Professor Russell Snell, Auckland University
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 Ė if you can imagine Ė 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 didnít. 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 Ė itís 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 itís the right length?
Russell - We don't really know. Even after 20 years, we know that itís absolutely required for embryo development. So, if you remove the gene in mice and they don't develop past day 7. We know that itís 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 itís 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 itís 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. Itís quite remarkable. The brain is quite a remarkable thing.