Naked Neuroscience, Down Under

Hannah -   Back to Russell to find out how this collaboration resulted in the successful identification of the gene involved in Huntington's disease.

Russell -   Again, it was a partnership between researchers and the families.  It was looking at families and looking at people - if you can imagine - like an upside down tree where the gene is inherited down the family.  We can follow the inheritance of that particular piece of DNA in a family and look at individuals that got it and individuals that didn't.  In doing it was molecular tools or DNA tools, we can narrow the region down until we narrowed it down to a single point.  They found an absolutely convicting mutation or variation in the gene which is like a lengthening of a piece of DNA in a particular tract in the gene.

Hannah -   So, that lengthening of that one section of DNA was being passed three generations and those individuals that we affected in generations then developed these symptoms of Huntington's and that's how you identified the genetic basis of Huntington's?

Russell -   Yes, absolutely and there was one other piece of information that came along with it that really nailed it.  It was that on average, if you inherited a longer repeat or the sort of tract, you can imagine that as like a bicycle chain that gets longer, where on average, when the repeat is longer because it varies between all of us, including people who don't get Huntington's disease.  If the repeat is longer, then the age of onset is lower.  So, you can draw a curve.  If you're unfortunate enough to inherit a very long repeat, say, over 60 or 70 units, then the age of onset tends to be younger than 20.  Again, there's a lot of variability with what convicted this gene is, the gene that causes Huntington's disease.

Hannah -   And going back to the analogy of the bicycle chain, so the longer the bicycle chain, the less far you're probably able to ride before actually the chain slips off, you can't ride anymore.

Russell -   That's probably where the analogy breaks down a little bit because Huntington's disease is a disease caused by - it's called a dominant disease.  It means that you only need inherit one copy of the expanded repeat.  There's still debate about whether it contributes a gain of bad function or a loss of good function.  The debate I think is falling on the side and this is what I believe as well, that there is a gain of dysfunction.  So, almost like one is inheriting something that takes on a brand new part bad function for the cells in the brain.

Hannah -   What does this gene usually do in the brain when it's the right length?

Russell -   We don't really know.  Even after 20 years, we know that it's absolutely required for embryo development.  So, if you remove the gene in mice and they don't develop past day 7.  We know that it's very likely to be involved in transport in axons.  That's the nerves in the brain, so transport of molecules up and along these very long sticky outy branches in the brain.  We also suspect it's involved in metabolism of the brain, so the feeding of the brain with glucose.  Huntington's patients lose weight dramatically towards the end and on average, over life, they're slightly lighter.  There appears to be some sort of metabolic deficit and I kind of favour this.  I quite like this theory that in some way, for some reason we don't know, the feeding of these neurons in the brain, the supply of glucose to neurons in the brain is not operating that well.  So, this is just another theory, but maybe these cells are being starved of food.  But beyond that, we really don't know and I think the reason for that is because it's involved in so many things.

Hannah -   Which is why you get this myriad of symptoms with the patients that have got this expansion of this gene?

Russell -   I think the range in symptoms and the range of how the disease progresses or proceeds and the age that it presents is to do with, at least in part, how we are able to cope with the gain of dysfunction.  I think some people are better able to cope with that because of what they inherited in their environment.  Other people are least able to cope with it.  A word that's quite often used is plasticity which is kind of a cool word and that it kind of means that how plastic, how malleable your brain is to cope with this terrible insult that happens.  We know that some people can because there's quite a bit of cell loss in Huntington's disease in most cases that people can cope with different amounts of cell loss before the symptoms come on.  It's quite remarkable.  The brain is quite a remarkable thing.

Hannah -   I wanted to find out more about these sheep and how they behave, so I met up with Jenny Morton, from the University of Cambridge.

Jenny -   Sheep in a flock have a poor reputation.  They follow each other, they do daft things if one sheep get stuck in a fence, another sheep will get stuck in a fence, and they also look a bit silly.  But I always liken them to teenagers.  Teenagers in a group don't always behave perfectly, but you get a teenager by themselves, and they're usually really quite civilised.  It's the same with sheep.  Sheep in a flock can be very silly.  You get a sheep by itself working under controlled conditions.  They perform very well.  They're very intelligent, a little bit moody, but they understand things.  They learn very quickly.

Hannah -   So, the kind of experimental tests that you do...

Jenny -   We're trying to design experiments that will test cognitive function in decision making in particular.  Sheep can do tasks where the rule changes and they can figure out that there is a new rule and what the new rule is and perform accordingly.

Hannah -   So for example, if I go down a corridor, I know at the left hand side, there's going to be a little treat for me, a little chocolate bar.  And so, I keep going down the left hand side and then suddenly, you might switch that treat to the right hand side corridor and then I'll learn to get on to the right instead of the left.  That's the kind of thing you do with your sheep?

Jenny -   Yeah, that's almost exactly what we do, except we use coloured buckets.  So, we'll say, "If you go to the yellow bucket, there will be a reward.  If you go to the blue bucket, there won't be a reward."  So, the sheep learn very quickly to go to the yellow and then you can switch colours so you can suddenly present them with a new pair of colours and they have to make a new decision.  First, they have to go, "Oh, that's just the colour bucket test.  I'll choose one of them and then I can learn what the new role of these new colours is."  What we now do though is we actually use computer screens.  So, we don't need to have buckets and they don't have to walk in.  They actually just use computer screens and choose symbols off of a computer screen.

Hannah -   And this type of decision making, it's important isn't it in everyday human life and as we're hearing, it can be affected in Huntington's disease?

Jenny -   It's absolutely critical.  In fact, that's why I started with two choice discrimination tasks because Huntington's patients can learn to do these sort of tasks that they have trouble with these sort of reversals that you were talking about.  So, they learn something, but then when the rule changes, they perseverate on the old rule.  So, they'll stick to the same thing they knew and they have great difficulty with flexible thinking.  That's why I chose to develop that task for the sheep.

Hannah -   I've heard that you've even managed to get some of your sheep playing games of football with proper goal posts and the sheep counting the goals as well.  Are they able to know who's the victorious team?

Jenny -   The sheep don't play football with each other but I did teach sheep how to kick a ball into a goal because again, I'm looking for tasks of skill and motor coordination.  I also wanted something that sheep didn't normally do.  Now, sheep don't normally kick a football.  If they see a football on the field, they would be afraid of it because it was weird.  But I taught the sheep how to kick a football because I know that it's a good test of balance, coordination, and skill that might be useful for testing balance coordination and skill in the HD sheep.

Hannah -   Thanks to Professor Jenny Morton from Cambridge University.

Mice are also being used to study Huntington's.  This time though, by accelerating the disease.  I spoke with Dr. Ailsa McGregor, also at Auckland University.

Ailsa -   So, our mice have also an increased CAG repeat lengths, but it's 120 repeats.  So, it's much, much more than you would see in a human patient because we need an accelerated pathology in the animals to fit with the lifespan of a mouse.

Hannah -   So, what are you seeing this mega long CAG repeats of this Huntington gene?

Ailsa -   So, we see this really classical motor impairments that human patients see.  We also see very early cognitive problems.  So, these mice are not able to learn how to do the motor test that we usually use to assess coordination in these animals.  They also really have a lot of problems with what we call delayed dependent memory.  So, can you remember this one piece of information in 5 minutes time or in a day's time?  They also are very poor in recognition memory.  So, recognizing that there is a new object in their environment.  We also look at psychiatric impairments in these animals which are much more difficult to measure, but we have ways that we can assess that type of behaviour in animal models and our transgenic mice also show a depressive like behaviour from about 6 months of age.  There is a very specific way that we look at depression in mice because they obviously can't tell you how they feel about things.  We typically use swim test and the mice will either swim or they're immobile.  In this environment, it's quite small environment and they can't generally get out.  So, we can correlate time spent immobile or floating with depression and that actually uses a screen by a lot of pharmaceutical companies to look at anti-depressant activity of new drugs.  It has a real correlate with human behaviour I guess.  So, if you imagine the time spent immobile, like despair or helplessness, we see a lot less of that after the drug treatment that we've been working on so the animals are swimming much more and they're much more active.  Another interesting correlation with human patients because other tests that we used to look at shifting strategies or cognitive tests where you have to change the way that you do something.  

Normally, we survey strategy shifting type behaviour.  It's how they find food.  They alternate between different ways of doing things.  Our Huntington's disease mice are very bad at that and they persevere with the same strategy over and over again even when it's not successful.  The types of compounds that we are interested in are involved in cholinergic transmission which is involved in attention and memory.  These compounds, even in normal mice are what we call cognitive enhancers.  So, they improve performance and memory tasks and attention to do these tasks.  We're also seeing really significant improvements in motor function in very, very elderly Huntington's disease mice.  So, we had really expected that by then we would be beyond the point where we could see any benefits, but we're actually restoring motor function in these aged Huntington's disease mice back to a normal aged mouse's performance which is great.

Hannah -   Thanks to Ailsa McGregor.