD - Itís unlike other mutations where itís a single spelling mistake. You know, changing one DNA letter to another. This is a genetic mutation in which one word, one three-letter word, CAG is repeated again, and again, and again, too many times, and that causes the protein to take on an abnormal shape. And the striatum does seem to contain cells with even more abnormal repeats than the rest of the brain and that may be one reason why it has this selective vulnerability early on in the disease.
Chris - And looking outside the brain, you're interested in the immune system because of course, this gene isnít just turned on the brain. Itís turned on in other cells in the body too. So how does it affect immune function?
Ed - Well, thatís right. The gene and the protein have been found to be expressed basically everywhere that they've been looked for. And what we did was to look in the blood of HD patients. Weíre looking for biomarkers, things that can be used to measure from the outside, whatís happening to a patientís brain on the inside. And we need, basically, accessible tissues. You can't go diving into someoneís brain so we look in blood to see if we can find changes due to the gene. And what we found quite surprisingly, we werenít really looking for it, but what we stumbled on almost was a signature of immune activation that the cells, that the blood of HD patients contains a signature of cytokine proteins that suggests that the patient is in a sort of chronic inflammatory state. The immune system is overactive and we did a bit of detective work to try and figure out what the relationship was between the gene that causes the disease and the cytokine production. And we think that weíve identified that itís actually the white blood cells which are expressing the gene and that in some way makes them over active. They become hyperactive and weíve detected that in the blood. Meanwhile, our collaborators in Washington and the US have been looking at expression of these cytokine proteins in brain and found that they're over-expressed in HD brain as well. So there seems to be a sort of commonality between the brain and the blood there.
Chris - And just to finish Ed, does that mean then potentially that some of the pathology could be because the immune system is attacking cells and making the situation worse or it could be triggering the cells to become diseased or is this just literally a red herring? The immune system has these useful predictive markers that tell you what the state of the brain is, but they're not in themselves bound up with whatís going on with the brain.
Ed - I think at the very least, it suggests that these might be useful as markers, but I think Ė to be honest, I think there is more to it than that because a number of people have looked at trying to adjust the immune system in HD in the brain. And have produced some very promising results showing that if you can damp down certain pathways involving the microglial cells, the immune cells of the brain, you can produce quite a dramatic survival effect on HD mice. So it seems that the microglial, immune cells of the brain are acting as policemen which are having a useful effect early on in the disease but later on as sort of becoming a rather unruly bunch of riot policemen, hitting innocent civilians in the face and doing more harm than good.