The Basic Science Perspective on the Role of Alpha-Synuclein | Congress 2023

[00:00:25] Prof. Poul Henning Jensen: Thank you, Tiago. Pleasure to be here. 

[00:00:27] Dr. Tiago Outeiro: It's also a pleasure to be here in your home country where the MDS Congress is taking place this year. So how are you enjoying the Congress so far? 

[00:00:36] Prof. Poul Henning Jensen: I'm really enjoying it. I visited the session yesterday about multiple system atrophy, MSA, which I particularly liked. It's a very good description of the status right now by Chin-Hsien Lin from Taiwan. And I think she made a very good case in actually pointing out that we might, in our models, model the wrong faces because we always think about synuclein, over-expressing oligodendrocytes. [00:01:00] but there's something wrong before that stage. And I think she made a very good case there. So, so that was thought provoking and, you know, it could actually be food for thought and how we could try to improve our models. 

[00:01:10] Dr. Tiago Outeiro: Mm-hmm. No, Chin-Hsien, she's doing great work. So I, I was there as well and I really enjoyed her presentation.

Yeah. And any, anything else caught your attention in what you were able to see so far? 

[00:01:23] Prof. Poul Henning Jensen: Yeah. Then I always have a great respect for human tissue. And there Gabor Kovacs presentation on the tauopathies was really revealing and I think that's also what I think we should keep an eye on in the synucleinopathies, which has, you know, are close to my heart.

So, so that was also a, a very, very good session. 

[00:01:41] Dr. Tiago Outeiro: Yeah. Great. So you will present this afternoon in our session on alpha-Synuclein as a therapeutic target. I know you will tell us a lot more during your presentation, but can you give us some highlights of what you will cover ?

[00:01:55] Prof. Poul Henning Jensen: Yeah, I think I'll give some basics, but then I think what [00:02:00] has been fascinating me for the last few years is actually the use of something called proximity ligation assay that was developed in Oxford in 2015. And that actually is a method to detect aggregates, but that's aggregates and other organized inclusions. And there's been two publications from Japan and we have some unpublished data I'll show that basically show us that you have synuclein aggregate pathology in brain regions that we would have considered, you know, not affected. 'cause we, before we only look for inclusions. And I think that's super important because these regions might contribute to the patient's symptoms. And so far we have considered them not involved in Parkinson's disease and dementia with Lewy body.

So I think that's very exciting to follow, and even something that'll be evolving in the next coming years. So that's more, let's say, the nature or history of the disease that we have to rethink, at least from my perspective. Then I will discuss a bit about the therapeutic strategies that has [00:03:00] been pursued.

And I'll also, being a little selfish, focus a bit on hypothesis we have been starting for the last few years, and where we have some very promising data in in vivo in mice models to discuss. 

And then finally, I would like to just highlight the new staging scheme. You rather say, okay, there's something wrong with synuclein, you can actually have Parkinson's disease before you get symptoms if you have a positive seed amplification assay. So I think these are novel thoughts that clinicians have to think about in the future.

'cause it's really changing the way we consider these diseases. 

[00:03:31] Dr. Tiago Outeiro: Yeah, those are all good points. And yesterday there was a session where the new staging system was presented and also an alternative proposal for classifying Parkinson's using, of course seeding amplification assays, but also maybe skin biopsies and other tests that are proving to be reliable. Yeah, but also to include other aspects like genetics and neurodegeneration. 

So I think it's exciting that we are living these times [00:04:00] when there are some ideas coming up. And I think it'll be really important that you said for the clinicians to, use these new concepts to help them define better what type of Parkinson's they have in front of them so that hopefully they can treat them better. 

There's also a current topic that we still haven't addressed fully that's related to this idea that maybe because of all the failures we've had over the years, that maybe we should not just think about these diseases as proteinopathies, but perhaps they are proteinopenias where because there's protein aggregation, then you lose the functional protein. And maybe the solution should not be to try to interfere with aggregation, but rather to increase the expression of the protein. 

Where do you stand on this discussion? I mean you are an expert in the field. You've been working on this for a long time. So give us your perspective.

[00:04:52] Prof. Poul Henning Jensen: Yeah, I agree with you that after 20 years of studying proteinopathy without breakthrough, we have to keep an open mind.[00:05:00] But we know that if you have too much synuclein based on duplication, triplication, you get an autosomal dominant disease. So I would not favor increasing synuclein expression too much. 

If there could be a way where you could say, oh, we could kind of stabilize a native confirmation, that might be tempting. But I guess the problem is we don't really know the native confirmation.

[00:05:23] Dr. Tiago Outeiro: And the function as well. 

[00:05:24] Prof. Poul Henning Jensen: And the function as well. But if there could be a way you say, okay, we have synuclein in the nerve terminals, it's decreasing because of aggregation — could we counteract that? But on the other hand, if you decrease the level, I would assume you just make more. I mean, this is a regulator, so I'm not a strong proponent for this idea about trying to increase synuclein levels. But let's see if somebody can come up with some model studies that can convince us.

[00:05:54] Dr. Tiago Outeiro: And so, when we think about this issue, what do you think would be key [00:06:00] experiments that have not been done that we need to do in order to definitively decide whether we need to really remove the aggregates or focus on something else, some other biological aspect? Can you think of any critical experiments that, even if they're difficult to do, but what we need to do to try to, to resolve this?

[00:06:23] Prof. Poul Henning Jensen: I think first of all, we need to Try to improve our models in the sense that we've been doing a lot of studies, both you and I, in cell lines, and I to some extent consider a cell line a, a bag of organelles, whereas in our brain, we know synuclein is very highly concentrated in nerve terminals. There's also something in the nucleus, but you know, the large majority and in high concentration nerve terminals. 

And the biology in the nerve terminal could be very different. I'm not convinced that you, in the process of developing the disease, you actually deplete synuclein out there. But I think we could try with human neurons or [00:07:00] primary cultures of randomized neurons, to see if we can induce an aggregate state that's not forced too strong and then try to see, okay, what happens to synuclein in nerve terminals? Could that be something that reflects what goes on in the brain of a patient? 

That might take years. But that's difficult to study. And, and I think our models now with, with human neurons that are, you know, more easy to cultivate and so on, might bring us there, even though they're not as polarized as, for example, primary neurons from rodents, which are more cumbersome to work with. So this is not easy, but I think we have to move in that direction. 

[00:07:36] Dr. Tiago Outeiro: And you are trained as a medical doctor, but then you've been a basic science researcher for a long time. So our audience is mostly clinical, although, fortunately we have a lot of basic science listeners as well.

I wonder if we focus on, again, the topic of the session where you will be speaking on alpha-synuclein as a target for intervention. What, from what you [00:08:00] know, and you know, a lot that is going on in the field, what do you consider are the best approaches to target alpha synuclein that we, we have being tested today?

[00:08:09] Prof. Poul Henning Jensen: You could say what has been in the clinic is where we try to remove synuclein by passive vaccination. It's not something that works like this. I think we should try to see if some of the more experimental strategies where we, we perturb signaling pathways may be affected by the aggregates.

If they could work and then the clinicians sitting in the audience could try maybe using these novel insights from, from the brain regions affected. Can we tease out symptoms from the patients that we haven't thought about before that are illicit from brain regions where you do not have, you know, cell loss, but dysfunction.

If that's possible, then you could say, okay, can we actually revert a symptom? Because you have a, a neuron, [00:09:00] it's kind of struggling, but it's still alive and kicking. So I think that could be really exciting. But that'll take clinicians to, to rethink. Okay, could there be other symptoms by our patients?

You have to talk to them and so on that we can quantify and, and, and maybe see, yeah, we start this treatment, you actually decrease this symptom. That, that could be fascinating. Mm-hmm. 

[00:09:21] Dr. Tiago Outeiro: No, it sounds sounds like a, a good suggestion. So, so Paul Henning, we are coming to the end time flies very quickly here while we have this nice conversation.

So are there any other thoughts you would like to share about the congress, about your research? At the moment? 

[00:09:37] Prof. Poul Henning Jensen: Well, I'll just say that, I mean, I just came from this grand rounds in, in the large auditorium It was you know, always moving to see. Real patience on stage because you know, there, there's so much more to it than when we read a paper, you and I, so I really appreciate the Congress here.

[00:09:54] Dr. Tiago Outeiro: Yeah, I think that's a very nice session. I think that's why it's always so well attended because everyone [00:10:00] really enjoys to, to see and watch the, the process, the thought process that the clinicians go through and trying to make a diagnosis. And for us as basic scientists, This is really interesting for me as well to, because I think for us, I feel it helps us also understand what we need to model in the lab.

It's not just about proteins that do this or do that, it's about trying to model a complex problem that is not limited to a simple or a single cell type and goes much beyond that. And I think this is, it's very humbling because then we realize really how complex the problems are. 

[00:10:33] Prof. Poul Henning Jensen: Yes. 

[00:10:34] Dr. Tiago Outeiro: So Paul Henning, thank you so much.

It was a pleasure having us you with us here on, on the podcast. I, I invite everyone, all our listeners to, to go and look for your beautiful work over the years. There's a lot for people to learn about what you've, you've been working on and all your contributions. So that's really great. And yeah, thank you again for joining.

I hope you, you enjoyed. 

[00:10:55] Prof. Poul Henning Jensen: Thank you for giving me the opportunity. 

[00:10:58] Dr. Tiago Outeiro: It was wonderful. 

So we have just [00:11:00] interviewed Professor Paul Henning Jensen from Aarhus University and discussed his participation at the MDS Congress 2023. So thank you all for listening and join us again in our upcoming podcasts.