The gene for Huntington's

22 April 2014

Interview with

Professor Russell Schnell, & Lynette Tippett, the School of Biological Sciences in the University of Auckland

Russell - Hi. My name is Professor Russell Schnell and I'm in the School of Biological Sciences in the University of Auckland. I was one of the members of the group that found the gene actually, now 20 years ago. I have to say that - so I'm going to witter on a little bit, but I have to say that the Huntington's disease research community is a little bit special because it's always had very direct input from people or families who were affected by the disease. And so, there's always quite a reality about our research meetings because generally speaking, there's somebody from a Huntington's family or a Huntington's patient who comes along to the meeting and presents in some way that is rather galvanising. It's great, so it's true partnership between the research community and the patients which is as it should be. Many years ago, when we found the gene, that was a collaborative group and great collaboration where we all shared the data prior to publication.

Hannah - We'll find out more about the gene and how sheep were involved in studying it shortly. But first, Associate Professor of Psychology, Lynette Tippett from Auckland University expands on how the Huntington's disease research community came about.

Lynette - It began really with Milton Wexler and Milton Wexler was a psychiatrist in Hollywood. His wife died of Huntington's disease, as did her 3 brothers. He had 2 daughters who are still alive today, Nancy and Alice Wexler. He decided he needed to find this gene and find a cure for Huntington's disease so that he could cure his family or save his family. And so, what he did was he started pulling together scientists from all around and just sort of putting them in a room and making them brainstorm, finding this gene and finding out how to cure Huntington's disease. It was unusual because instead of people fighting for grants and all the competitiveness that goes on in a lot of science, he managed to get these scientists in a room, get them all in the same page, and all just being open and brainstorming ideas. That's really how the Huntington's research field began. So, the gene was finally found in 1993. So, that's 20 years ago. That sort of legacy of a lot of collaborative and interactive and international groups working together, that legacy of collaboration I think continues today. I think it's down to that very unique start to focused Huntington's research that came from the efforts of Milton Wexler.

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 with molecular tools or DNA tools, we can narrow the region down until we narrowed it down to a single point. In Jemma Marcey's lab, they found an absolutely convincing mutation or variation in the gene which is like a lengthening of a piece of DNA particularly tract in the gene.

Hannah - So, that lengthening of that one section of DNA was being passed three generations and those individuals that were 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 this little track, you can imagine that it's 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 as, 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 to 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 but 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 and 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 - in effect - terrible insult that happens. We know that some people 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 - And you're studying this remarkable brain, this remarkable gene and how it's involved in leading to Huntington's with these expansions of the CAG repeats, you're studying it in quite unusual and remarkable animals I believe.

Russell - Yeah, why sheep? I grew up in a farm in South Otargo. Sheep docile, but they're also intelligent. They've got big brains. I could see models wondering around a paddock, eating grass and living an ordinary sheep life until we wanted to look at their brains. And so, it seemed to me, at least for these late onset neurodegenerative diseases or Huntington's disease, is that we could make an ethical model where they live a normal sheep life until they don't, if that makes sense. So, that is just the ethical line that I draw. We knew something about the sheep brain structure and actually, how to manage them in a farming situation. We're good at looking after sheep. We're good at understanding sheep. So, it's a combination of things. The sheep genome or the sheep gene is a little bit closer to human. Also, we knew that we could do behavioural things for sheep because sheep have behaviours or we imagine we could but Jenny has really taken it to a major different level. Well, she's done an incredible job there.

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