Genetic spelling mistakes lead to Dementia

Neurodegenerative diseases like Alzheimer’s are incurable conditions which cause the degeneration or death of cells in the brain, and can result in deterioration of movement, memory and cognition. Scientists are desperately searching for a cure - but we still don’t know what causes it in the majority of cases. Now, a team at the University of Cambridge have used a new technique to discover the mechanism behind the development of these diseases. Georgia Mills spoke to Patrick Chinnery, professor of neurology at the University of Cambridge.

Patrick - Late onset neurodegenerative diseases like Alzheimer’s disease are on the increase because as the population gets older, more and more people are suffering from these disorders. And the truth is, we don’t know the cause in the majority of cases so we were keen to try and work out whether or not some new genetic mechanisms might be responsible for some of these problems. In 99 percent of cases there’s no family history, and we don’t quite understand the cause in those patients. It might be partly environment and it might be partly some genetic risk factors and we were keen to explore a new genetic mechanism by studying the brains that we’d collected from patients who’ve died from these conditions.

Georgia - Right. So how did you investigate these brains?

Patrick - We took advantage of a resource that the medical research council has been investigating for decades actually. These are brains that people have donated for medical science and research, and we identified about 50 of these brains partly from people affected by Alzheimer’s disease and another kind of dementia, and also some healthy brains that had been given by people who’d died, for example, from a road traffic accident who weren’t suffering from the condition. And we developed a new technique that allowed us to look at the genetic code in extreme detail across bits of the genetic code that we know can cause Alzheimer’s disease and related conditions. And what we found is that almost all of these brains were containing spelling mistakes in the genetic code affecting some of the cells in the brain. We found these all over the brain when we looked, but not all the cells in the brain were affected, only a small proportion of the cells were affected. In fact, the technique we developed, for the first time allowed us to do this on brain tissue.

Georgia - Could you tell me a bit about that technique?

Patrick - Essentially, what we do is we sequence a bit of the genetic code, the DNA, many times over, and this study we sequenced it 5,000 times in each sample of the brain that we looked at. And that allows you to look for very rare genetic changes that you wouldn’t detect if you only sequenced it perhaps 2 or 3 times.

Georgia - What has this told us the fact that these spelling mistakes are appearing in certain cells but not all of them? What can we take from this?

Patrick - Well, what we’ve learnt from this that, contrary to what people previously thought, which is that the genetic code in your brain and my brain is all identical, actually there’s a lot of heterogeneity, a word we’d use to describe that is a mosaic, so there are all sorts of different genetic variants in the cells in our brain. Now some of those might be completely innocent and not cause any problems, but by measuring the frequency with which they occur, we can make some predictions about how likely it is that they’d affect a bit of the genetic code that could predispose to a disease in one of the cells. And if that happened to enough cells iot could contribute to something like Alzheimer’s disease.

Georgia - So when do we think these mistakes are happening then?

Patrick - The thing about the brain is that the cells generally don’t divide, so they're not being copied because they’re set in place when the brain develops in the womb. And the pattern of the genetic changes we saw suggested that actually these spelling mistakes had occured when the brain was being formed as the cells were being copied and divided to grow from a simple embryo, which is a ball of cells into something more complicated with a brain structure itself.

Georgia - And this would explain why some areas of the brain are slightly different if these mistakes happened when some of the brain had already sort of formed?

Patrick - You’ve hit the nail on the head exactly. If you could imagine, in very simple terms, ultimately the brain derived from a cluster of cells, when we’re actually fully formed we have 100 billion cells in our brain, so you can imagine this is a branching tree-like process as the cells divide and form more and more daughter cells. And depending on when the spelling mistake occurred would determine how many of the cells were affected. If it happened really early, most of the cells would be affected; if it happened really late, only a few of the cells would be affected, and what we saw in our experiment was that all these possibilities were occuring.

Georgia - Now we’ve discovered this mechanism, is there anything we can take forward from this that might give us insights into one day treating it?

Patrick - I’m sat here talking to you know and I know from this work we’ve done that I’ll have spelling mistakes in different bits genetic code in my brain. It doesn’t really change the fact that those were there before we discovered this was happening, so I don’t think it has a major impact now on how we would diagnose or treat people. But by getting these insights I think it’s given us a clue as to the mechanisms.

And I thinks that’s important because it may be that using an adapted version of this technique we might be able to help diagnose these conditions at an earlier stage. That’s really important because I think the field generally agrees that the sooner we intervene with treatments, the more likely they are to be effective. And by understanding the mechanism, of course, we can start to develop treatments targeting that particular mechanism that the protein that’s altered by the genetic change, and thereby move to a position where we have actually got effective treatments which, unfortunately, are not there at the moment.