Presidential Lecture Awardee - The importance of alpha-synuclein research | Congress 2024

[00:00:48] Prof. Virginia Lee: It's very nice for you to invite me. Thank you. 

[00:00:51] Prof. Tiago Outeiro: So, we are all curious about what you will be talking about in your lecture at the congress. I mean you've done tremendous work [00:01:00] for many years So, I'm sure there would be many options for you to, to present at the Congress.

Can you give us some ideas of what you plan to talk about this time? 

[00:01:11] Prof. Virginia Lee: Yes. As you know, I spent my entire career trying to identify these misfolded protein that are part of the pathology in neurodegenerative diseases. And we were very excited. And it actually started with people that work on genetics implicated alpha synuclein as very important for the pathogenesis of Parkinson's disease. And we immediately demonstrated that actually alpha synuclein is the building block of these inclusions called Lewy bodies. They're found in, in brains of Parkinson's disease patients and also in dementia with Lewy body.

And because so little was known about alpha synuclein, particularly as it related to disease, so and my late collaborator and partner, John Trojanowski and myself and decided to embark to understand the role of alpha synuclein in Parkinson's [00:02:00] disease. And I was very lucky in doing this type of work because John Trojanowski was a neuropathologist, and so he knew right away, from the get go when we started collaborating and in order to study and understand the disease, we need to go to the patient's brain and to see what's wrong with the brain before we can even talk about cure or things like that. So then he immediately collaborated with a neurologist and we get these big grants and with clinical component and basic science component, so that we get the clinicians involved. So this is a very important lesson for everyone that wants to work on disease, is that, you know, you need multidisciplinary research.

So you need people with clinical expertise, with pathology expertise, with basic science and neuroscientists and so on, in order to be able to be successful in understanding the disease.

[00:02:54] Prof. Tiago Outeiro: Yeah. And and so you will be talking about all the work you've been doing in this field, which is, as I [00:03:00] said, quite, quite impressive.

[00:03:02] Prof. Virginia Lee: Well, actually, I want to focus on really, on alpha synuclein, and really on some of the newer work on alpha synuclein. And in a sense that it has been really difficult to purify and study Lewy bodies from Parkinson's disease, brain and dementia, but Lewy body.

And more recently, we have been successful in doing so. And then we actually show that the pathology that you isolate from patient's brain and their structural confirmation are different than what you can make in the test tube. Because we and many laboratories have generated alpha synuclein amyloid fibrils from recombinant alpha synuclein proteins.

So that approach worked quite well at the beginning. But now what we realize is that the pathology that the preformed fibrils induce in brain of cells and of animals and also Lewy body that we isolate from patients. and induce different types of pathology. And in brain and in [00:04:00] cells and also in brain of animals as well.

[00:04:03] Prof. Tiago Outeiro: Yeah. And that will be very, very interesting for the community. And Virginia, I need, I need to ask you this because as you know, you know, we've, we've known about protein aggregates for centuries actually, and about the components, the protein components for some decades in some cases, and there's still some doubt and some debate on.

whether these protein aggregates are culprits or they are just bystanders that form because of some pathological process. So where do you stand on this, on this issue? Can we say that these protein aggregates are causing the problems in these diseases or is it still controversial? 

[00:04:46] Prof. Virginia Lee: I really think that it's not controversial and at least from my perspective, it's not controversial anymore.

And I think that it's, basically what we call the fat lady had sung. And I think that what we've been able to do, [00:05:00] and the field, not just me, the field has been able to do, is really to identify mutations. In the gene, and that that when, when it's mutated, and it caused a disease in the autosomal dominant manner.

And then the gene the misfolded protein itself. So in other words, if it alpha synuclein for Parkinson's disease, and there are not that many families, but it's a proof of concept. And there are families that have been identified. And with mutation and on the alpha synuclein gene and also gene duplication and triplication.

And actually what was really interesting was that when the first mutation was identified in this large pedigree as you remember and from Rutgers, and they had a big family. And so people were not really convinced and particularly that the mutated residue, amino acid residue was the sequence in rodent and so in mice and so I remember I had a conversation [00:06:00] with John Hardy, who is a geneticist, and he basically said it isn't impossible because at least history.

Tells us that the mutation in another species generally are safe, you know, safe in the sense that they're not, they don't cause a disease, but he was wrong. And, basically you make a mouse model with that mutation and you express that mutant gene in an animal. The animal and develop pathology and they have, phenotype type and they even die.

[00:06:29] Prof. Tiago Outeiro: No, those are all very good points. And in terms of the, the normal functions of these proteins, I mean, there's been a lot of work as well, and. We have some ideas for what Alpha synuclein and Tau might be doing, but do you think we still need to continue to investigate the function of these proteins so we can really define the pathological processes?

Or do you think that we should really focus just on the aggregation? 

[00:06:58] Prof. Virginia Lee: Yeah, I really think [00:07:00] that it's both. I really think that, all these neurodegenerative diseases are both loss of function and gain of function. Toxic function. And so we need to absolutely study alpha synuclein. And actually it has been challenging.

It's actually a different problem than other proteins. Because alpha synuclein is a very small molecule. It's easy to make it in, in bacteria. You can make lots of it. But to have it fold the right way, to study the folding, even right now, we don't know the abnormal folding in Lewy bodies.

Okay. And we are trying to see whether we can generate enough material and either from from isolated from patient's brain or be able to take some of that material that amplify that abnormal confirmation with recombinant alpha synuclein protein. So we have more of this stuff that we can study by using past physical techniques to confirmation and also other techniques to be able to understand.

Why and [00:08:00] how, in brains that default in this confirmation that induce pathology. 

[00:08:07] Prof. Tiago Outeiro: And I, I can sense and I've always known this, that you, you speak about all of this very passionately. So, With such a long career, What are the scientific questions that still excite you, that make you want to, you know, get to the lab, talk to the people, and, try to understand?

Can you give us some ideas of things that still excite you today after such long career and success? 

[00:08:31] Prof. Virginia Lee: You know, the long career is because I really truly enjoy doing science. I enjoy going to work every day. And I, I really think that, I actually would be I wouldn't know what to do with myself, be very bored if I don't go to work and, and also the other thing, the other really nice things for me to go to work is that I really actually.

I like to interact with young people, and I think that it's really nice to get them excited about science, because [00:09:00] usually, some of the kids that we get, they could be even high school and college kids, and to see them kind of get excited about science, and it's so amazing, to get them turned on so that they would continue to do science, because there's still so much to do, and, even though I have a long career, I'm very, very grateful.

This is not for Parkinson's yet, but for Alzheimer's disease, and I'm actually, I would not believe that we're at a point where we're treating patients and with antibodies, you know, so, I mean, there would be other drugs that are coming up, I hope, but I think that with Parkinson's disease, we just, I don't know why, but it's more difficult.

Maybe there are less people working on it, and maybe now there are more people working on it, and we don't even have good diagnosis. For example, and basically the molecular biology approach for diagnosis, not just, clinical looking at, behavior and so on and clinical phenotype.

And so we still have a lot to do. And as you pointed out that we still don't know what alpha synuclein is. [00:10:00] And normal function is or are, and there may be a number of them, we just know that it's probably involved with, vesicle recycling or something like that. But we don't know actually, and it's very humbling, that such a small molecule and yet, you know, so many people working on it and yet we still don't have good idea.

I mean, we have some idea, but we're not there yet. 

[00:10:24] Prof. Tiago Outeiro: Yeah, and Virginia, you are a role model for many of us working in this field. And so I would now like to ask you to share a bit what have been your major career steps, what brought you to this position that you have, and maybe also some advice you might be able to give to younger scientists that are entering the field.

[00:10:50] Prof. Virginia Lee: Yes, and I really think that there's several turning points in my career. Because when I was young, I always liked science and I just kept going to school [00:11:00] and so I think that the first turning point was actually meeting my late husband, John Trojanowski. I kept going to school, so I did my, my undergraduate, my master's, my PhD, my postdoc.

But I didn't really have good mentorship and I didn't even know what it was, would be like having a career in academia. And while I was in the middle of the postdoc, I met John in Boston and he was finishing his medical school and then was going to do a residency.

And so because I didn't know what I wanted to do. And I was, actually the first job I had was in a pharmaceutical company at SmithKline in France, which is FlexoSmithKline right now. And actually a neuroscientist recruited me. and now I realize that she, her, her job was to try to recruit more women.

And into come into the company and with the Ph. D. particularly. So I did. I joined the company. I thought, okay, it's a job. I don't know what it means, so I actually dragged John to Philadelphia. He really didn't like it so [00:12:00] very much. But fortunately, and University of Pennsylvania had a great neuropathology program.

So he wasn't so upset, so disappointed. And I came here to go to the company, And worked there for a year and I hated it, just to be very honest, because at that time, the science It's not that great. And particularly, if you're at a manager level, you don't do very much science. And so I went back to university and because I thought that if I want to do science, I really need to go back to university.

And, but it was tough for me because basically my then boss, said to me, And I will give you a job if you have funding, if you can get a grant. And so I was very lucky. I got two grants within a year. Two R01s within a year. And then that's where I just took off. So John and I met, and then we were working the same space, but we didn't collaborate.

And then it's not until later. Then we decided that we would, [00:13:00] collaborate, and then that was the first thing. And then the second question is that what area of research? So John was a neuropathologist, as I said, so we could go into area of brain tumors because at that time, one of the, my research project was in the, on a group of protein called intermediate filaments and particularly neurofilaments, which are found in neurons.

So these intermediate filament proteins are cell type specific. So we thought maybe we can develop that direction and use these intermediate filament as markers. of brain tumors, disease, because, you know, when you see a brain tumor in the brain, you don't know what the origin of the cells are.

So we thought that that would be one direction. And then the other direction is to go into neurodegenerative disease research. And actually to go into neurodegenerative disease research actually was, was fortunate because one of the antibodies that I generated to neurofilament cross reacted with tau.

And so, because at that point, people thought that maybe neurofibrichangles are comprised [00:14:00] of neurofilament. And I basically said, no, no, no, it's not. it's cross reaction. That actually got me into doing Alzheimer's research, and tau research. 

[00:14:11] Prof. Tiago Outeiro: Well, so that's that's always interesting to hear how serendipity sometimes brings us to fields that we may not have imagined before.

So that's, that's very interesting. And so we live now times when people are very concerned about work life balance. But we know that in academia, this life is extremely competitive. So, how do you see this, on one hand, balancing work life balance, and on the other hand, just, working super hard in order to, to have a chance in this complicated world?

Is there any advice you can give to, to young listeners? 

[00:14:52] Prof. Virginia Lee: My advice is that particularly for women. Don't give up, keep working, and even if you have to have [00:15:00] a gap because of, young children and so on, go back. And because if you give up, then you wouldn't be able to do any more and go back and then you wouldn't be able to make a difference in the area of your choice professionally and to be a scientist.

And so that's my advice is that just don't give up and keep going and keep learning. And it's really a short period of time, maybe 10, 15 years or so, that you have to devote your time to your children, and maybe to your parents when they get old and sick. But, by the time you're in your early 40s, late 40s, early 50s, you still have a really, really A long life ahead of you, particularly now we all live longer.

You know, the longer you live, particularly in the U S they don't really make you retire so you can work for as long as you want. And the nice thing about that is that you would have more savings. Later on because we don't know we all could live to a hundred. You know that, right? Mm-Hmm, . 

[00:15:58] Prof. Tiago Outeiro: Yeah. Yeah, that's right.

[00:16:00] So you need to, to be prepared in all, all ways. That's right. So 

[00:16:02] Prof. Virginia Lee: that's why you have to keep working so that you would stimulate your mind. And as long as you stay active and so that your body is, is active, and your mind is active, then you can live for a long time and enjoy life. 

[00:16:15] Prof. Tiago Outeiro: Well, that sounds, sounds good.

And on, on that positive note, I would really like to thank you again for taking the time to talk to the MDS podcast. It will be a pleasure to see you in Philadelphia at the Congress. 

[00:16:28] Prof. Virginia Lee: That's right. 

[00:16:29] Prof. Tiago Outeiro: Yeah. So thank you so much, Virginia. It was, it was really wonderful to talk to you. 

[00:16:33] Prof. Virginia Lee: You're very welcome, Tiago.

I'll see you later. Okay. See you. Bye bye. 

[00:16:37] Prof. Tiago Outeiro: So we've interviewed Professor Virginia Lee on the David Marsden Award 2024 at the MDS Congress in Philadelphia. And I invite you to join us for our upcoming podcasts. [00:17:00]