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[00:00:33] Prof. Tiago Outeiro:
So we are at the MDS Congress 2024, and you gave a lecture yesterday in the session on the neurobiology of Parkinson's. Can you start by giving us an overview of what were the topics covered in the session?
[00:00:46] Prof. Jeffrey Kordower:
Okay, so there's sort of a little debate. Dr. King, who's the first speaker, talked about the role of alpha synuclein in Parkinson's disease. And he presented a fantastic talk, a tremendous number of slides, and points he was trying to make. And he was very well appreciated because it was a very high level.
And on the other hand, I spoke next, and I was demonstrating that Tau, not often associated with Parkinson's disease, plays a significant role in nigrosteroidal degeneration. And then the third talk was by Dr. Lorraine Kalia. There's now a debate about two different staging protocols, one called the neuronal synuclein disease, the other one called Synergy. And she was trying to reconcile the two.
There's a paper that just came out that I was part of — I think you were actually part of the Synergy one. And so trying to converge the two and trying to optimize things and that's really part of the scientific issues committee at at the MDS. And we're trying to make this convergence best for everybody: best for the scientists, best for the clinicians and ultimately best for the patients.
[00:01:57] Prof. Tiago Outeiro:
Okay, so now let's Go a bit deeper on your presentation.
So I really liked how you phrased it: is tau the elephant in the room? So we tend to be very focused on particular proteins in different diseases, and synuclein, we relate to Parkinson's; and DLB and MSA. Tau, we relate to Alzheimer's and PSP and FTD. So how should we really look at this? And are we just oversimplifying things when we think about one particular protein?
I mean, your data support that, so.
[00:02:29] Prof. Jeffrey Kordower:
Yes, we are we're very much oversimplifying it . Parkinson's disease is a copathology disease. Alpha synuclein occurs in most Parkinson's cases, but not all. Also 55 percent of Parkinson's cases have amyloid and 55 percent cases have tau. So that's already known and been demonstrated.
And this is important for a variety of reasons. There's a lot of money being spent and in clinical trials, where we're trying to remove one misfolded protein, mostly alpha synuclein. And so if you're successful at doing that, you're still leaving two other misfolded proteins that likely play into the clinical profile of patients with Parkinson's disease, especially the major unmet need in Parkinson's disease, which is cognition.
So, tau in cortex and tau, maybe in the nigrostriatal system, is likely involved in people having cognitive decline, a symptom for which we have no treatments. There are two reasons patients get into nursing homes: they fall and break their hip, or they get demented. So, this is a primary goal going forward.
We need to address the cognitive decline that's involved with patients with Parkinson's disease. And amyloid and tau likely play a significant role in that regard.
[00:03:50] Prof. Tiago Outeiro:
And this connects very nicely with the second half of your presentation where you presented some really exciting data on a strategy that may help neurons or even other cell types clean up this protein mess.
So can you mention that?
[00:04:07] Prof. Jeffrey Kordower:
I'd be delighted. Bruce Spiegelman from Harvard, National Academy of Science, National Academy of Medicine member, discovered a trophic factor called irisin.
This irisin is secreted from muscle when you exercise. And exercise is the one thing we know slows progression of Parkinson's disease.
You can't exercise enough to clear all these unwanted proteins, but it likely plays a role in why progression slows in patients with Parkinson's disease. It's been demonstrated by our group and others that irisin clears tau, clears alpha synuclein, and clears amyloid. And not only structural data, but functional data. It prevents the motor deficits that are seen in alpha synuclein models. It prevents cognitive deficits in an amyloid model. And we've also shown that it clears tau in, we're just starting our tau studies because I just developed this model an AAV model of two mutations of tau, which is a fantastic model.
And the first thing we saw is that not only does irisin reduce synuclein in tau, both in vitro and For Tau, where it would have studies ongoing in vivo. But it eliminates it. I mean, these are not modest effects. And one thing I've always learned is when you go from preclinical to clinical, you better have a big effect preclinical to, to, if you hope to get something clinically.
So I have a program that is being built up now, both in mouse models and in monkey models, and we're very excited about applying AAV irisin into these models.
Well, let me just say one other thing here. The delivery of the this trophic factor is intravenous, so we don't have to do direct injections into the brain like many of the gene therapy models that I've done in the past. It lodges in the liver. There's no damage to the liver. It secretes into the bloodstream from the liver, and it generously crosses the blood brain barrier. So there's a likelihood that we can just give this injection one time and you're done. Although even if you need, down the road, a second injection, as long as you change the capsid, which is part of the delivery method, then you're, you're fine. You can give a second injection and likely will work as well as the first.
[00:06:35] Prof. Tiago Outeiro:
Wow, sounds very exciting. I'm really looking forward to seeing the next set of data on this.
And so this brings us to this fundamental question in the field that is related to these protein aggregates being pathogenic.
There's also an alternative hypothesis that, is that what's happening, in fact, is that because we have this aggregates. They are siphoning the protein, the soluble protein that would otherwise be functional, into these inclusions and then you don't have enough protein, so the proteinopenia hypothesis.
Where do you stand on this? Should we keep the two options on the table? Is one really dominating?
[00:07:17] Prof. Jeffrey Kordower:
So, I'm an aggregate guy, in terms of causing the pathology. And I'll tell you why I'm not a monomer protein guy. That is, Parkinson's disease is an age related neurodegenerative disorder. And if you look at normal aging, the monomer accumulates in the cell body. Normally, someone who's under 40 years of age, and you stain for alpha synuclein, you can't see it, because it's fast tracked down the axon.
Remember the monomer is a synaptic protein involved with vesicle trafficking and other processes. So when it accumulates in the cell body, you know what it does? It down regulates dopamine. I've seen this in human brain. I've seen this in primate brain. So the last thing we want to do is to down regulate dopamine in patients with Parkinson's disease. So I think we need to clear the aggregate and let The normal levels of the monomer equilibrate in the cell body, get it down the axon.
Now one of the things I think we have to work on that's rarely talked about, is I think one of the earliest defects in the nigrostriatal system is defects in axonal transport.
Again, synuclein goes down the axon to work at the synapse. And that's what we have to preserve because the nigrosteroidal degeneration is an axonopathy. The degeneration happens first at the terminal and not at the cell bodies. Everyone is cell body centric. And so, I think if you fix the aggregate, you'll get a more normal neuron. It'll shuttle it down the axon. And then we'll have more excellent dopamine neurotransmission.
[00:08:58] Prof. Tiago Outeiro:
mm-Hmm, Yeah. So, I mean, this, this really speaks to the need for understanding the biology or pathobiology of alpha synuclein and all these proteins. And MDS is trying to contribute to that by having people like you and me that are basic scientists participate and contribute. do you think that it's enough, what's being done?
Do you think we need to bring more basic scientists to promote more interactions that could enable the field to move forward faster?
[00:09:28] Prof. Jeffrey Kordower:
I think we do. So nine percent of the registrants at this meeting and nine percent of the people who are members of the MDS are researchers. And we need to make that higher. It used to be higher and it shrank because a lot of the people who are here are clinicians who are interested in clinical science, and that's fine.
And if there's too much basic science here, then they're less happy about how the program is. I can tell you I actually work the other way. So I'm a basic science, and I spend most of my time in clinical sessions, because you can't be a great researcher in Parkinson's disease unless you understand the clinical Parkinson's disease.
That's why I come to this meeting, and that's why I've been honored to be in leadership here with the International Executive Committee, and now I'm on the Scientific Issues Committee. So I think we need a bit of a balance, but I still think we need more basic science going forward.
[00:10:28] Prof. Tiago Outeiro:
Yeah, I know, I fully agree. That's also my motivation. I've learned a lot, and I continue to learn every time I participate in the congresses. And for me, that's really important because I also understand that it's not enough to just stay in the lab working with our mice and monkeys and flies.
We need to know really what the clinics is about.
[00:10:50] Prof. Jeffrey Kordower:
It's amazing how many really elite scientists think they know about Parkinson's disease when they really know about the laboratory work in Parkinson's disease. You know, When the cell to cell propagation phenomenon came about, I used to give a talk entitled, "Cell to Cell Propagation, Real Biology or a Parlor trick?"
Because sometimes you can create something in the lab, but it really doesn't apply to the human disease, and that's critical. That things that we do are really applicable for the human patients with Parkinson's disease.
[00:11:27] Prof. Tiago Outeiro:
Yeah. We need to use examples like the one you just told us about your work, about the clear application of a molecular mechanism, the clearance of the aggregates promoted by irisin, so that they see that there are things that are low hanging fruits that maybe can be transformed into therapies, hopefully in the not so distant future, and that they should understand how these things work. So maybe we can try to contribute to this education as well.
[00:11:55] Prof. Jeffrey Kordower:
I can tell you after my talk yesterday to this part of the day today, I've gotten a number of emails from clinicians asking me, when can we go into clinical trials?
And so this is exactly what you're talking about.
[00:12:08] Prof. Tiago Outeiro:
Jeff, anything else you've seen at the Congress so far that you want to highlight? I know we are only halfway through, so there's still a lot to see, but anything caught your attention?
[00:12:17] Prof. Jeffrey Kordower:
I really enjoyed the session this morning on environmental factors in Parkinson's disease.
Richard Smeyne is a great friend of mine and he has a hypothesis that viruses that you're exposed to early in your life is a one hit of a two hit process. I thought that was quite enjoyable. Little, little scary that one person presented that if you have Lots of Like, if you have smoking, not smoking, environmental issues that you have a great, I think it was a greater chance of getting a neurodegenerative disease. And that was surprising to me, because smoking is usually regarded as a protective factor in neurodegenerative diseases. And there were a number of other people talking about climate change and pollution, and I thought that was quite interesting. So, that was my favorite thing so far.
[00:13:08] Prof. Tiago Outeiro:
Yeah, I, I agree.
That was very thought provoking and there's a lot to learn there as well.
Jeff, it has been a pleasure. Thank you so much for joining on the podcast. So we've just interviewed Professor Jeff Kordower and discussed his participation at the MDS Congress 2024. Thank you all for listening, and join us in our upcoming podcasts.