BNA Interview Series: The Genetics of Neurodegeneration With Professor John Hardy

At the British Neuroscience Association (BNA)’s Festival of Neuroscience in April 2019, we were lucky enough to sit down with some influential neuroscientists to discuss their work. We’ve assembled these transcripts into our BNA Interview Series. Here we interview University College London’s John Hardy, whose work into the genetics of neurodegenerative disorders saw him share the Brain Prize in 2018.

Ruairi Mackenzie (RM): How significantly do genetics influence neurodegeneration conditions such as Alzheimer’s for example?

John Hardy (JH): I think it started slowly in the 80’s and 90’s, as we, and I mean we generally, started to find genes for disease but I think gradually it’s become the dominant force for how people in general start to get at the pathogenesis of all neurodegenerative diseases. So I think there was a bit of a slow uptake of people understanding the significance of genetics, but now it’s become the dominant way people understand pathogenesis, I think. 

RM: What’s the difference between an inherited form of a disease and other forms?

JH: There is no clear answer to that, but to deal with Alzheimer’s disease first, in the early onset autosomal dominant forms of the disease, where you have mutations in either the amyloid gene which we found, or the presenilin genes which Peter Hyslop found, those people over produce amyloid.  In the sporadic forms of the disease, the late onset forms of the disease, the predominant problem is a failure to degrade and remove amyloid from the brain.  So, there is a distinction but they’re consistent with each other. 

RM: How have these genetic researchers contributed towards the search for treatments and therapies?

JH: Well we haven’t got treatments and therapies, let’s be honest.  So, we haven’t scored any goals and so talking about who has been the best goal scorer is a bit premature really.  I think that of course, the genetic findings have driven the way we look for treatments but to be honest we haven’t got them and so we have to be a little bit modest about that.

RM: What role do you think going forward these genetic studies will have advances our understanding of these diseases in getting that goal, eventually?

JH: Well I hope that they will have profound, successful implications.  What we have found recently, and again I use the word ‘we’ in a general sense and not to mean my own group, but we have found genes involved in the microglial response to amyloid induced damage and I think that’s a significant understanding which should help us think about how we might fine tune the response to amyloid induced damage. 

RM: I understand some of the genetic studies – you mentioned microglia – have implicated the immune system in Alzheimer’s.  Could you talk a bit about how those are related?

JH: Well by the immune system, in terms of the brain we mean microglia.  That’s what we mean, so when we say the immune system which is clearly involved in Alzheimer’s disease we largely, perhaps not exclusively, but we largely mean how do microglia respond?  How well do microglia respond to amyloid deposition? One of the genes we have found is called TREM2.  That is a microglial gene and it’s involved in the chemotaxis of microglia towards amyloid deposits that damage membranes.  Another gene I’ll mention is a gene called AVCA7, that is a gene involved in the clearing of phospholipids and phospholipids are the major component of membranes.  So both of those genes are implicated as amyloid membrane damage response genes. 

RM: We’ve mentioned Alzheimer’s but in the same way that there is a lot of common mechanisms in neurodegenerative diseases. Are microglial responsible for clearing up TSP-43 or other pathological proteins?

JH: Actually, TDP-43 is the one I know least about, so we might slide past that.  I’d just say that TDP-43 is involved in the damage response of all cells, but let’s say specifically motor neurons and what it’s involved is in the sequestering of messenger RNAs when neurons are damaged.  So, it is a damage response protein itself and what it looks as if the mutations in TDP-43 do is mess up that damage response.  When neurons are damaged they sequester their RNA and switch translation to heat shock proteins for example and the TDP-43 is involved in gathering up the messengers that are currently being translated and then when the damage is passed, they release those messengers and what the mutations seem to do is hinder that later release of the messengers. So, again it’s a damage response protein.

RM: Are we seeing a move more towards seeing these diseases as a problem with the response to proteins like amyloid and therefore shifting our therapies towards targeting that response?

JH: Yes, in part for sure.  I think we also should be thinking more than we have done perhaps, what was the original damage that led to that pathological response and maybe we haven’t thought enough about that for all of the disease categories.

RM: Do you think it’s an inevitable part of ageing? 

JH: You know, inevitable is a strong word.  I think one thing that science can take credit for, though not neurodegeneration researchers, is the fact that the incidence of dementia has dropped about 25% over the last 30 years. We haven’t understood why that is precisely but one of the leading ideas about that is that it coincides with better heart health, through blood pressure control, for example. One might suppose that inadvertently we have made progress but it’s sadly not through research into neurodegenerative disease, but through the good efforts of our heart disease colleagues basically.  So I don’t think inevitable.  Inevitable is too strong a word but also, I don’t think we neurodegeneration researchers can take the credit for it.

RM: I see.  Do you think we will eventually have some sort of either set of lifestyles or even a medication that people can take as a prophylaxis, something that would prevent damage happening in the first place?

JH: Yes for sure, I think one thing I do think is that – and I think the field is in agreement with this – there is going to be no magic bullet for Alzheimer’s disease.  I think it’s going to be a mixture of maybe drugs and lifestyle suggestions.  I will just mention, because I think it is the most exciting thing of the last two years, that the treatment of spinal muscular atrophy through antisense treatment is really perhaps something we should be looking across the board for, in terms of treatments and I have been very excited by the anti-Huntington therapies based on the antisense therapies.  If they work, one can see a way of using the same approaches across the board in neurodegenerative diseases.  So I do think there is hope, I’m very excited about those things, but I don’t think there is going to be a magic bullet.

RM: If there is to be no magic bullet drug, do you think that pharma companies will remain interested partners in the field, or will we need to have institutions and public funders take a lead instead?

JH: It’s going to be a mixture of both.  I was alarmed to see Pfizer pull out of neurodegeneration research two years ago.  I think that was a mistake, but we know a huge amount more now about these diseases than we did four or five years ago and genetics has been a big part of that.  We understand the disease mechanisms I think a lot better than we did, so I think there is definitely hope but it is going to take a mixture of big pharma, biotech and academic funding, These three main areas need to be joined up.  They need to be talking to each other in a constructive way.  One of the things that I have been excited about at UCL is the funding by Alzheimer’s Research UK of the Drug Discovery Institute to try and bridge the gap between those three areas of research, to try and make a more seamless pipeline.

John Hardy was speaking to Ruairi J Mackenzie, Science Writer for Technology Networks