Modelling neurodegeneration - Professor Lizzy Fisher

Lizzy - Now one of the aspects of Down syndrome that's very interesting to study is that people with Down syndrome get the changes in the brain very, very early on that go with Alzheimer's disease, but they don't get the dementia until a couple of decades or so later at a greater propensity, a greater frequency, than in the rest of the population. But there's an interesting disconnect between having Down syndrome, why they get particular brain changes, and why the dementia occurs perhaps a couple of decades later.

Kat - So tell me a bit about this mouse model for Down syndrome. What exactly does it involve? How do you model a disease like that?

Lizzy - We took a human chromosome 21 out of a human cell - just from a normal cell that has been grown in culture for many years - and we transferred that into another type of cell line called an embryonic stem cell line, a mouse embryonic stem cell line. We can take these cells and inject them into very, very, very early embryo. So these are embryos that are so early that they're what we call pre-implantation - they wouldn't even have been implanted into the uterus yet.

We simply take those embryos and using the same techniques that you'd find in a human IVF clinic we re-implant those into recipient mothers, into foster mothers if you like, and then our embryos are born from that and a certain proportion of their cells will carry the human chromosome 21.

Kat - So what sort of features do you see in these mice?

Lizzy - So where we've looked, our mouse model does seem to recapitulate certain features of Down syndrome. So, one example is that we found very characteristic changes in learning and memory which appear to be similar to what we would find in people with Down syndrome. So for example, people with Down syndrome have certain differences from the rest of us in terms of laying down long term memories, and this appears to be the same in our mice as well. Similarly, 40% of babies who are born with Down syndrome have a very characteristic type of heart deficit and we're seeing exactly that same change in our mice as well.

Kat - And tell me a bit about these changes in the brain that look like Alzheimer's disease. What sort of thing do you think is going on there?

Lizzy - Alzheimer's disease is characterised by particular changes in the brain that are called plaques and tangles, and they're deposits of protein material that you don't find in normal brains, very, very characteristic of Alzheimer's disease. And the people with Down syndrome, they also have these deposits in the brain, probably rather earlier than the rest of us in the population. So, we would like to know why that is and also, what's the connection between those protein deposits and the appearance of dementia some decades later.

Kat -所以与大脑有什么其他问题development or the brain function in these Down syndrome model mice that you see?

Lizzy - Yes, there's one very interesting characteristic that we find and this is in the structure of the brain called the cerebellum. So this sits at the base of the brain near where the brain joins the spine. This structure is responsible for fine motor control. It does lots of things - it's also involved in what we call motor learning - and it's known that in people with Down syndrome, there's a particular set of cells, a particular very characteristic group of cells that don't really develop properly in this structure of the brain.

So we've gone back to have a look at our mouse model and sure enough, exactly the same cells have difficulty developing in our mouse model. So we know because Down syndrome is a genetic disorder, it arises from having an abnormal number of genes, we know that there must be a gene or genes in chromosome 21 that are responsible for that aspect of Down syndrome. We see exactly the same thing in our mouse and we can use mouse genetics to get to the individual genes responsible for that feature of the development of the human cerebellum.

Kat - You're also looking at mouse models of motor neuron disease. Is there anything particularly interesting you've seen in these mice?

Lizzy - Well, it's very early days for us with these mice but in the field generally, there's a lot of excitement because human geneticists found some new genes that are quite rare, but they are responsible for a small proportion of familial forms of motor neuron disease and it looks as if what these genes do is they're involved in processing of a chemical called RNA, and this is the chemical that moves between the DNA in the chromosomes, and sort of gives the instructions for how to make proteins.

And it turns out that there's a whole area of what we call RNA metabolism which is really the study of what happens to RNA in cells, what does RNA do? Because it turns out to have lots and lots of complex functions. And at least two and possibly more of the genes involved in motor neuron disease actually seem to be acting in RNA metabolism. So the field generally including us is now starting to work with mouse models and other models for example and now, in fruit flies to try to work out what's going wrong with RNA metabolism in motor neuron disease.

Kat - Have you started looking at the mice that you've got now to see if they have these problems?

Lizzy - We've started looking at one strain of mouse and we have a quite interesting finding for us which is that there's a type of processing of RNA which is called splicing - it's just cutting and pasting bits of RNA together - and we think that this is defective in one of our mouse models and so, this is something that we're going to follow up in the future.