Podcast – Investigating Parkinson’s Disease

Voice Over:

Welcome to the NIHR Dementia Researcher Podcast, brought to you by dementiaresearcher.nihr.ac.uk in association with Alzheimer’s Research UK and Alzheimer’s Society, supporting early career dementia researchers across the world.

Dr Fiona McLean:

Hello, my name is Dr. Fiona McLean, and I am an Alzheimer’s research fellow at the University of Dundee, where I investigate high metabolic diseases like obesity and type two diabetes can lead to diminished brain function. And within that area of research, I have a specific focus on the blood-brain barrier. Today I’m really pleased to be hosting this Dementia Researcher episode on Parkinson’s disease . With me is Dr. Sarah Marzi from the Dementia Research Institute at Imperial College London and Dr. Dean Beccano-Kelly from the Dementia Research Institute at Cardiff University. Hello to you both. XX

Dr Sarah Marzi:

Hello.

Dr Fiona McLean:

So now I’ve done a quick introduction. Let’s find out a little bit more about each of our researchers. Why don’t we start with Dean?

Dr Dean Beccano-Kelly:

Okay. So, my name’s Dean Beccano-Kelly. I am a UKRI future leader fellow and group leader at the Dementia Research Institute at Cardiff University. And my research focuses on Parkinson’s disease and the temporality of Parkinson’s disease, really trying to understand the order in which phenotypes appear in an effort to really increase the efficaciousness of therapeutics and the design of them so that we can really, temporally lock in disease-modifying therapeutics.

Dr Fiona McLean:

Fantastic. And Sarah, what about yourself?

Dr Sarah Marzi:

I’m an Edmond and Lily Safra research fellow and UKDRI emerging leader at Imperial College. And my research focuses on gene regulation and epigenetics in neurodegenerative diseases, specifically Parkinson’s and Alzheimer’s disease. And the main hypothesis that really underlies all of my work is that I want to understand how non-coding genetic risk and environmental risk factors act on disease risk. So, what does it do to the cells that are involved, to the cells that are vulnerable to the disease, and how do these cells change their regulatory programs in response to these external and internal in cells, and how might that promote the disease?

Dr Fiona McLean:

Amazing. Both sounds absolutely fascinating research, and we’ll get into a little bit more in depth in a minute, but I think for our listeners it’s a good place to start, and it’s actually talking about what Parkinson’s disease is, and what are the classical symptoms, and how does it differentiate from other neurodegenerative diseases. So, I’ll let Dean start with this one. So, what is Parkinson’s?

Dr Dean Beccano-Kelly:

Parkinson’s disease is the fastest growing neurodegenerative disorder in the world. I think it’s predicted, actually, by 2030 to surpass and exceed Alzheimer’s disease in its prevalence worldwide.

Dr Fiona McLean:

Wow.

Dr Dean Beccano-Kelly:

And so-

Dr Fiona McLean:

I don’t think that’s something many people would actually be aware of. It’s actually-

Dr Dean Beccano-Kelly:

Yeah, it’s-

Dr Fiona McLean:

… this growing increase.

Dr Dean Beccano-Kelly:

It’s this growing increase. All neurodegenerative disorders are impactful. They’re all incredibly difficult for people that are witnessing it happen to loved ones and obviously going through it themselves. But when you hear of one on the rise, it’s obviously something that helps us all to focus and redouble our efforts in trying to battle against it.

Dr Fiona McLean:

Absolutely.

Dr Dean Beccano-Kelly:

Yeah. And-

Dr Fiona McLean:

What are the classical symptoms of Parkinson’s?

Dr Dean Beccano-Kelly:

Parkinson’s disease is typically thought of as a motor disorder. You normally end up with lots of issues with goal directed, coordinated movement, so reaching for something to move, to a drive to get yourself a cup of tea, and move it back to yourself, and drink it. These goal orientated movements are disrupted by this hallmark motor tremor that you get. So, you get this resting tremor, which is the shaking of ambulatory systems. And so, you’re constantly, well, shaking in this guise.

And so, you also, though, have maybe things that are less well-known things like truncal rigidity, stooped posture, masked facial expression. And so, you have a lot of different things that seem to almost be counter, possibly, to the continual dyskinesia, the movement, that resting tremor. You have lots of rigidity in various areas of the body. But yeah, it’s got a lot of disruptive motor symptoms. But there are also other symptoms, things like anosmia, loss of smell, that happens quite early in Parkinson’s, constipation. And then these are things that maybe get talked about a lot less but are probably just as important. And there are indeed cognitive dysfunctions as well, this way.

Dr Fiona McLean:

Well, that’s what I was really interested about when I looked into Parkinson’s a bit more, is that typically we do think of it as a motor disease and that resting tremor, which a lot of people may be seen in people they know or even out in public, this continual tremor that people typically display in their hands, I guess, is where you probably must notice it. But actually, when I was looking into it, I found a stat that said about quarters of patients actually go on and develop some form of dementia or cognitive disturbances. So, is that something, do you think, in the field has been enough awareness and is there enough research into the more cognitive side of the symptoms of Parkinson’s? Sarah, what do you think?

Dr Sarah Marzi:

Yeah, I think that is something that we are becoming increasingly aware of and that more research is targeted towards. I have several colleagues who work on this now, but like you said, I think historically maybe it’s been ignored in P Parkinson’s, it’s been thought of as just one simple disease, but then you get these differing trajectories. I thought it was almost half of people who develop some sort of cognitive impairments at some point in time and it might take a while, so it’s usually a later stage symptom than the motor symptoms. And we don’t really understand why some do and others don’t. And it’s really important to figure that out. Are there basic underlying differences in these diseases or is it just a temporality? Is it a downstream effect of the original degeneration that’s happening?

So, Parkinson’s disease, neuropathologically in the brain, what we see is the loss of dopaminergic neurons in the substantia nigra. So, this is one very small part of the mid-brain. And although it’s not been too definitive answered, whether none of the other surrounding dopaminergic neurons or related neuron types are affected, it seems to be quite specific to that area and to the dopaminergic neurons. And then as they die, they also stop sending signals out to the neurons that they connect to in the areas in the front of your brain. And so, it’s thought that maybe because they don’t receive signals anymore that these neurons then also start to degenerate. But I don’t think we understand it really well. I’m sure Dean has some thoughts on how that might work with the nigrastriatal to frontal signaling. Yeah,

Dr Dean Beccano-Kelly:

Yeah, no, I think the rates-

Dr Fiona McLean:

Because, well, your research is electrophysiology based, isn’t it-

Dr Dean Beccano-Kelly:

Yeah.

Dr Fiona McLean:

… Dean, and your research focuses on the early stages of Parkinson’s, and you look at synaptic health. So, I think that’s quite a good place to start is can you tell us about synaptic health and how it’s affected in Parkinson’s disease?

Dr Dean Beccano-Kelly:

Yeah, sure. Following from what Sarah was saying, I’m hugely biased, by the way because I’m-

Dr Fiona McLean:

That’s okay.

Dr Dean Beccano-Kelly:

… I’m an electrophysiologist, so I’m-

Dr Fiona McLean:

We’re all biased about our research.

Dr Dean Beccano-Kelly:

Yeah. But I’m definitely right. No, I’m obviously joking. No. I was-

Dr Fiona McLean:

So, electrophysiology is the best.

Dr Dean Beccano-Kelly:

Of course.

Dr Fiona McLean:

That’s where we’re starting.

Dr Dean Beccano-Kelly:

Of course, we’re looking at neurons, but neurons are the thing susceptible in Parkinson’s disease. To a degree, there are other cell types that are destroyed in Parkinson’s disease. You have, the guts affected, and for instance, you got actually it’s liver might be affected as well. [inaudible 00:09:01]-

Dr Fiona McLean:

Which is very interesting about the gut.

Dr Dean Beccano-Kelly:

Yeah.

Dr Fiona McLean:

Maybe we should start to set out to [inaudible 00:09:03] but we’ll come back to the gut because-

Dr Dean Beccano-Kelly:

Sure. That’s-

Dr Fiona McLean:

Gut technically has some neurons in it, right?

Dr Dean Beccano-Kelly:

Oh yeah, no.

Dr Fiona McLean:

That’s something.

Dr Dean Beccano-Kelly:

… definitely. So-

Dr Fiona McLean:

But let’s not-

Dr Dean Beccano-Kelly:

We can come back to that, I suppose.

Dr Fiona McLean:

We’ll come back to it.

Dr Dean Beccano-Kelly:

Yeah, but if we are going to sidle back to the neurons in the brain, the main role that they have is this neurotransmission, this amazing ability for them to encode information in a temporal sense using chemical release and electrical transduction of information. And it’s their specialized role. And so, if we’re looking at a neurodegenerative process, we probably should be looking at their normal function and how that’s disrupted. And it’s my belief that it’s likely that this is allowing some level of susceptibility in Parkinson’s because of this specialized role and because of the specific destruction of neurons. It must be something to do with their specific role. And so, we focus on looking at temporality of the disease, looking at the earliest stages. But we think that this will be in and around functions that specifically contribute to this synaptic function, this synaptic role.

So, we’re looking at multiple different features, calcium release that drives and helps neurotransmission release. We’re looking at things like ATP production, which again modulates and affects synaptic function, and many other functions in and around electrophysiological function and dysfunction, I should say. Because what we really want to know about is the dysfunction that precedes that neurodegeneration. Because what we are interested in is maybe helping to modify and delay the onset of the cell death that will then occur after that dysfunction. And there’s a lot of work that’s gone on in the field looking into synaptic function now in Parkinson’s disease. It’s a lot of work that’s happened fairly recently in the grand scheme of the literature that’s-

Dr Fiona McLean:

Which is exciting.

Dr Dean Beccano-Kelly:

… around Parkinson’s disease. Yeah, no it’s-

Dr Fiona McLean:

Because it means-

Dr Dean Beccano-Kelly:

… fantastic.

Dr Fiona McLean:

… that you’re right at the forefront of it. I have a question. Here’s my research bias coming in, because I’m obviously interested in metabolism and energy, and you mentioned ATP at synapses. So, do you think that there is a role of mitochondria synapses that’s perhaps becoming defective? Do you think it could be actually something to do with energy regulation at those synapses that then prevents them doing their job and communicating with-

Dr Dean Beccano-Kelly:

I do. I do. Mitochondria, excuse me, are very, it’s well defined that mitochondria contribute to the mechanisms of cell death in Parkinson’s disease. We know that from genetic models of Parkinson’s disease, recessive models have shown quite a lot of impact on mitochondrial function. But that cell death that it seems to be contributing towards also might be, if we look earlier, there might be dysfunction in the mitochondria and mitochondria unknown to be functionally as active at the synapse. We actually just had a guest speaker up here who’s really looking at that as well. Mike Devine at the Crick Institute, and its fantastic work where he’s looking at migration of mitochondria, and movement to the synapses, and it’s definitely involved. I myself have found some data suggesting mitochondrial deficit in their functionality can then contribute to a lack of efficaciousness of the synapse. So, they don’t work as well when they have a decline in calcium input into the mitochondria, which will decrease their ATP output. And so-

Dr Fiona McLean:

Makes sense.

Dr Dean Beccano-Kelly:

They’re all in-

Dr Fiona McLean:

Right?

Dr Dean Beccano-Kelly:

It does definitely make sense. They-

Dr Fiona McLean:

Because when you think about just as people and existing, we all need energy to do our jobs.

Dr Dean Beccano-Kelly:

Exactly.

Dr Fiona McLean:

So, it makes absolute sense that on a cellular level, you know, these cells-

Dr Dean Beccano-Kelly:

There something that’s-

Dr Fiona McLean:

… need energies to do- [inaudible 00:12:40]

Dr Dean Beccano-Kelly:

… so, energy demanding as synaptic information and transmission of electrical signal in dopaminergic neurons, which are these, they’re huge. They’re these long unmyelinated projections that extend for extended period of time and they fire this pacemaking activity.

Dr Fiona McLean:

Because they’re unmyelinated, does that mean that you need more energy because they don’t have that insulated?

Dr Dean Beccano-Kelly:

Likely. It’s likely this. And also, the fact that they fire almost like a heartbeat, a regular pacemaking. So, they’re continually active. So, this requires a lot of energy to drive them. So maybe, and I just quickly go back to what Sarah was saying, the interconnection between all of the nuances in the brain, we’re talking about these dopaminergic neurons, specifically the ones in the substantia nigra parts compactor versus the reticulata. The ones in the substantia nigra parts compactor are projecting up into the striatum and the basal ganglia, which is just a mess of crazy connections. It’s a really complicated area of the brain. But if you can imagine that they’re all dependent and reliant upon each other, you’ve got GABAergic neurons reliant upon cortical neurons. So, one disruption to one area might then manifest in a different area. So actually, that’s what some of the things that we are working on is it might not actually be starting in the dopaminergic neurons, it might well be starting elsewhere. And dopaminergic neurons are just the ones that are more susceptible to said change and die first. And-

Dr Fiona McLean:

Do you think that that area of the brain can be maybe thought of as the London tube map? So, it’s like-

Dr Dean Beccano-Kelly:

I like that.

Dr Fiona McLean:

It’s all, there’s loads of different paths and it looks really crazy and complicated, but actually there is an organization to it. But if you get a problem on one line, it can affect other lines even if they’re meant to be different things. Is that quite a good analogy?

Dr Dean Beccano-Kelly:

It is. I’m sure Sarah can talk about the disruptions on the tube lines, and how everybody then rushes to the district line, and can’t get … It’s just a nightmare. But no, I think that’s actually a really good analogy. It’s an organic-

Dr Fiona McLean:

You can borrow it for yourself.

Dr Dean Beccano-Kelly:

… development. I’m definitely going to use that. That’s amazing.

Dr Fiona McLean:

You’re-

Dr Dean Beccano-Kelly:

I’ll mention the tube map and then yeah, can talk about all-

Dr Fiona McLean:

It’s not-

Dr Dean Beccano-Kelly:

… no, but it’s-

Dr Fiona McLean:

It’s not like Glasgow tube map, which is like a circle.

Dr Dean Beccano-Kelly:

Yeah. Nice and simple.

Dr Fiona McLean:

A little bit easier to understand. Sarah.

Dr Sarah Marzi:

Yes.

Dr Fiona McLean:

Your research investigates Parkinson’s disease from a different angle to Dean’s and you-

Dr Sarah Marzi:

It’s-

Dr Fiona McLean:

… study something called epigenetics. So, can you just explain in a little bit more depth what epigenetics is and why is it relevant to Parkinson’s disease?

Dr Sarah Marzi:

Right, okay. Epigenetics is basically all the mechanisms that our body has, biochemical mechanisms, to regulate gene expression because every cell in our body has DNA and it has exactly the same DNA, in fact. It’s your personal DNA code that encodes all your information that you’ve inherited from both of your parents. But then how does every cell know what to do? Because our body is made up of hundreds of different types of highly specialized cells that do very different things. You might have a muscle cell that’s involved in muscle activation and movement. You have skin cells that cover your whole body. You have receptor cells in your eyes, and then you have lots of different cells in your brains, like the dopaminergic neurons that degenerate in Parkinson’s. And they look very different in terms of their shape and morphology. They do very different things like neurons would be sending electrical signals, for example. But not all the cells in our bodies do that.

So how do they know how to become what they are? That’s epigenetics. So, epigenetics is basically, you can think of it as an annotation that tells this really, really large genome, your DNA, which parts of it to use. So, like, “Silence down all of these genes and then use this class of genes because you’re going to need it, for your calcium signaling, whatever receptors. Produce all of those proteins because you’re going to need it as a neuron.” And so, one really important part where that is seen most clearly is cell development and differentiation. And that is thought to be driven primarily through epigenetic mechanisms. But then it’s not completely locked in and stable for the rest of your life. It’s also a bit dynamic, and it can respond to environmental factors.

So, for example, when we have an immune activation, when our body’s infected by something, immune cells will react to that. So, our body needs responsive mechanisms that can react to things that come in from the outside, or also from the inside, or regulate temporality throughout the day, throughout the life, throughout different cycles. And so therefore epigenetics, these mechanisms allow some sort of temporal dynamic-ness and flexibility.

And so yeah, I study these mechanisms pretty much to interpret how environmental risk and how genetic risk will act on the disease. And we know that both environmental risk factors but also variation in our genome can change the epigenome in specific places in specific cell types. So really taking a deep dive into that and understanding what cells are affected by these given changes, where is it changing, what is it doing to these cells? I did want to come back once more, too, because you were talking about the mitochondria, which, also from my angle onto the disease, have become really prominent because both when we look at the genetic risk factors for Parkinson’s, sporadic, but also more familial Parkinson’s disease, there is certainly a class of genetic variants in mutations that we know specifically affects the mitochondria. And equally-

Dr Fiona McLean:

That’s so interesting.

Dr Sarah Marzi:

Yeah. And equally from the environmental side, one of the best known and strongest associations for my environmental risk factors are actually pesticides, so agricultural pesticides. And one really well-known one is called rotenone. And it’s primarily a complex one inhibitor. So, it inhibits the function of complex one respiration in the mitochondria and therefore energy processing and energy delivery through the mitochondria. And it results in a substantially increased risk of Parkinson’s in humans.

And also administering this to animals, it’s done in rats for example, will give the rat a pretty much Parkinsonian symptoms. So, the rat will get the tremor, will get the rigidity. And I think eventually if you do it long enough, also you can test some of the cognitive symptoms as well. And you can see some of the cellular dysfunctions that you would see in the human brain as well in the rat. So, it seems to represent Parkinson’s as a syndrome in the animal really well. And it causes the disease, so to say, both in the human and in the model, making it a really convincing and strong risk factor. And it acts primarily on the mitochondria. So there definitely is a really strong link there.

Dr Fiona McLean:

That’s so fascinating. I actually have heard of rotenone, and I use it in my own experiments, because I do metabolic stuff, and I used it to shut down the mitochondria and I actually didn’t know that it had previously been used as a pesticide. And now I know what I used it for in the lab, that’s terrifying. Oh my-

Dr Sarah Marzi:

That is.

Dr Fiona McLean:

… goodness. That should not-

Dr Sarah Marzi:

And you say-

Dr Fiona McLean:

… be used as a pesticide.

Dr Sarah Marzi:

You say previously, it has previously been used in places like the European Union and the US where it’s forbidden now. But it is actually still used in several other countries, I think in Brazil and in India for example. And so, it’s really important. This association is well known. So, I think there needs to be more policy [inaudible 00:20:23] being to ensure that these kinds of toxic substances get regulated and phased out across different places.

Dr Dean Beccano-Kelly:

It’s not the only one. There are quite a few pesticides that have been linked. There’s work done by Beate Ritz and other people over in the States, and then they found that there’s a number of different pesticides that could contribute to the decline and maybe Parkinsonian features. And then our differences in our own genetics may increase the risk of that by not being able to break it down as well or breaking it down faster. And it’s interesting because some of those have been presented to various government bodies, and some of those have been removed from being used, and then sometimes been reintroduced despite the information being present. So that’s a worrying stuff.

Dr Fiona McLean:

Not good.

Dr Dean Beccano-Kelly:

Yeah.

Dr Fiona McLean:

It is actually interesting, because I’ve just been thinking while you were talking, and my grandfather had Parkinson’s disease and he was a farmer and now I’m sitting here thinking-

Dr Sarah Marzi:

I wonder what-

Dr Fiona McLean:

… if he ever-

Dr Sarah Marzi:

… he was supposed to.

Dr Fiona McLean:

Yeah.

Dr Sarah Marzi:

Yes.

Dr Fiona McLean:

He was in his 90s when he died. But yeah, he had Parkinson’s for a while. And he was a farmer for a long time. So, it does really make you think. And I’m sure there’s been studies looking at farmers, especially we have such a big-

Dr Sarah Marzi:

Absolutely.

Dr Fiona McLean:

… agricultural-

Dr Sarah Marzi:

So-

Dr Fiona McLean:

… in the UK.

Dr Sarah Marzi:

The best evidence for this association actually comes from studies of farm workers who have extremely direct, and constant, and continuous exposure to these toxic substances.

Dr Fiona McLean:

Wow.

Dr Dean Beccano-Kelly:

But they have-

Dr Fiona McLean:

So-

Dr Dean Beccano-Kelly:

… also done some stuff where they’ve looked at the drift to things like nearby schools and seeing-

Dr Sarah Marzi:

Oh, wow.

Dr Dean Beccano-Kelly:

… the number of pesticides that are in the walls. They can tell how much has been used nearby and the rate of Parkinson’s in those towns, usually in the States, but in those towns, because you know where you’d see those films where they fly the planes over and they crop dust, basically.

Dr Sarah Marzi:

Yes.

Dr Dean Beccano-Kelly:

And obviously that’s going to drift in the wind and so it’s really bad for any neighboring places as well. It’s-

Dr Fiona McLean:

And of course, this is then going into the water, it’s going into our ecosystems, and it’s probably doing a lot of damage that we don’t even know about because if we only know about the association with Parkinson’s in humans, goodness knows what it’s doing to other species as well. Yeah. Oh, my goodness. Quite scary.

Dr Sarah Marzi:

That’s right. And-

Dr Fiona McLean:

So-

Dr Sarah Marzi:

Make it even worse, pesticides are just one class. There are lots of other things that have been associated with Parkinson’s.

Dr Dean Beccano-Kelly:

And then we wonder why it’s on the rise.

Dr Fiona McLean:

Well, yes. My next question was aside from pesticides, what other environmental and genetic factors are there? And do you know what the split is? How important is genetics versus environment in terms of risk?

Dr Sarah Marzi:

This is my kind of question. Usually, we would estimate something like that, how genetic is a disease by looking at twins. So, you would look at twins that are genetically identical and then twins that are dizygotic, so that are like siblings, essentially sharing 50% of their variants. And so, then you compare how often does it co-occur in one versus the other. And then you could quantify how heritable it is. So, Parkinson’s, I would say, is really only moderately heritable. It’s around 20 to 40% across different studies that have estimated it. Whereas, for example, in contrast to Alzheimer’s disease, which we think is around 70%. So that’s quite a bit higher.

That’s not to say that the genetics isn’t as important. And I would say the genetics and the genetics studies in Parkinson’s have been really thorough, and really good, and have shown us lots of potential pathways and mechanisms into the disease. But that’s just to bear in mind that environmental factors are going to play a more important role in this disease than in others. And that we also need to look at things like gene environment interactions like Dean was saying, so maybe an environmental exposure affecting different people differently depending on their genetic makeup.

Dr Fiona McLean:

Yes, absolutely. It’s really interesting and-

Dr Dean Beccano-Kelly:

It is, isn’t it? I think there’s, just to add on, the longest time people thought Parkinson’s disease was just environmental because of that reason that Sarah just said, because it’s not as a prominent feature as in other disorders, neurological disorders, until the advent of, or the defining of alpha synuclein mutations, which causes slightly earlier onset Parkinson’s disease. But there’s a number of them that we find.

Dr Fiona McLean:

So just for our listeners, could you explain about the links between alpha synuclein?

Dr Dean Beccano-Kelly:

Alpha synuclein is a very small synaptic protein. It’s involved in membrane curvature. And think that it’s very important in neurotransmission and other functions like this. In Parkinson’s disease, it starts to aggregate, and you start getting these intracellular inclusions known as Lewy bodies, which after Fritz Lewy, which basically are one of the main ways that you can identify Parkinson’s disease postmortem, because you can only define definitively Parkinson’s disease postmortem. So, you’re looking for these kinds of inclusions. And actually, you can have things like point mutations in alpha synuclein, which causes or seems to increase this level of aggregation and synuclein triplications, which is one of the earliest ones to be discovered. So, you’ve got triplication of alpha synuclein gene and then you’ve basically got increased levels of it, which theoretically and factually empirically leads to an increase in the aggregation.

It does cause earlier onset; we’d just like to pause that point out. And then actually in those mutations you probably get more formative pathology, pathology that’s probably closer to MSA. And I think we were talking about it just before, but Parkinson’s disease is a bit of a spectrum, actually, if we’re actually looking at it objectively. And it’s to say that it’s just one thing, it’s a bit hard to define it like that because the synuclein is definitely involved at some stage of the disorder. But when you have these mutations, it causes earlier onset and these differences in pathology. Whereas if you have something like LRRK2, which is more later onset, that’s more similar to the age of onset of sporadic Parkinson’s disease, you basically have less of that pathology and more cognitive impacts. And so, it’s good to look at all of these.

Again, I think all of the models are really useful. They all provide us with different information. I think they definitely, you have your autosomal dominant forms, which cause later onset, which are more similar to the sporadic forms. You have your recessive forms, which cause earlier onset. And then you have mutations that in the genes that cause risk factors like GBA, glucocerebrosidase, which is enzyme found in lysosomes, which helps the processing of lipids and mutations in that increase a person’s risk factor. But the penetrance isn’t as high. And so that 20 to 40% is probably a bandwidth of how much penetration there is for how much penetrance, sorry, there is for the genetic factors.

Dr Fiona McLean:

That’s interesting. I guess maybe if there’s a spectrum at some point, hopefully in the future if you get a Parkinson’s diagnosis, it’ll be maybe more tailored to you have this subtype and then that can help towards more targeted treatments and precision medicine, which would hopefully give people more successful treatments in-

Dr Dean Beccano-Kelly:

Unless, I don’t know, should we discuss it? Let’s all have a-

Dr Fiona McLean:

Yeah, go ahead.

Dr Dean Beccano-Kelly:

… sit down a bit. No, but unless of course if we find commonalities, like a common thread between all of them, but then that is accelerated in some and lengthened in the other. So, if we found one common theme and trim out the fat, then perhaps we can use it, just modifying that one common theme in all of them. That might be a longer shot but maybe there is-

Dr Fiona McLean:

Yeah, I guess-

Dr Dean Beccano-Kelly:

… something that’s similar to one.

Dr Fiona McLean:

It’s two approaches, right?

Dr Dean Beccano-Kelly:

Yeah.

Dr Fiona McLean:

You either try and find something that is affected in everything and hope that improves it all, or I guess if that doesn’t work, then you start to look more in depth at these different subtypes.

Dr Dean Beccano-Kelly:

Yeah. It’s just-

Dr Fiona McLean:

And far across the spectrum.

Dr Dean Beccano-Kelly:

… the rate might be affected. Yeah.

Dr Fiona McLean:

Yeah.

Dr Dean Beccano-Kelly:

Yeah, it could be that.

Dr Sarah Marzi:

That’ll be wonderful-

Dr Fiona McLean:

Interesting.

Dr Sarah Marzi:

… to find the super superpower drug that cures them all. But realistic-

Dr Fiona McLean:

I know, that would be amazing.

Dr Sarah Marzi:

I’m a bit pessimistic, maybe. Maybe not. Realistic, pragmatic. And I think maybe as we’ve seen in other complicated diseases like cancers, maybe there are subtypes that do distinguish themselves through certain biological pathways and mechanisms that make them easier to act upon and then at least we can target those.

Dr Dean Beccano-Kelly:

Nope, I do agree. Just pragmatic, like arguing devil’s advocate, there’s possibilities, I suppose, into both ways. I’m not married to the idea.

Dr Fiona McLean:

Do you know what? You’re going to look at it all, though. Because if you don’t look for it then you’ll never find it. I guess talking about risk factors, is there anything that we can do as individuals to lower our risk factor for Parkinson’s disease?

Dr Sarah Marzi:

This is tricky. You have to live in the right areas, probably don’t live where the pesticides are. We didn’t quite touch upon what the other big classes of environmental risks are, actually.

Dr Fiona McLean:

Let’s talk about that.

Dr Sarah Marzi:

Other big classes would include heavy metals, so people who work in mines of different sorts, copper mines, mining heavy metals have a substantially increased risk of developing the disease. Then we’ve seen pretty good evidence for industrial solvents, like halogenated chlorines, basically like tetrachloroethylene and other variations of those that are quite strongly associated again with Parkinson’s. And we’ve seen this especially in people who have dramatic exposure. So, who literally work on top of a vat with that industrial solvent decreasing, I don’t know, metal components in automobiles or whatever. But we’ve also seen it in some contamination of sites. Again, in the US there’s this famous military base that got a big spillage into the groundwater of tetrachloroethylene and then after many, many years, because it takes a lot of time and these exposures build up, you see an increase in Parkinson’s occurrence.

So those are two big classes and once they’re in the environment, some of these are really hard to break down as well, like the tetrachloroethylene, TCE, unfortunately forms structures that are relatively stable for potentially decades. So, it is a problem. So, we need to, I guess that’s more at the policy level, ensure that politics knows about these risk factors, and acts upon it, and minimizes the usage, and thereby the exposures. Some other things are a bit more lifestyle factors. So, one really puzzling one is that smoking is actually negatively associated with Parkinson’s disease risk.

Dr Fiona McLean:

That’s so weird.

Dr Sarah Marzi:

Which is weird.

Dr Fiona McLean:

We’re not advising that-

Dr Sarah Marzi:

We’re not.

Dr Fiona McLean:

… you all take up …

Dr Sarah Marzi:

I’ll just- [inaudible 00:31:51]

Dr Fiona McLean:

Disclaimer, we’re not advising you take up smoking.

Dr Sarah Marzi:

With all sorts of other really terrible diseases like lung cancer and cardiovascular-

Dr Fiona McLean:

And dementia in general, actually-

Dr Sarah Marzi:

… and dementia.

Dr Fiona McLean:

… because-

Dr Sarah Marzi:

So, I don’t-

Dr Dean Beccano-Kelly:

I was going to say, is it not the reverse in something like Alzheimer’s disease?

Dr Sarah Marzi:

That’s right. But it’s also not known in entirety whether there is a causal association because as a devil’s advocate, one could argue that maybe the general prevalence of dopaminergic neurons, so how many you have to begin with as a human might be associated both with your propensity to smoke and Parkinson’s. So, saying that if you have a lot of dopaminergic neurons, because dopamine is actually involved in the reward circuitry in our brain. So, if we do something that we like, our brain goes like, “Oh, we’re happy about this.” And that might be things like smoking or drinking alcohol, and therefore having more dopamine activity might predispose you to become addicted to things more easily. So that could also be an underlying cause that has not been- [inaudible 00:32:55]

Dr Fiona McLean:

Fascinating. What is-

Dr Dean Beccano-Kelly:

How risk adverse you are and how risk taking you are. Yeah, it could be affected by dopamine.

Dr Fiona McLean:

And what about stuff like exercise and diet? Sorry, back to my bias point of view from my research.

Dr Dean Beccano-Kelly:

No, I think that’s fair, actually. Yeah, I think exercise has been shown to be very effective at maintaining your level in Parkinson’s, for instance. And even perhaps staving off the deterioration-

Dr Fiona McLean:

So, slowing progression.

Dr Dean Beccano-Kelly:

… slowing the progression. It’s been shown that that can be enormously helpful. And so, for the similar reasons, exercise and eating well is never a bad thing. So, it’s got to be something that we could utilize in our daily lives to improve upon this. It’s just that when we’ve seen during Parkinson’s that you utilize an increased level of exercise, and coordination, and control, things like dance, things like boxing, I think. I think I was watching the same documentary that happened on ITV the other day with Jeremy Paxman. And he was talking about how people have joined things like bowls and anything that needs coordinated, controlled movement. But there’s all sorts of information that seems to be tied with things like increased blood flow, increased concentration, and diet has been also linked. Obviously, we’ve talked about the gut earlier, and there’s the idea that it’s a bottom-up progression of the disorder. You can see sort of a Lewy body pathology and the spread of dysfunction and destruction up from the gut and then into the brain. So-

Dr Fiona McLean:

So could you-

Dr Dean Beccano-Kelly:

… it’s possible.

Dr Fiona McLean:

Could you explain that a bit more because I find that fascinating. So, is there early change you’ve seen in the gut? Is it linked to gut microbiota? Is it linked to signaling from the gut? Why is this connection?

Dr Dean Beccano-Kelly:

I’ve got to say that the gut microbiota for me is not my strength. However, I know that there is a lot of work going into looking into that. There are definitely early signs of pathology within the gut. And you obviously have the enteric neurons going up from the gut that are affected in Parkinson’s disease. It seemingly occurs incredibly early. And obviously we were talking earlier as well about constipation being one of the main features, which actually occurs pretty early. And I would actually argue that there is a lot of the non-motor features that are affected pretty early in Parkinson’s. It’s just that the motor features are prominent, that’s usually what people come to the clinic for. But you have all sorts of issues with neuropathic pain, or chronic anxiety, or sleep behavior disorders, getting to sleep, remaining asleep, and having a restful sleep is completely disrupted in Parkinson’s.

And, sorry, not to digress too much from, moved from one non-motor future to the others, but that does turn up very early sometimes, well, quite often earlier than the motor features and progress with time so that they become more prominent later. But they are triggered earlier. So, you can have people with REM sleep behavior disorder that convert at quite a high rate to Parkinson’s disease. There’s a lot of work done in Oxford by Michele Hu and [inaudible 00:36:14] Cole that shows that this are almost the, for want of a better word, the precursor to Parkinson’s. And so-

Dr Fiona McLean:

Yeah. So prodromal-

Dr Dean Beccano-Kelly:

… you can see a lot-

Dr Fiona McLean:

… phase of the disease.

Dr Dean Beccano-Kelly:

Prodromal?

Dr Fiona McLean:

Yeah.

Dr Dean Beccano-Kelly:

Yeah, I suppose. But there’s a lot of non-motor features that seem to contribute. But the gut is one of those that, whilst it does contain the neurons, it’s probably not readily associated with the neuron or degeneration. And so maybe it gets left out a bit, but there is a lot of work going on in it, and it probably ought not to be. And I think that there is definite, it might not be directly linked to the things we’re eating that’s causing it, because there might well be some underlying genetic differences that cause them to be more susceptible to change. But if you think about it, it’s another energy, highly energy dependent area of the body.

Dr Fiona McLean:

And we know that if you have issues in the gut, you can get a leaky gut, and then things can leak out into other systems that can cause an inflammatory response in your body, can cause an inflammatory response in the brain. And that’s never good if it becomes a chronic thing. So, I guess it’s one of those things where if you have a trigger then it can just cause a cascade of problems down the line. I find it really fascinating, the links between the gut and the brain, because I think historically, we think of these as very separate things. But actually, I think in the last decade we’ve really started to realize how influential the brain is on our gut and the gut is on our brain, which is, I think it’s a really exciting area of research.

And so just to think more about where the future of Parkinson’s research is going, what do future therapeutics look like? There was a recent story that I just thought was amazing, which was about a woman who says that she smelled her husband’s Parkinson’s disease before he was diagnosed, and she basically just thought he smelled differently and musty, and she thought it was just him. But then when he was diagnosed and she went along to a Parkinson’s group, she realized that the whole room smelled like he did. And I would just love to know what you guys’ take us on that and where are therapeutics heading in Parkinson’s disease?

Dr Dean Beccano-Kelly:

I think that stories awesome.

Dr Fiona McLean:

It’s amazing.

Dr Dean Beccano-Kelly:

It’s so fascinating. Perdita Barran, up in Manchester, is really heavily involved in trying to transfer that, because yes, she’s a super smeller, I suppose. And she can smell that, and detect, and she can even get down to the level of maybe stage of Parkinson’s as well.

Dr Fiona McLean:

Oh, my goodness.

Dr Dean Beccano-Kelly:

Which is just-

Dr Fiona McLean:

She’s incredible.

Dr Dean Beccano-Kelly:

… it’s just incredible. Oh yeah, she’s amazing. And so, they’re trying to get towards a way of then quantifying that and understanding what’s being expressed in the sweat of these individuals. Because effectively, if you could then just mop somebody’s brow, and then analyze it, and be like, “You are early stage.” We’re now getting into the realm of biomarkers that can tell us about earlier and earlier stages of Parkinson’s disease. And that’s going to be really critical in treating because the earlier we can treat, the more chance we have of staving off the onset of the cell death. And it all goes full circle, it all comes back down to trying to stop the dysfunction at the synaptic level. So, if we can get that to that stage, then we can be like, “Well, we can give you a drug to stop the breakdown or at least delay the breakdown of the neurons, which means that you’d end up with developing symptoms much later in life, you know, into the 60’s-

Dr Fiona McLean:

Amazing.

Dr Dean Beccano-Kelly:

… 70. You could be doing it-

Dr Fiona McLean:

I’m-

Dr Dean Beccano-Kelly:

… 80, 90.

Dr Fiona McLean:

… so glad that, because she must have thought, she was like, “What is going on, here?” I’m so glad that she kept talking about it because she’s clearly kept saying, “I can smell something, I can smell something.” And eventually people have listened to her and said, “Actually- ” [inaudible 00:39:58]

Dr Dean Beccano-Kelly:

I wonder how many other people have done that before and gone, “I’m not going to say anything because that’s just rude.” Or “I don’t know what some, I’m talking … ” Do you know what I mean?

Dr Fiona McLean:

Right.

Dr Dean Beccano-Kelly:

“You all smell different.” That is a bit of a … You know.

Dr Fiona McLean:

Yeah, that’s a really good point. I don’t know, I just think she’s amazing. Sarah, what do you think about therapeutics in Parkinson’s and where are we headed?

Dr Sarah Marzi:

I feel like I don’t have good answers for you because my approach to the disease is very basic, very fundamental, foundational, going back to what I think are the earliest causes of these diseases. So, starting from the environmental exposure, starting from the- [inaudible 00:40:35]

Dr Fiona McLean:

Your strategy would be prevention, basically. So-

Dr Sarah Marzi:

[inaudible 00:40:40]-

Dr Fiona McLean:

Yeah, how do we prevent?

Dr Sarah Marzi:

I think there is a good argument for that, like Dean already said. The earlier you can get in there, the better. So twofold ways. One, if you’ve had a lot of neurodegenerations, I don’t see how we can recreate or rebuild the lost neurons, the lost connections, and everything. I don’t think that’s realistic. So, we need to stop it as soon as possible. There’s maybe even an argument that it is a cascade. So, if you don’t get in early enough, it’s basically unstoppable. That might be an option, too. And in either of those cases we need to get in there as early as possible so that the damage isn’t even done. So, I think that that is absolutely right. But the other reason why I go to the environmental and the genetic risk factors is because I really want things that are mechanistically causal to the disease.

So, we have lots of associations of different things with diseases and Dean mentioned, for example, sleep disorder, REM sleep disorder, and different things that’s been associated with various types of dementias and neurodegenerative diseases. But there the causality is really not that clear. So is the sleep disturbance, is it increasing your risk for the disease? And there is some evidence for that, because if you don’t sleep well clearance of aggregates in your brain, things like the Lewy bodies that we talked about or other aggregates in other diseases doesn’t work as well. So, it’s certainly not good if you don’t sleep well.

But equally, people who have these diseases tend to not sleep so well. So, the sleeping poorly might be a consequence of the disease and of ongoing neurodegeneration. And it’s just a vicious circle that is driving each other. So, it’s hard to establish causalities for many of these factors, and that’s why I want to go back, and I really want to understand what is causing it. Because if we can act on the pathways and the mechanisms that are the original cause and onset of the disease, then we have the best chance of preventing and stopping it.

Dr Dean Beccano-Kelly:

So, Sarah, do you want to work on both? Do you want to work on both the epigenetics and the genetics? Because you need to look at the genetics to see the initiation and what that’s actually driving?

Dr Sarah Marzi:

Absolutely.

Dr Dean Beccano-Kelly:

And then the epigenetics and how that model? Yeah, because-

Dr Sarah Marzi:

I-

Dr Dean Beccano-Kelly:

… that’s fascinating. Your stuff is- [inaudible 00:42:53]

Dr Sarah Marzi:

I’m maybe unusual in that I don’t see epigenetics as separate from genetics. And I know genetic variants can drive epigenetic mechanisms. And not everyone would agree with me. Some people tend to think of epigenetics as something that is very malleable and environmentally driven, but I don’t think that’s right. I use some sort of more biological definition, biochemical mechanisms that regulate gene expression, basically. And so, I really want to understand it particularly in the context of the genetic risk and background. So yes, I’m really keen to combine these two things together and leverage the causal information that we have from the genome because your genome is basically set at birth, and it’s not going to be changed by any influences, environments, and anything. So therefore, we can leverage it to understand what a cause is and what is a consequence.

Dr Dean Beccano-Kelly:

We should work on the IPSC RBD lines that we have, because not to limit the sleep disorder, but when talking to people with Parkinson’s, they actually say that, well some of them, not all of them, talk about how the non-motor features are actually much more impactful on their daily life. I mean anxiety, if you have a sort of wave of chronic anxiety that’s going to be quite debilitating. And sleep, I don’t know about you. If I don’t get good enough sleep, which I often don’t, my anxiety goes up. The synaptic connections don’t work as well. So cognitive processing and problem solving becomes harder. When you’re talking about a cyclic event, Sarah, I truly believe that that is exactly what happened.

So, if you imagine every time, you don’t sleep properly, your coordination goes, so movement becomes harder, your processing becomes harder, your anxiety levels do go up. And these are all symptoms that happen in Parkinson’s disease, and they seem to be driven. So maybe it’s initiated by Parkinson’s disease, but I think the sleep may well make it worse. And so, it’s one of the things that actually we really want to work on in the lab, because we think it’s probably turning up quite early and it’s something that maybe if we could modify, may delay the perpetuation of the symptoms.

Dr Sarah Marzi:

Super interesting. But also, oh- [inaudible 00:45:04]

Dr Dean Beccano-Kelly:

It is.

Dr Sarah Marzi:

I slept very poorly last night, and these are not things- [inaudible 00:45:08]

Dr Dean Beccano-Kelly:

No, these are not great. But I suppose it’s then how [inaudible 00:45:11]. But let’s not too deep and go, but I don’t think you’re causing yourself to have PD just by not sleeping properly.

Dr Fiona McLean:

You’ve got the weekend to catch up.

Dr Dean Beccano-Kelly:

It’s true.

Dr Sarah Marzi:

I suppose.

Dr Fiona McLean:

This is what I say about people with their diets as well is that I think we sometimes focus too much on a single day, and “What did I eat that day?” And it’s same with sleep. Like, “Did I sleep well that day?” It’s better to look at it over a week because if you have one out of seven days of not eating well, if you’ve eaten well six of the other days, then that’s really good. And I think it’s the same maybe with sleep as well. “Okay, you might not have slept well for one day, but if you’ve slept well the other six days.” Because people get very anxious about their lifestyles and that’s not going to help it. That’s not going to help you have a good lifestyle if you’re anxious about your lifestyle.

Dr Sarah Marzi:

Exactly. But it is Friday, and I am going out, and so my good night’s sleep was going to be tonight.

Dr Dean Beccano-Kelly:

True. Just have a long line tomorrow, that’ll be fine. Right?

Dr Sarah Marzi:

Right.

Dr Dean Beccano-Kelly:

Okay.

Dr Fiona McLean:

Thank you both so much for coming and speaking about Parkinson’s disease today. It’s been absolutely fascinating, and I think I’m so excited for your new collaboration that’s going to happen.

Dr Dean Beccano-Kelly:

Yay! It’s going to be awesome.

Dr Fiona McLean:

Yeah, that sounds fantastic. And you both do incredible work. And it sounds like a really exciting field at the moment. So, thank you so much for coming to speak.

Dr Dean Beccano-Kelly:

No, thank you. It’s been a-

Dr Sarah Marzi:

Thank you for having us. It’s always a pleasure.

Dr Dean Beccano-Kelly:

Yeah, always a pleasure.

Dr Fiona McLean:

I’m afraid that’s all you have time for today. However, if you just can’t get enough of this topic, then please visit the Dementia Researcher website, where there are several blogs and articles on Parkinson’s disease. I would like to thank our incredible guests, Dr. Sarah Marzi, and Dr. Dean Beccano-Kelly. I’m Fiona McLean and you’ve been listening to the Dementia Researcher podcast. Bye.

Dr Sarah Marzi:

Bye.

Dr Dean Beccano-Kelly:

Bye.

Voice Over:

Brought to you by dementiaresearcher.nihr.ac.uk in association with Alzheimer’s Research UK and Alzheimer’s Society, supporting early career dementia researchers across the world.

END