The quest to cure Parkinson’s

Publication Date
15/09/2023
Featuring
Professor David Price
Dr Esther Sammler
Professor Miratul Muqit
Dr Xingui Liu
Brendan Hawdon

Around 1 in every 375 adults live with Parkinson’s disease in Scotland with about 30 people diagnosed each week. In this panel discussion, we discuss the latest research taking place in Dundee and the real-world impacts it will have.

Around 1 in every 375 adults live with Parkinson’s disease in Scotland with about 30 people diagnosed each week. The current treatments have not changed in over 60 years and only treat the symptoms, not the disease. Scientists and clinicians at the University of Dundee are aiming to change that and are making significant advances in understanding this disease with the assistance of those living with Parkinson’s.

In this panel discussion, we will discuss the latest research taking place in Dundee and the real-world impacts it will have.

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Transcript

This transcript has been automatically generated and may feature errors.

00:06

Hello a warm welcome to you all from the Royal Society of Edinburgh for this event ‘The quest to cure Parkinson’s.’ My name is David Price. I’m professor of developmental neurobiology at the University of Edinburgh. And my research is on how our brains develop. I am the chair for today’s session. This event is part of the RSE Curious programme, which is running up to the 17th of September, so there’s still some events that you can sign up for. This offers insights from some of the world’s leading experts on an array of topics addressing the theme of under the surface, please visit the website www.rse-curious.com for more details. Okay, today, the event asks, How do we find a cure for Parkinson’s disease. Parkinson’s affects around 1 in 375 of us across Scotland. Current treatments have not changed in over 60 years and only treat the symptoms not their underlying causes. Today we will hear from scientists and clinicians at the University of Dundee who are aiming to change that with the assistance of those living with Parkinson’s. So I’m going to introduce the speakers to you nw. We have today Dr Esther Sammler is a clinical programme leader in the School of Medicine University of Dundee. Brendan Hawdon is the chair of Dundee research interest group and was diagnosed with Parkinson’s disease in 2017. Dr Xingui Liu is a Marie Curie fellow at the University of Dundee. And Professor Miratul Muqit  is professor of experimental neurology at the University of Dundee. So I’m now going to hand over to the speakers to give their presentations and I will return later for the question and answer session. Okay,

02:10

thank you so much, David, for for hosting this event. And thank you very much for everybody who’s joined online. So I think I’m starting so my name is Esther Sammler. I am a clinician scientist and Scottish senior clinical academic fellow here at the University of Dundee. As a clinician, I’m a consultant neurologist, I see people with movement disorders, including Parkinson’s disease, and I’m also the principal investigator on a large range of clinical trials in Parkinson’s disease. As a scientist, I investigate what goes on in Parkinson’s disease on a molecular level, mainly using clinical samples from patients with Parkinson’s disease. I think it is really important to emphasise that Parkinson’s disease is the fastest calling neurological disease worldwide second only to Alzheimer’s disease, one in 37 people will develop the condition at some point during their lifetime. So for example, in Scotland, there are over 12,000 people living with Parkinson’s disease. So Parkinson’s disease, despite all the advances that have been made over the last decades, is still poorly understood and under researched. So for example, as a clinician, we don’t have a test for clinical diagnosis. So sometimes people is it multiple doctors and it can take years to get the correct diagnosis. And by the time, the hallmarks of clinical symptoms, tremor, stiffness, slowness of movement, scale abnormalities, but also non motor symptoms, but especially with regards to motor symptoms, by the time these symptoms which are needed for the diagnosis develop 60 to 80% of the critical new ones in the pain that produce dopamine have already generated. In terms of treatments, what we have available, I think David already alluded to this. So the best available possible symptomatic treatment was has been announced since Lance Armstrong set foot on the mall. And I think that is really not good enough. If you compare to other medical specialties, in order to tackle, emerging cases of Parkinson’s disease and really offer our patients in clinic something better than just symptomatic treatment, a lot of more research and basic science needs to be done. And I think that is really like the key for moving forward. And this track record of this collaborative, open science that is spanning the globe, with who they like, you know, starting from fundamental mechanisms towards treatments. That’s the key for moving forward. And I think that you know, one of one of the things But we are extremely pouty and dandy proud to be at Dundee. Is is all of our research relating to one of the main genetic causes of Parkinson’s disease, which is the leucine-rich repeat kinase 2 (LRRK2) gene. So it’s now been about 20 years, but 19 years that LRRK2  genetic changes in LRV2 have been discovered as a cause for Parkinson’s disease. And why is this important? This is important because it gives us a starting point, rather than a needle in the haystack to start unravelling what goes wrong in a Parkinson’s disease it gives us this it gives us an opportunity to really study molecular mechanisms in cellular systems and other models to then see how this can be applied to the human system. And there has been a lot of focus here. So since since 2004, when the gene was discovered as a cause for Parkinson’s disease. So a lot of research that was actually done here in Dundee by you know, by Professor Dario Alessi who is who is the director of the protein MRC protein phosphorylation and ubiquitylation unit. So he has slowly unravelled the pathway and the signalling of what goes wrong when LRRK2 vcell signalling misfires. And I think like, you know, that is really like the, you know, the backbone of the work that has led to us having new clinical targets under evaluation and clinical trials. Thank you.

06:37

Go next to my name is Brendan Hawdon, and I’m the person here who has Parkinson’s. And therefore, I’m not going to talk about the technical part of the solution found in Parkinson’s. I was diagnosed in 2017. I should say, I was misdiagnosed in 2016. Where my GP Dr. Fuller had carpal tunnel syndrome. As it transpired after a lot of investigation and ability to urologist in Belgium, right? I discovered that I had all the right symptoms of correspondence to to Parkinson’s. Now, two things happened after that. One was that she wrote me a document saying, I have hyperbaric Parkinson’s. And I thought it was very peculiar, because Why could you not see I had Parkinson’s in a document with my employer. And I discovered that there was no definitive test for Parkinson’s. And this is the reason that she gave me this document, which was supposed to go to my employer for insurance, health insurance reasons. They said, I had a high probability to have the condition. And then when I showed it to my employer, they wrote back to me saying, we have now accepted fully that you have Parkinson’s, which by the way, this certificate only lasts five years. And I thought, Oh, my God, it could be possibly I cured because it only can be a document that says that they will fund me for for consultations for five years. I was absolutely wrong, but that I discovered very rapidly afterwards that there was no cure for Parkinson’s. Oh, no, no, no, no accurate for Parkinson’s. And that I decided to go into this mode of self denial. I didn’t want to know anything about the condition. I more or less, went through a phase of trying to discuss it, and all people just trying to live a normal life as far as possible. When it came to retire on I retired here in St. Andrews, which is very close by to Dudley, I think became my neurologist here. And my conversations with her, I actually hooked up enough confidence to be able to start finding out more about Parkinson’s. And there was this book called Ending Parkinson’s, which has been well known book written by Ray Dorsey, and as my basis for trying to understand what was wrong with my body, and what chance to work for the future. And through that particular, avenue of having read the book, and I found out that she was involved through my wife as well with a group called the Dundee research interest group, which was a group of people who were made up of Parkinson’s sufferers, plus carers plus research, researchers and clinicians as well. And we have here Esther and Myrtle, who are both clinicians and researchers. And that was quite an amazing breakthrough from my perspective of trying to understand issue because they both had the clinical experience of dealing with people with Parkinson’s but also the research side of things, which is an amazing benefit to have be bringing it to a group of people who are suffering from the condition. This this, this particular DRIG, so called DRIG – Dundee research interest group – was specialised in as a as a forum for exchange on condition. And we found out lots of things about it, we got involved with some of the clinical trials, as already referred to, and we actually got to meet famous people as well. In fact, we got to meet a Nobel Prize winner. In some of our work when we were working within the context of this forum. I think that we’ve we’ve gone through a lot of cycles in the forum itself, one of the cycles is trying to understand the language of our researchers, we rapidly found out that all of us where we live people who are who were living with Parkinson’s, rapidly did not understand what we will do with the  language was about to very complex language. And so we set a whole process in motion where we try to understand what words will when it came to discussing Parkinson’s. And we had a system where we paired person with Parkinson’s with a researcher or condition and try to make sure that they were they were presenting the public is understandable by by by using simple words in the presentation or suggestion, as simple words, for the for the for the condition. And it leaves us with a series of wealth of events we have planned as well. Later in the year, we hope we will bring people into the lab to show them the work that’s been done here in Dundee as well as I try and make sure that the presentations are done in a way. That’s understandable by all. And maybe I’ll leave it there for the moment. But one of the big issues that we will roll with grappling with is trying to find the cause of Parkinson’s. In my own personal case, I don’t know how it happened. A bit like Michael J. Fox, I went back to my past to try and see what foods I was exposed to what chemicals I was exposed to and could have led to me to having Parkinson’s, I don’t know. But one thing I discovered, when I when I went to my memory banks to try and see what could have caused was that I discovered that I had lost my sense of smell. notes have been written about by personnel had written in the past. And I had lost my sense of smell in the year 2000. And therefore, I feel that even though I was fully diagnosed in 2013, I had the condition from the year 2000, when I lost my sense of smell, and losing your sense of smell is one of the only precursors to developing this condition. So had it a long time. And like Esther  says, I probably lost a lot of my neural neurons. And therefore, it puts the whole issue of finding a cure in a far more complex environment. Maybe I’ll stope there.

13:50

So thanks for organising this event. My name is Dr Xingui Liu I’m a postdoc fellow at the Centre for Targeted Protein Degradation at the University of Dundee. So I’m a medicinal chemist by training, which means my mission is basically to discover small molecules for treating diseases, including Parkinson’s disease, for sure. So I’m fortunate enough. So in the past three years, I’ve been working on discovering protect molecules for degrading ARRK2, which has been mentioned is one of the most promising targets for Parkinson’s disease. So we managed to discover the degrader in the scientific community, so it can degrade structure very efficiently in the cell. So I think the challenges of finding treatment for Parkinson’s disease lies in the complexity of the diseases itself. So we really need to scientifically know innovation for sure to discover a cure for this disease. So, so currently thetargeted protein degradation is one of the most popular and emerging and drug discovery strategy in the field for treating diseases. So I think there are some, a lot of protein degraders for targets of Parkinson’s disease have already emerged. So, so I’m pretty positive about those researches.

15:25

So, maybe I will thank you. So first of all, it’s an honour for me and my colleagues here to be addressing you. And thanks very much to the Royal Society of Edinburgh for inviting us to talk about our research background and interests and how in Dundee, not only the science, but as Brendan alluded to, as scientists and clinicians we’re working with people affected by this condition. And together collectively, that is, how we think progress to progress will be made. Just a, you’ve heard that really Dundee has become extremely well known for basic science of Parkinson’s and particularly, understanding what is are occurring deep inside the brain and deep inside individual brain cells. And what is it that goes wrong to lead to people developing loss of the cells and ultimately, that causes symptoms. I think it would be maybe wanting to be familiar with this. But Xingui has suggested this that to understand a complex problem and and Parkinson’s is an extreme is one of, I think, understanding brain diseases, degenerative disease to the brain. These are the really most challenging questions in biology, and in life sciences, and the neuroscience. And there are different approaches that one could take to understand that problem. I think where we are now in 2023, is very much underpinned by previous research previous advances, I think we’ve reached an exciting phase, we understand very well known Parkinson’s, for example, which part of the brain is affected? We understand very well, if, if a pathologist were to look into the brain, which brain cells are affected, and in fact, 100 years ago, to, literally 100 years ago, in Germany, there was a new sort of era of science in which you could look into the brain using microscopes, they could see within brain cells of people with Parkinson’s, the formation of, of aggregations, and, and deposits that were in people with Parkinson’s, and not in those who had died of other causes. And so, as you know, he has highlighted technologies are very important to understand this problem. So I started my life as a clinician, and for me, the most important thing is to try and bring to the clinic, how under understandings that will then lead to new ways to diagnose and treat. And I saw 20 years ago, a pathway potentially to do that. And as Esther has highlighted, that the big the biggest, probably the biggest breakthrough in Parkinson’s has been the identification of genes in people with Parkinson’s. So most people with Parkinson’s develop it. And we don’t understand why. But in a very small number of people, 5% of people, they inherit a genetic cause. And we in Dundee believe that by studying why those genetic causes lead to Parkinson’s could be very informative for everybody with Parkinson’s. Now, why do we think that? So for me, I think the best analogy is in the cancer field 40 years ago, we didn’t have a good understanding inside cells of how a cancer developed. And that largely came from our early studies in the 1980s, where they discovered genes that would cause cancers in humans. And then it took about 2030 years of studying how those gene pathways operate. That led to know for example, you probably see now every year, at least a dozen new treatments for cancer based on understanding of those gene pathways. So in Dundee, that is very much the blueprint for how we think we can help find a cure for disease. And so based on that, that that sort of blueprint, we have been particularly interested in a class of gene that makes I mean, we call them proteins. Another way to think of them are nano machines. So within all of our cells, we have these tiny little machines that are performing very important functions in the brain, and the new brain cells and, and so a particular expertise that we have in Dundee are machines that are called kinases. These are machines that that actually work as enzymes to speed up certain types of reaction. And it turns out in Parkinson’s, there are a number of genes which make these kinase machines. So one of these has been the LRRK2 gene. And I think there’s an Esther as mentioned this, thanks a lot to the work of our very esteemed colleague, Dario Alessi. There’s been tremendous advances in his laboratory, which have led to how the LRRK2 kinase becomes dysfunctional in people with Parkinson’s. And just to sort of summarise that work. What his work has shown is that in our cells, we have to be able to get rid of damaged products and damaged components. And that’s all done in our parts of the cell called the lysosome. It’s, it’s sort of like what we regard as being the dustbin of the cell. And if you can’t get rid of all of the damaged materials in your cell, then that can build up and lead to a sell, sell, sell vulnerability and loss. And Dario lAlessi’s work and I know Esther is following this work up in terms of the clinical trials, has found that the LRRK2 pathway ultimately is trying to make sure that damaged, the accumulates in brain cells is efficiently gotten rid of in the lysosomes. And that has led to know this really, really new designer based trial, which Esther is now leading, and Dundee is one of the sites along with other sites in the world, for patients to have treatments against LRRK2, in my own laboratory, our work has been involved with a different machine called pink 1, it’s another kindness machine. But just to sort of, again, use the another analogy, all our brain cells need our batteries to provide all the energy for all of the processes. And our work has shown that if you can’t make competent levels of pink one, then we can’t repair our batteries, and keep our batteries intact through our lifetime. And, and ultimately that will lead to cell vulnerabilitues. And, and we wouldn’t actually understand things about the batteries of a cell or the dustbin of ourselves without doing this very detailed in depth,  basic science, and so I think that’s where we think in Dundee, we want to basically find new ways to diagnose and treat. And that’s through basic science. Now, we don’t work in a silo. So in our laboratories, we work as, as Brendan said, we work with patients, but we also in Dundee are connected with many, many companies around the world for so many drug companies that want to develop treatments. It’s a hard business, you know, now they can develop treatments for cancer. But as you might have read about Alzheimer’s, there were many failures before there were in the last year or so some glimmers of success. And likewise, Parkinson’s is going to be hard. But we are in Dundee are very much networks in to some of the leading companies. And it’s great actually to see big pharmaceutical companies take an interest in Parkinson’s, we’re also very connected to all other leading clinical centres. So Esther in her busy busy week has often to travel to all the major centres in Europe for her research, the United States, we’re very connected to all the big centres in the UK, including London, Oxford and Edinburgh. And we see actually that whilst the basic research is important, we constantly have to take that knowledge and and cross reference it to what the patients are telling us to what the clinicians are telling us to what drug companies are telling us and only if work together in an open way, can we ultimately make progress. So I think I think we have a very unique way of doing science in Dundee. It’s very much based on collaboration and openness. That is actually in some ways, often not how scientists have pursued things, they’ve often done this more secretive, competitive way. But this is such a complex problem. We think that we have to be open and collaborative. And that’s very much one of the hallmarks. And so ultimately, you know, the four of us sitting here all represent little pieces of a very large body of people that together we think can make make progress. And so thank you again for for your attention.

24:55

Well, thank you all very much for those fascinating insights. We have some questions that have come in during your presentations. And hopefully, there’ll be more to follow. But we have quite a few here already. So I’m going to start off with one from one of our attendees who was anonymous. And this came in during your talk Esther but I think it’s for anyone to answer. And it refers to the LRK2 gene and they’re asking, can people therefore be tested for the gene?

25:32

I can answer this. So LRK2 is not the only gene that is implicated in Parkinson’s disease. But it is one of the most frequently implicated genes. So 1-4% of people with Parkinson’s disease will have a genetic change in LRK2 maybe even without knowing it, and sometimes even without having a family history of it. But this is like no, this is worldwide. But there is quite a lot of variation with regards to population specificity. There are some parts in the world and populations where LRK2 mutations are much, much, much more frequent. For example, when you look at the 100, people with Parkinson’s disease, up to 40%, up to 40, people have this LRK2 gene . At the moment, genetic testing for Parkinson’s disease is not really embedded in NHS clinical care for Parkinson’s disease, only in like the selected cases, if you are for example, from Ashkenazi Jewish background. So that is like genetic changes in LRK2 is quite frequent if you have a family history, like a dominant family history of Parkinson’s disease, or, and that’s probably more applicable to other genes. So what is working on if you have particularly young onset Parkinson’s disease. So and that is like an aware with some NHS centres, you know, there’s also quite a lot of variability across the UK across Scotland across the world. But some centres do genetic genetic offer genetic testing for this. However, from the research side, there’s a huge drive with the GP to movement funded by ASAP aligning basic science with Parkinson’s disease, to really unravel the architecture, the genetic architecture of Parkinson’s disease. So hundreds of 1000s of people are being tested in early like now in a much, much, much larger fashion, so that we get a much better understanding of the genetics of Parkinson’s. And I think like if people are interested in getting tested, they need to somehow see what centre is close to them. And there are certainly lots of clinical observational studies. We have some here in Dundee. There are other you know, there are other studies and other centres in other parts of the UK and in the world and in Scotland. And it will just be a matter of speaking to the clinical research team or their consultant neurologist.

28:07

Thank you. So Fiona Newton asks, Does Parkinson’s disease occur at a higher level in Scotland than the rest of the UK? How does it compare with other countries?

28:23

I can also answer this, so not necessarily. I think like Parkinson’s Disease is a worldwide problem. And while we don’t really have, you know, like epidemiological data and surveillance data, that’s absolutely accurate. We actually think that there are nine to 10 million people with Parkinson’s disease worldwide. And I just picked Scotland because we are, you know, we are based here, but the prevailing rates of Parkinson’s Parkinson’s is the same in Scotland and UK, and the best of the best.

28:56

Okay, thank you. I just wanted to raise a question from Allison White. And actually, I’ve heard of this as well, that there was a lady who could tell by smelling the sweat of Parkinson’s Parkinsonianism sufferers as the way she puts it has any further work been done on this?

29:21

Perhaps that I can answer that question. So indeed, that’s a very pertinent question to Scotland because this is very much a Scottish discovery. So in Perth, which is very close to where we’re sitting now is a remarkable lady called Joy Mill. So Joy was Joy’s husband unfortunately had Parkinson’s for many years and, and, unfortunately, that has passed away but but but after he passed away, Joy had mentioned to a colleague research of ours at Edinburgh called Taylor, that she could smell Parkinson’s, where and had this sort of very, very highly specific and selective ability to pick this up, perhaps in layers before his symptoms where they’ve even advanced. And so she did a study with Taylor initially where they took some clothes from people with, with with Parkinson’s and joy was asked to see if she could tell which patients were the close from Parkinson’s, or which were those that didn’t. And she was almost 100%. Correct. And remarkably, the one t shirt that she thought wasn’t that she thought was Parkinson’s. But the patient, the person at the time, hadn’t had symptoms turned out that person then went on to get Parkinson’s. And so this was the initial discovery. And in terms of your question, what’s happened since so now Joy is now on the faculty of the University of Manchester. She’s, she’s an honorary faculty member there. And she has been collaborating with a very talented scientists called Perdita Barran, who’s been using this technology of mass spectrometry, and so Joy in  Perdita Barran have been able to identify, so what they’re what Joy is smelling, are particular chemical signatures that are arising from your sweat. And they’ve been able to now, break this down into what are the actual nuts and bolts of that chemical signature. And they’ve now published many papers on this area of research. And it’s looking very promising that this could be in the future, a diagnostic test for Parkinson’s. And Joy is actually also very closely associated with our Dundee research interest group. And it’s actually not just in this one particular project, I think is a fantastic ambassador for Parkinson’s really inspiring how she wants to help the field with her amazing ability, but also generally as a as a advocate, to do to get more interested in investment in this area. So I hope I’ve answered that question. And, and you can find out more from from online.

32:16

Yeah, so I mean, actually, this is generating quite a lot of interest. Another person has asked, if there are more people who can smell Parkinson’s, would it be helpful if they reached out to someone in the research community? And if so, who?

32:32

Yeah, so this came up, I mean, I can just follow this upside. I’ve also encountered other people like joy in my practice, I think that there are people who have this remarkable, I mean, our ability to smell is to take determined by your panoply of smell receptors, and there are these people that have these sort of these super smelling traits, my understanding of the moment is, based on the work that’s now been done by predictive Baron. There, they now have quite a quite sort of now defined chemical signature. So as far as I know, I don’t think they’re looking for more human volunteers. But certainly Joy’s details will be available, and they could reach out to Joy to perhaps ask if they wanted to help with that.

33:22

And then Julie Mirvis, has raised an interesting question. I think maybe dogs can be used for this as well.

33:30

So again, absolutely part of it, because you’re absolutely. So that has been also exploited very successfully. So dogs have remarkable abilities to smell. And I think there has been an I’m not it’s not my research says joy in particular research. I think there has been work. I think has also been involved in this. And he really is hard to get, as you say, in this whole, you know, area of research. It’s actually the observation of Tila Kuna, and together with Joy, that really was the catalyst, but I think there has been some work with super sniffing dogs in this area as well.

34:08

Okay, thank you. I’m gonna shift gears a little bit now to ask from Robert P Lau. About the nomenklatura and the language that we use and as someone who, whose work is particularly related to conditions such as autism, this is a thing that comes up for us all the time. Can we please stop calling this Parkinson’s disease and instead call it Parkinson’s syndrome? This would better reflect the fact that symptoms vary from case to case that would also assess both patients and their friends, families and co workers, etc.

34:48

I can I can take this question and then maybe like lead over to Brendan. I mean, there’s a there’s a there’s an ongoing discussion about Listen, I think this is really, really, really important. And we will only be able to, you know, like to solve this question in, in the discussion and discourse with people affected. I think like, you know, there’s a lot of discussion about, like, you know, how do you refer to a person or, you know, people, you know, people living with this lived experienced of Parkinson’s disease, or living with Parkinson’s disease, because you don’t want to be defined by a disease. So you don’t want to be called a patient or you don’t want to be defined by your Parkinson’s disease, because there’s so much more to a person. So I think so I think that is really, really, really important. And also, like, you know, what, what the, you know, what person referred to is that people with Parkinson’s disease are so different from each other. So if you know, one person, the Parkinson’s disease, or the Parkinson’s syndrome, you know, one versus the Parkinson’s, the, the, you know, like the age of onset, the rate of progression, the clinical presentation in terms of motor symptoms, non motor symptoms, how functional somebody is how somebody can engage with the environment literally differs from from person to person. So, I probably have some, I’ll pass this question on whether we should call it Parkinson’s disease or Parkinson’s syndrome, to maybe like Brendan and also be quite interested to hear what you guys have to say,

36:24

yes, yes. I was recently at the Barcelona conference on the world Parkinson, Congress, on Parkinson’s disease. And I met for 800 different people there who are living with Parkinson’s, and everybody was talking to each other. But we all had different symptoms, and a range of different symptoms. And we’re all progressing at different rates. We all have different doses of the drugs we were taking, I think it was more akin to having a syndrome rather than having the disease itself. And therefore, I would find it very easy to be able to justify changing work disease syndrome for that reason.

37:08

I mean, I would just add that I completely agree with what Brendan and Esther said, I mean, in my own practice, I, I usually tell people that they have Parkinsonism, I mean, that’s sort of a broader term, reflecting actually their variability. And, and then then later on, I try and sort of modulate that. I mean, I think what’s what will probably help with classifications in the future are, obviously, as Brendan mentioned, you know, 100 people, and they’re all very different, is what we can’t do yet, is really able to group people in to what is their subtype of Parkinson’s. And that is really the next sort of frontier of classification. That will be important, for example, in clinical trials and targeted therapies and precision neurology in this area, there has been a recent breakthrough in the diagnosis of Parkinson’s using spinal fluid. This has been funded by the Michael J. Fox Foundation and the aligning science plus Parkinson’s PPMI programme, they’ve been able to, you know, show that you can take people with Parkinson’s, the link watch is similar, but showing their spinal fluid, the pathological correlates are different. And there is no some discussion to to take such testing, and be able to then refine somebody’s subtype classification. So I think at the moment, that question is, I think I agree with you, I think syndrome is probably very appropriate at the moment. And as we get more better at doing the subtype part identification, we can then become more more accurate.

39:01

Okay, thank you. So I’m going to put two questions together here. They they’re really about the genetics. One is from Helga MacFarlane and other from an anonymous attendee. So Helga asks, given that we have many 1000s of genes, do you think over time, many more may be identified to be implicated in a person’s likelihood of getting Parkinson’s? And the other question is, is Parkinson’s genetically linked in any way to Huntington’s as the early symptoms can be fairly similar?

39:35

Okay, I’ll take that I take that question. So the first question is with regards to other many more Parkinson’s genes to be discovered. I think that you know, traditionally the first gene to be implicated cause Parkinson’s disease was I first new clean in 1997 1997 1998. And up until then, you know, we always knew that there was like an audit there could be for billion clustering, but it was considered not necessarily a genetic condition. And since then, there has been like a constant discovery in this kind of era of gene hunting and gene discovery, very much helped by the presence of these large Kindred, Kindred families with Parkinson’s disease. So I think I can all just really common genes have been have been discovered. But I do think that there are many, you know that there are many more genetic factors that either have a small effect or larger effects can be implicated in Parkinson’s disease. So I think like in clinical practice, five to six genes are really relevant. But we have about 60 to 80 genes that can potentially cause monogenetic, hereditary Parkinson’s disease. And when we then look at the whole genome sequencing is large jgenome studies where you compare lots of people with Parkinson’s disease, and not Parkinson’s disease, we now know that there are about 90 genetic signals that may be enriched in people with Parkinson’s. And you have to somehow imagine this, like on a scale, so you have really rare genetic variants, they are mutations, this large effect, you know, so you can even have these genetic changes, and the probability that you then develop Parkinson’s disease is quite high. And then you have lots of other small, you know, smaller effect size changes that are actually quite frequent in the general population. But the effect size on its own is rather small. So you have fully like, no, a whole genetic landscape of it. I don’t think that, you know, over the next few years, one, you know, a few more genetic discoveries will be made. I think, especially as all our knowledge of genetics of Parkinson’s disease is mainly based on Caucasians. And I think like, with the effort of fully unravelling genetics and non Caucasians in Asia, India, China, that will really probably bring in, you know, pretty modest genetic discoveries. The next question with regards to Huntington’s disease, so Huntington’s disease is, is really like the prototype of a mono genetic disorder. So it’s caused by three nucleotides, repeat expansions and the Huntington gene. I think that was also discovered ninth in the 1990s. And, and I think I cannot there are a couple of extremely rare causes look alikes of Huntington’s disease that can also be caused by genetic changes other genes. I do look at my SQL as my as my job as a consultant neurologist that also look after Huntington’s disease patients. And, you know, and yes, that is correct. There can be sometimes overlap, especially, you know, like, usually Huntington’s disease develops in middle age and your 30s 40s. But there are these like, you know, extreme types when the onset is extremely young, like, you know, in their early 20s. And there’s a particular phenotype of Huntington’s disease called  variant, and that can actually present very much like Parkinson’s disease in the beginning, but then like, you know, as the condition progresses, you know, like, I think like, you know, the whole story unravels, and the trajectory of the two conditions has been very different. Yes,

43:22

I just follow up. Sorry, did somebody have something to add? No, just following on from that Sarah Dinah’s? I’m a PhD student at Edinburgh, whose father died of Lewy body dementia. I know there is a large overlap in symptoms and progression of the diseases and was wondering if your work would impact treatment for this disease?

43:46

Perhaps I could answer that. So Lewy Body Dementia is mediated by very much one protein, or machine or nano machine called Alpha synuclein. So this is actually the the protein that’s found in deposits of people that fastens what, what are called Lewy bodies discovered 100 years ago. Now, it turns out the dementia with Lewy bodies libo. Dementia has several names. It’s probably a variant. It’s on the spectrum of of Parkinson’s, but it’s much more extensive in the regions of the brain that are affected, and the rapidity the evolution of it is a lot more faster than Parkinson’s. And so, that is it is not understood yet why it’s more extensive than Parkinson’s syndrome, and why is it more rapid? So, at the moment, I would say that the work that is done in in Dundee is been mainly focusing on these kinase machines and the links of At to this nucleon is still mysterious. I would say though, that in the UK community amongst movement disorder specialists, there is now very much an effort to really try and do more research on on Lewy body dementia. So at the moment, there are there are two neurology professors in the UK, who have together set up a cohort, which currently is in England, but I think it will extend to Scotland one of them is Professor emotive aisle at University College London, what they wish to do is to really, first of all study, many patients dimensionally body, try and recruit them to their cohort studies, try and really define the clinical problems and features that they get trying and then and then use things like brain imaging and other types of biomarker approaches to figure out how are they different from Parkinson’s? So I would say that there’s a lot of new activity in that area, maybe not from Dundee, but certainly in the UK. And if that person wants to reach out, I’m happy to pass on the details, for example, to to Professor ammonia vile who we know well.

46:18

Thank you, I’m going to jump to a question that’s addressed, primarily to Brandon, but maybe others can chip in as well. So Simon starters, curious what Brendan’s definition of a cure would be. And what he thinks is missing from current research efforts to address this.

46:42

The Cure, one of the things that we had one of our online seminars, was a discussion with Ray Dorsey. And wherever he was talking about a cure, he was saying, Hold on here, a cure is a very difficult thing to manage. And when I thought about it afterwards, I think he was referring to was that a cure has two parts. One is replacing the Lost neurons that create dopamine. And the stopping of the condition. So you had a bi-approach to cure. Getting rid of the the condition was was was the more challenging one, because, of course, up there, at the moment, there seems to be some very good work done on stem cell replacement therapy, which is replacing the damaged, but the actual cure, the condition itself, is something that’s far more more challenging. So how do I define cure? I define cure where you replace what’s lost, and you stop the condition.

48:00

 Does anybody else want to chip in on that? Or?

48:04

I think for me, I mean, just to maybe, again, using a different disease as a good analogy. I mean, for me, it’s, it’s the development of a drug or intervention, that can that can arrest progression of that, of that process. And it might be the, the process is still there, but you are you You have basically blocked progression. So the best example of that would be when I was are a medical student in the 1990s, early 90s. In Edinburgh, there was this terrible wave of HIV in Edinburgh, partly because of various policies about how they were managing sort of illicit drug abuse in Edinburgh. And they did had some policy misfirings. And so there was very large rates of HIV in Edinburgh. And at that time, HIV was very much our, as everybody knew back then, pretty much fatal disorder, which then evolved to flute full blown AIDS, Acquired Immune Deficiency Syndrome. Now, with the advent of combination treatment for HIV, you have people now with HIV, who every day, take medication, and live normal lives. If the date the minute they stop it, the HIV will work. This has not gone away. It’s still there. But there is no progression. So for me, it’s it’s an interruption. There are actually interestingly, have been a few examples of HIV now being cured through various people that have had bone marrow transplant it funds for other reasons. But nevertheless, for me, it would be some intervention that stops progression, not necessarily taking away the the origin or the driver. Louise is working on the cutting edge of new approaches to cure Parkinson’s using targeted bridge and degradation? I don’t know, generally, if you want to mention,

50:07

yeah, sure. So thanks for the introduction. So we work on degrading the disease causing proteins, for example, ARK2 is one of the targets that we have been working on. So we use small molecules to get rid of the disease causing proteins. So without the protein poverty, the disease can go away in a way. So another very important protein, as Roger has mentioned before, it’s Alpha synuclein. So it’s also a disease is also can cause is a, because the pathology of the Parkinson’s disease, I know a lot of companies are starting working on making degraders for alpha synuclein, that means they can remove this alpha synuclein aggregates form the sale, so which potentially can also stop the progress of the disease? Potentially?

51:04

Thank you. I’m going to link together two questions. One from Vivian Kitterning and the other from Julie Mirvis. Vivian asks, What are the advantages currently of early diagnosis of Parkinsonism? And perhaps related to that? Are the GP sufficiently trained or knowledgeable about conditions such as Parkinson’s?

51:27

I can maybe start here. So I think, you know, like, there is a benefit for early diagnosis, because like, you know, then, you know, usually you go and see your GP because something is not quite right. And I think getting an answer to the problem that you’re experiencing, is quite important, with regards to, you know, trying to find treatments that slow down, or stop the progression of Parkinson’s disease. I think like, you know, treating the I think the belief and the field is that trying to treat people and identifying them as early as possible. And starting intervention at an early time is probably much better than further advanced. So I do think there is, you know, there is there is there is really like quite quite a lot of scope there. There are, in fact, clinical diagnostic criteria for Parkinson’s disease that are being published by the respective bodies, movement disorder society, for example. But there are also like research criteria. So to identify, Parkinson’s disease, and that is really, really, really important. For example, there are also like worldwide, several cohorts of people with conditions that we know, put them at risk for Parkinson’s disease. And again, like, you know, we really learned quite a lot of this, like, you know, following the application, the natural progression for disease conversion, and then also like, you know, hoping that they will eventually be able to stratify people or sub co people with Parkinson’s better, and then eventually much the person with the most appropriate clinical trial or intervention. And the second part was GPs. I do think like, you know, that, you know, Parkinson’s Disease is a very common problem. And GPs are extremely well educated and trained to discover, you know, like, and identify symptoms, symptoms of Parkinson’s disease, which would then lead to the movement to a disorder specialist. However, it is really quite clear that even specialists sometimes get it wrong. And especially like, you know, when you see someone who presents maybe out of what you would expect. So for example, if you see someone who presents with typical Parkinsonian symptoms, but at the age of 20, it’s probably much higher that this person will be seeing multiple GPs, it takes time to see a specialist. And maybe like the cause, Parkinson’s is not considered as the most likely diagnosis in that case. But I think like for most people who develop the disease at the expected or the condition, the syndrome at the expect expected age, I think, if you develop shaking, or you know, a slowing down, I think like GPs are very able to pick that up and then refer to us.

54:24

Yeah, I would just follow on from Esther and say that I said with regard to GPs, absolutely. I agree that I think they are all familiar with the, you know, they cut the textbook and clear major features. In terms of early diagnosis. I mean, I’d probably put my physician hat on rather than my. I mean, as a scientist, you could argue, we should know as early as possible if somebody’s on the risk trajectory for Parkinson’s, because of the because of future trials that are becoming the emerging and, and that they may benefit for recruiment. But the fact is, at this moment right now, there is no treatment that can actually, that can that can modify their disease course. So it’s not like so so for example, going into so if somebody comes to see see you with symptoms, it’s important that you define why they have that and give them a diagnosis. But I think starting to go into more pre symptomatic populations, one has to be a little bit more careful, because, you know, you know, telling some, someone who’s 31, is perfectly healthy, and is looking forward to all the things in life that they have potentially, you know, very, very strong chance in the next 10 years, they can develop Parkinson’s, without any clear interventional option. I’m not sure that’s, that’s good, good medicine. I don’t think that says a physician. I’m not sure that that’s knowledge that they would want to know, obviously, if they come in a context of a strong family history, and they have awareness of that, and they want to know, for maybe family planning purposes, that’s sort of a separate question. But I’m not I wouldn’t be in favour of, for example of screening really early in a very kind of more sort of on sort of filtered way to make early early detection, because at the moment, it’s not I think somebody’s overall well being an interest for that information.

55:05

Thank you. So We’re nearly out of time. I’m just going to squeeze in a last question. This is quite a technical question from a doctor. If you can manage to answer it. In less than a minute. I think it would be excellent. But he asked, Did I miss the bit about progressive Supranuclear palsy, and Parkinson plus syndromes?

56:52

I can take that question. I think like we spoke a little bit about Lewy body dementia, which would also fall under the umbrella term of a typical Parkinson’s disease, such as multiple system atrophy, Lewy Body, dementia, and then also the classical terminology of progressive Supranuclear palsy. So these all have in common that there are types of parking of syndromes with Parkinsonism. And they usually have a faster rate of progression. With regards to pockets, Supranuclear palsy or progressive Supranuclear palsy, there is actually a little bit of overlap and a potential link to work that we do here in Dundee, so some of the experts in, you know, in PSP in the UK, Professor, Yumothis and one of his former PhD students at Dr. At Jabbari, who’s a neurologist, both in London, and they have looked at the genetics of the Supranuclear palsy, and they’ve identified that LRK2 so the gene and protein that we’re working on at Dundee is a marker so that some, you know, the IS can can differentiate people with PSP that have a faster progression than others. And actually, we have an ongoing research collaboration with with the team and UCL around new models and extra body where we are looking at clinical examples from people with PSP. And they’re signalling with regards to look to looking at activity in these individuals. So that’s ongoing research directly related to PSP.

58:24

Thank you very much. Our time is up. I would just like to thank all of the speakers, I would like to thank all of the attendees. I would like to remind you all to look for upcoming events at Curious, you will receive an evaluation email for feedback. I hope you find this session today interesting and informative. And I look forward to seeing you at another Curious event in the future. Goodbye