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MUS IN

When Dr. Serge Przedborski was a resident he joined a lab that specialized in mapping normal neuropeptide distributions in the brain. And while he was working on this mapping he discovered something.

Dr. Serge Przedborski:  I stumbled on structure of the brain that's called basal ganglia, which are deep structures inside the brain, and which happened to be very important for Parkinson. And believe it or not, I fell in love with the appearance of these structures.  Of course there are beautiful landscape all over the world, but to me that was the most beautiful things that I have seen.

He was so moved by the basal ganglia that he told his advisor who suggested that he combine his research with clinical practice for Parkinson’s Disease. So he began looking for an institution where he could pursue both…

Dr. Serge Przedborski:  And I applied to  our wonderful former director, [01:00] Dr. Stanley Fahn, who was very generous to accept me in training. And I came at Columbia to train under him in movement disorders and particularly in Parkinson while I was able to continue my work in the lab. And honestly, these combinations of investigation in the lab and seeing patients… to me it's the most beautiful job in the world.

It has been thirty two years since Dr. Przedborski came to NewYork-Presbyterian and Columbia. Throughout that time he’s continued to study the brains of people with Parkinson’s Disease with a specific focus on the role of neurons and how they influence its progression. He and his team have identified a pattern of neuronal death by researching what causes some neurons to die while others survive. Their work has created a map of what Parkinson's related neuron death looks like in the brain. This map will be a crucial step in creating [02:00] novel treatments for Parkinson's disease.

BEAT

I'm Erin Welsh and this is Advances in Care, a podcast about groundbreaking developments in modern medicine.

In this episode, I speak with Dr. Przedborski, Chief of the Division of Movement Disorders at NewYork-Presbyterian and Columbia, about what is happening in the brains of people with Parkinson's disease, how a biomarker could improve prediction and prevention for patients and new cutting edge gene-therapy treatments that could drastically alter symptoms.

MUS OUT

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Erin: Dr. Przedborski, thank you so much for joining me today.

Dr. Serge Przedborski: It's a pleasure.

Erin:  I am really excited to chat with you today about the incredible work that you are doing on Parkinson's disease. But before we get into some of the how and the why, you know, how does this disease progress at a cellular level or why some people get it and others don't, [03:00] I want to get into the what. So could you explain what is happening in the brains and bodies of people diagnosed with Parkinson’s disease?

Dr. Serge Przedborski: So first and foremost, Parkinson's disease is a clinical diagnosis. We see patients essentially will present with between three and four motor cardinal features that are shaking, or what we call tremor, slowness of movements, which we call akinesia or bradykinesia rigidity, and postural instability, which is to have a poor balance. So that's clinically.

Erin: Okay.

Dr. Serge Przedborski: What it means in terms of the chemistry of the brain, which give rise to those manifestations, is the fact that in Parkinson's disease, there is a loss of specific subset of brain cells that produce a chemical called [04:00] dopamine. You need to lose more than half of the brain cells that produce dopamine before you're becoming what we call symptomatic.

Erin: Symptomatic meaning those motor symptoms specifically.

Dr. Serge Przedborski: Correct.

Erin: Okay. So how is treatment for Parkinson's disease typically approached?

Dr. Serge Przedborski: If you have a deficit in dopamine, it's very tantalizing to say that every patient then needs to be started on therapy that will be replacing or replenishing dopamine in the brain. The reality of the fact is that so far we do not have compelling evidence that any of the treatment we have are what we call disease modifying. It will control your symptoms but not the disease itself.

Erin: And so, you study how Parkinson's disease affects neurons in the brain – can you walk me through what exactly you’re [05:00] looking at in the brain when you’re doing this research?

Dr. Serge Przedborski: The alterations of some kind of mechanism in the brain cells are responsible for their demise, but not necessarily in isolations. Because although the brain cells are what we rely on to be able to execute neuronal functions such as movements, et cetera. Those cells are surrounded by non neuronal cells called glial cells.

So the questions that many labs, including mine, have asked is, these other cells, are they sitting there and doing nothing and watch basically the neurons dying? Well, it's possible, but certainly I don't believe so. I think that those cells  whether it's microglia or astrocytes or oligodendrocytes, which are a few names of these glial cells, are likely to participate in the overall process. [06:00] And so the potential role of what we call neuroinflammations, it's becoming more and more important.

Erin: That's really fascinating. The glial cells would normally help mediate neuroinflammation but in this instance they’re not doing that, and so it's kind of like an autoimmune reaction.

Dr. Serge Przedborski: You're absolutely right. So now those glial cells are not responding exactly as they should respond normally in response to an infection.  They misread what's going on and they produce toxic or non toxic molecules that basically are in complete exaggerations to the reality of the system. And so this kind of communications may eventually lead to dysfunctions and neurodegenerations.

Erin: Okay, so it's essentially like there's some disruption to the ecosystem of all these cells in the brain. And then once that happens, then that sets off this cascade of [07:00] the point of no return?

Dr. Serge Przedborski: Correct. I think that then you have kind of a self sustained or domino effect on the system.

Erin: So what makes these neurons different or special?

Dr. Serge Przedborski: And so that is a main aspect of the research in my lab is to try to understand what is the molecular basis of this differential susceptibility. Because when you look under the microscope, the neurons that are affected and those that are not affected basically look exactly the same.

So at the molecular level, they should be kind of a characteristics that makes them more likely to withstand the injury than others, because I don't believe that those neurons are completely resistant. I think that they're more able to withstand the injury because, for example, if you take in the case of hereditary form [08:00] of PD, all the cells in the brain will express the bad protein that caused the disease.

To me, that means in those that do not die, there is something that allow to mitigate whatever bad effect this mutate protein can exert.

Erin: Right. Is it increased resistance in other neurons, or is it increased susceptibility? And so I understand that you have used the New York Brain Bank at Columbia to validate some of your hypotheses. But first, what is the New York Brain Bank?

Dr. Serge Przedborski: It's an effort that at Columbia has been in place for many years, the New York Brain Bank, it's a group of neuropathologists that basically develop a protocol to collect in a standardized manner, a postmortem sample, that basically process those sample in

a very strict and rigorous manner. So that if I'm [09:00] asking to be able to study the brain of eight different patients because I need sample size, I will be able, thanks to them, to have sample from these eight different patients that are absolutely from the same area, the same structure, taken the same way with all the quality control aspect that I need to trust my results.

Erin: Yeah it sounds like the New York Brain Bank gives you really high-quality data. And so how did you use this brain bank to test some of your hypotheses in your study about the role of microglia in Parkinson's?

Dr. Serge Przedborski: So we have developed this interest in the behavior of microglia in Parkinson's. And basically our goal has been to use those post-mortem sample to assess what those microglia are doing through sophisticated [10:00] analysis of basically their genes. And then we process the sample to analyze at the cellular level what those different microglia are doing and see if there is some kind of signature that follow the differential susceptibility. So that's the goal of the study.

Erin: Using these samples to create sort of a landscape of what should be happening to then overlay what seems to be happening in different levels of Parkinson's advanced stages. Okay.

Dr. Serge Przedborski: Correct. And then the idea, of course, is that when we have this kind of signature or landscape, as you said, then we can develop mechanistic hypothesis and said, okay, it seems that these factors is changing this way. And from there work with collaborators at Columbia to think about devising small molecules or medications that could [11:00] maybe do the same thing.

Erin: Aha. Right. And so that is kind of where I want to go next, the importance of what a biomarker could give us in terms of early diagnosis and measuring treatment efficacy. And so where are we with a biomarker for Parkinson's?

Dr. Serge Przedborski: Yes. So I think that we are at a good place, not a perfect place, but a good place. I think that most of the progress we have made I would say the past five years or so, it's really at the level of the diagnosis because, before the only way that you could diagnose Parkinson's was clinically, to do some additional investigations like functional imaging, et cetera, but the specificity of that for Parkinson's disease is not perfect. And so still, we had a number, non negligible, not enormous, but non negligible, of false diagnosis, right?

And that was difficult. [12:00] So now, we can do some tests that will tilt the balance in favor of a diagnosis of Parkinson's versus not. the new technique consists to look at the behavior of a small protein called alpha synuclein either at the level of the skin or in the liquid that is around the nervous system that called the cerebral spinal fluid, or CSF. I can tell you that I have used some of these tests in some of my patients. And in some, it was kind of a revolution but it in some was much more ambiguous. So at the individual level, we still have work to do, but in terms of progress, this is representing already a completely different landscape.

Erin: Yeah, and so having those biomarkers that are more accurate to predict progression of Parkinson's sounds like it could be really helpful in early diagnosis and give doctors the

opportunity [13:00] to intervene early. I mean, that’s really promising. I’d like to switch gears here, though, and touch briefly on gene therapy, which is another space where there seems to have been some significant innovations in Parkinson's treatment. Can you explain how your research on neurons in Parkinson’s patients could lead to gene therapies as a more effective treatment option in the future?

Dr. Serge Przedborski: So, If we gain in the future a better understanding of the mechanism, you can try to target some of this molecular mechanism by gene rather than by medications. So that's a possibility. But for the moment, I think that where I see the most promise for gene therapy, it's for neuromodulation, in the sense that if we have Parkinson's symptoms it's because what we call the chemical neuroanatomy of the brain, it's altered in response to the deficit in dopamine.

Thanks to the work [14:00] of many wonderful investigators in the field of basal ganglia we know now that there is a kind of well defined circuitry in the brain that if we modulate it, we can improve the symptoms and that in absence of any replenishment of dopamine. It's almost like you act downstream to that.

And so where I see the gene therapy, and we have already had the pleasure of participating in a multi center clinical trial for gene therapy along this line in collaborations with your colleagues at Cornell, basically what we can do, it's to use a gene therapy to kind of emulate what deep brain stimulation is doing.

So, in other words, we use gene therapy to normalize the alteration in the circuit. And so there is where [15:00] I see a great promise for gene therapy to have a durable and controllable modulations of the basal ganglia circuit.

Erin: It’s amazing that with continued research, this gene therapy could lead to improvements in symptomatic treatments. And so you mentioned the collaborative partnership between Columbia and Weill Cornell Medicine and I'd love to learn a bit more about what makes NewYork-Presbyterian uniquely suited to study Parkinson's and other movement disorders?

Dr. Serge Przedborski: There is many factors. The first one is that the hospital and the university are located in a city that is very busy. One. We are serving a community where we are the main medical center and hospital in the area. So the sheer number of individual [16:00] seeking medical opinion and support from CUMC slash NYP is gigantic. So that's very important because to become leaders, you have to have access to enough patient.

Second point is the fact that we had a generation after the generations outstanding chair and leader who basically strive to stimulate excellence in our department. And often with thoughts and visions out of the box. Everything, whether it's skill, the way to diagnose, the way to treat has, I would not say solely, but in great deal started at Columbia. You know, the first test at least in the U.S. with Lipidopa for Parkinson's patients, the way we diagnose dystonia, the genetic of dystonia.

You can name it. I think the reason is in [17:00] part the excellence in the center and talented individual like Dr. Fhan, it really create a reputation that became a magnet. The term movement disorders was invented at Columbia, which of course now it's used all over the world. And since then all over the world the divisions or the activities that deals with this type of conditions, it's called movement disorders.

Erin: Yeah. And to have that visionary mentor and then to be able to pass that knowledge down. I mean, that definitely seems like at the heart of what has led to so many of these milestones happening at NYP and Columbia. Well, this was an absolutely fascinating conversation. Thank you so much, Dr. Przedborski, for taking the time to chat with me.

Dr. Serge Przedborski: No, no, it's my pleasure. And as you probably realize, it's my passion. So anytime. [18:00]

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Huge thanks to Dr. Serge Przedborski for taking the time to speak with me about his important research on the patterns of neuronal death associated with Parkinson's Disease.

I’m Erin Welsh.

Advances in Care is a production of NewYork-Presbyterian Hospital. As a reminder, the views shared on this podcast solely reflect the expertise and experience of our guests. To listen to more episodes of Advances in Care, be sure to follow and subscribe on Apple Podcasts, Spotify, or wherever you get your podcasts. And to learn more about the latest medical innovations from the pioneering physicians at New York Presbyterian, go to nyp.org/advances.

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Przedborski Trailergram

Transcript

When Dr. Serge Przedborski was figuring out what medical work he’d like to pursue, he joined a lab that specialized in mapping normal neuropeptide distributions in the brain.

Dr. Serge Przedborski:  I stumbled on structure of the brain that's called basal ganglia, which happened to be very important for Parkinson. And believe it or not, I fell in love with the appearance of these structures.

It has been thirty two years since Dr. Przedborski came to NewYork-Presbyterian and Columbia. He and his team have identified a pattern of neuronal death in Parkinson’s by researching what causes some neurons to die while others survive. This map will be a crucial step in creating novel treatments for the disease.

Dr. Serge Przedborski: When we have this kind of signature or landscape, then we can develop mechanistic hypothesis and from there work with collaborators to think about devising medications that could maybe do the same thing.

I'm Erin Welsh, host of Advances in Care. Follow the show to listen to my conversation with Dr. Przedborski and other physicians making groundbreaking developments in modern medicine.