Parkinson’s disease is linked to clumps of misshapen proteins that damage brain cells and lead to the disease’s hallmark symptoms.
Dr. Michael Henderson, an assistant professor in Van Andel Institute’s Department of Neurodegenerative Science, gave an in-depth primer on Parkinson’s and these proteins as part of the Van Andel Institute Public Lecture Series. He explored how scientists are working to better understand the role proteins play in the disease in order to develop new treatments.
Watch the lecture below:
Video transcript
Note: The following transcript has been edited for readability. Click a timestamp to jump to that part of the video.
Maranda [0:02]:
Hello, good afternoon. Thank you so much for joining us. I like the vocal interaction. So hello! We are so glad you are here today. We have an exciting conversation and we are thrilled that you’ll be a part of it. I’m Maranda from WOOD-TV8, and I’d like to welcome you to the Van Andel Institute to our Public Lecture Series. You are in for a treat today. We will be talking about Parkinson’s — specifically the proteins that play an important role in this disease. But what are proteins and why do they matter? Well, that’s what we’re gonna find out today. We have Dr. Michael Henderson with us, and he’s gonna walk us through things. I want to tell you a little bit about him and then we’ll turn it right over. Dr. Henderson is an assistant professor here at VAI. He and his lab investigate the causes of neurodegenerative diseases like Parkinson’s, and the factors that control disease progression. He’ll give us an in-depth primer on Parkinson’s and proteins, and shine a spotlight on how this knowledge may inform strategies on how to slow or stop the disease. Please join me in welcoming Dr. Henderson.
Michael Henderson [1:22]:
Thank you for that introduction. And also thank you all for taking the time out of your day to come down to the Institute and hear what we’re doing in Parkinson’s disease research. That was a nice introduction of me, but now I want to tell you, I’m gonna say in this talk several times, “we” study or “we” found this. This is who “we” is. This is my team at the Institute. We study how neurodegenerative diseases begin and spread through the brain with the goal of developing and evaluating potential therapeutics for disease. So why do we study neurodegenerative disease? Well, Alzheimer’s disease affects more than 6 million Americans. The lifetime risk is higher for women than it is for men — 1 in 5. And I just modified this slide recently. It used to be that there are no disease modifying treatment. Now through recent clinical trials, we can say a few.
So recently clinical trials have found a couple different potential therapeutics that seem to slow the progression of disease. Parkinson’s disease, on the other hand, affects 1 million Americans. It’s, lifetime risk for Parkinson’s is actually higher for men than it is for women. And for this, unfortunately I have not been able to modify. There are currently no disease-modifying treatments. We have symptomatic therapies. We have nothing that can slow the progression of disease. And importantly, these are not faceless diseases. We all know someone affected by them. For me, it was my grandfather and aunt who were recent, who were affected by these diseases and recently passed. So what are neurodegenerative diseases? But before we get into that, first I want to talk about what the function of the brain is. This is the organ that’s affected by these diseases.
The brain is a wonderful network made up of billions of neurons. These are the individual cells that do the work. Each brain region has a different function. So this is different than your liver or kidney, where different regions may be able to be excised and you retain the function. In the brain, you have each — individual functions assigned to individual regions, and that’s what makes the brain distinct. And further is the communication of different regions of these brains, different neurons within the different regions, that is critical for even the most basic thought or movement. And that occurs through connections between regions. So I want to go into this and describe what I mean by the most basic thought or movement. You’re all sitting here right now watching this talk. While you’re doing that, you’ve got your central nervous system. You got a friend up there called upper motor neuron sitting in your motor cortex.
That motor neuron sends this process called an axon all the way down into your spinal cord where it contacts a lower motor neuron — creatively named. That sends an axon all the way out through your arm where it contacts a muscle, where it causes it to contract. All that is essential for you to give that thumbs up, say, “I’m loving this talk.” And, and so this is what we call a motor circuit. Of course, this is a very basic design. Much more is involved than that. How did that neuron decide to make that movement? You have a planning part. This is your premotor cortex. It has to tell that neuron, “We need to contract that muscle.” How did you decide that you needed to do that in the first place? This is called the executive function part of your brain. You have to make that decision that you’re actually enjoying this talk and you want to give a thumbs up.
Of course, in order to make that decision, you had to have some input from the external environment. You had to see the talk. This occurs in your eye. A specialized neuron called a rod or a cone can sense light and then transduce that information through a couple other neurons, including the retinal ganglion cell back into the middle of your brain region called the thalamus. This is a relay station of the brain that relays the information to the very back of your brain, to primary visual cortex. Primary visual cortex can see things like light, dark colors, potentially shapes, but that’s about the extent that it can do.
So you want more complex information, you gotta go to the dorsal and ventral stream where you can see things like motion, places, landscapes. And then you can go back to the front of your brain, decide that you like this and make that decision to put the thumb up. So this is what I mean when I say you really need that whole brain functioning properly for even the most basic thought movement. And that all occurs through these connections.
So now we’ve taken away the outside of the brain. Now we’re only looking at the connections of the brain, different regions to the other. If this looks like a really complex highway map, that’s because it is. The brain is really well-integrated, all the different regions with each other, and this is how the brain can communicate and we can decide we like something, decide perhaps now that this is getting a bit complicated and we got a thumbs down, but that’s all right. We’re gonna turn this around. Hopefully we’ll simplify this and, give you a good idea of how the brain functions and how it’s affected in neurodegeneration. So, neurodegenerative diseases: you can probably tell by the name, but they affect the central nervous system of the body. That’s the brain and the spinal cord and all of the nerves.
If it affects something that controls movement, that leads to motor dysfunction, it affects your thinking, leads to cognitive dysfunction. The two most common of these diseases, as we just discussed, are Alzheimer’s and Parkinson’s disease. Alzheimer’s is a form of dementia that interferes with memory, thinking, and behavior. Parkinson’s, on the other hand, leads to movement problems such as tremors, difficulty balancing, and difficulty walking. Parkinson’s is interesting and also there are many other symptoms that don’t directly relate to movement, such as gastrointestinal function, loss of sense of smell, and eventually in some patients it can lead to dementia. So what causes these diseases, in particular Parkinson’s? Let’s take a look inside the brain and find out. Here’s our old buddy, the upper motor neuron. And so we’re gonna take a slice through the brain to, to get a glimpse inside. If you now take those slices, you can see there are regions that we call gray matter and white matter.
So gray matter is where all those neurons are hanging out. They do the, do the work of the brain, but all that white matter, which is extensive, those are all the connections. So those are that roadmap that I had shown you earlier. So I showed you that motor circuit that’s needed to give that thumbs up, but what is actually required to make that movement smooth, to make it, to be able to initiate that movement smoothly and carry that movement out, are regions inside the brain called the basal ganglia. And that’s what we’re showing in different colors in the middle. And what controls the basal ganglia? The substantia nigra. You may have heard of this. This is the region that’s affected in Parkinson’s disease. It’s Latin for “black substance.” That’s because if you actually look in the brain, it’s black. And what happens in Parkinson’s disease is that black color is gone.
You’ve lost those neurons. Those neurons carry dopamine. And what happens is you have the loss of dopamine, which is an important neurotransmitter that helps control the smoothness and initiation of movement. We can actually treat some of the symptoms of Parkinson’s disease, at least those movement-related symptoms, through the replacement of dopamine with a chemical called levodopa. And that works well in many people. But another hallmark of this disease is called the Lewy body. The Lewy body I’ve kind of illustrated there, hangs out inside the neuron. We think it leads to neuronal dysfunction. But you can see in this image that Lewy bodies are not only found in the substantia nigra, we can find them in many other regions of the brain. And we think that their location there is associated with some of the other symptoms that are not well-treated by dopamine replacement.
So what are those Lewy bodies made of? This talk is called “When Good Proteins Go Bad,” this is a good protein. It’s called alpha-synuclein. This is its happy form. It’s nice, it forms these nice alpha helices, sits on membranes, but for reasons we don’t quite understand, it has also a misfolded form. And this misfolded form, in addition to having a completely different structure, has a unique property that can recruit more monomer, creating eventually these elongated fibrils. And that’s — these elongated fibrils are what we find inside Lewy bodies.
So I’d like to explain this by analogizing. Proteins are like paper. Paper is, uh, very useful and we can write on it, we can print on it, we can paint on it. And so for that reason we keep reams of paper around our houses and our offices. This is what our brain does. Alpha-synuclein is a useful protein. We keep a lot of it around. But paper can also go through a misfolding process. We know that this is no longer a useful piece of paper. And so we throw it in the trash bin. The brain does the same thing about these proteins and it discards them. What happens, though, as we age, the trash man comes less often — [audience laughter] — and we get these accumulations of misfolded protein, in this case misfolded paper, in the brain, and this causes problems for those neurons.
Speaker 3 (10:50):
You have probably heard of these in Alzheimer’s, we accumulate tau tangles and amyloid beta plaques. In Parkinson’s disease, we accumulate alpha-synuclein and Lewy bodies. So on the top right, this is just a stain in the human brain of what Lewy bodies actually look like. This is an image taken in my lab where we stain the Parkinson’s disease brain for neurons, in green, and then in magenta we see these Lewy bodies. If we zoom into a part of the brain that we’re looking at, you can see many of the neurons don’t have Lewy bodies and they’re going on living a happy, healthy life. But then there’s these three gigantic Lewy bodies. This is the trash bin that did not get emptied for those neurons. And those neurons are not having a good time. And if I take away the image of the neuron, you can see that it’s not just those Lewy bodies actually there’s these thread-like structures throughout the brain.
Those are in the connections. So all that connection of regions, and connection of neuron to neuron, is disrupted by the fact that they have these inclusions in those connections. We also know that where in the brain matters. If you have pathology in a region that controls memory, you have memory dysfunction. If you have pathology in a region that controls movement, you have motor dysfunction. We also know that these pathologies can progress with disease to different regions of the brain. And we think that’s associated with the progression of disease exhibiting different symptoms over the progression of disease.
So how does this process begin? Well, we know that we’re all born with a certain risk of developing disease in our DNA. That’s called genetic risk. But we also have different exposures and different life experiences, and those can also predispose us to developing disease. So that’s some background on neurodegenerative disease. What are researchers doing to try to understand and encounter these diseases? This is, our department currently, led by Dr. Darren Moore. And I just wanted to highlight some of the work being done in our department and then I’ll zoom out to how this is related to, research around the world. So in our department, we focus on a variety of different topics and I’ll go through each of these individually. The first is genetics. Well, we know, I told you, some of the risk of developing disease is in our DNA. About 10% of this we call genetic risk, but there’s also a larger percentage, too, that’s hereditary.
So that means that we can’t nail down a gene that is causative, but we know that it runs in the family. And so, up to 25% of Parkinson’s is considered hereditary. What we try to understand is which rare variants — that would be, you know, they have this genetic mutation and it leads to disease or which, much more common, so we have many, many different single mutations in our genome but that don’t lead to disease, but they can predispose to it. We try to understand what those are, try to identify them by looking at genetic sequencing. And then the main question of course is how? How these lead to disease and can we take these — what’s called monogenic, so they’re caused by a single gene — forms and try understanding something about all of Parkinson’s, about the pathways that may be disrupted by those genes. We also look at environmental toxins. So we know especially this is prevalent for Parkinson’s, that there clearly seem to be some environmental exposures that are linked to developing Parkinson’s disease. Bacteria, viruses, chemicals, have been linked epidemiologically to increased risk of Parkinson’s. How do these changes predispose the brain to developing Parkinson’s?
We also look at epigenetics. That’s a little— long word, just means, basically, which genes are expressed in which cells: what make— makes the heart the heart cell and what makes a brain cell a brain cell are which genes it actually expressed. Every cell in your body has the exact same genes. It just gets to decide which ones to express and make a heart a heart, or a brain a brain. And so we can study, then, the modifications to that DNA and try to understand what genes are being expressed, and what tissues, and how that relates to development of Parkinson’s disease.
The cell are the basic unit of the body, or of life. And it’s very useful in our labs because we can culture these in a dish. And what that allows us to do is then, for example, if we can understand something fundamentally that has gone wrong at a single-cell level, then we can try to understand how that applies to the whole organism. It also allows us the ability to screen thousands of molecules. So if we find a phenotype that we think is related to development of Parkinson’s disease, we can screen against that phenotype for things that would modify it, make it better. And so this is really a critical tool because there’s no way we can test all these things in humans, not even in preclinical models. So cells give us that opportunity. But as I told you, the brain is not a single cell. The brain really requires this communication of region to region.
And so, often, we look at communication between cells. We can look at neurons and how they communicate with each other. We can still do some of this in a dish, but eventually we also have to look in the human brain. Or we prefer to look first in another animal model such as mice. So mice have complex brains, very similar in many ways to ours. Obviously much smaller, but they have a lot of the same brain regions. And, and so we can understand circuits and things like environmental risk and genetic risk and how they interact in a simpler model before we try these things in humans. Importantly for therapeutics, let’s say we screened a thousand molecules. We found these, this top one. This is really modifying our cellular phenotype. We need to take it to a more complex system before we try to think that’s actually a useful molecule to treat therapeutically.
And finally our clinical trials. I’ll talk a little bit at the later, um part of the talk about where we are currently with clinical trials. Van Andel Institute does not do clinical trials — this is a basic research institute — but we help facilitate them. And that’s through the Linked Clinical Trials initiative. That is that we partner with Cure Parkinson’s and we help fund clinical trials for, often therapeutics that may not have gone to the clinic otherwise. And the reason for that is, that the goal is accelerating clinical trials. Clinical trials take a long time and that’s because we have to prove that the therapy is safe to use at all before it can go to disease modification trials. What this International Linked Clinical Trials does is basically skip that first step. It takes molecules [sic] that are already proven safe, that are FDA-approved or approved by another organization, and then — but they have a good biological reason they could be useful for Parkinson’s. So we take those now, apply ’em and they can advance quickly through the stages of clinical trials for that reason. And I have a couple examples. I’ll share them.
So these — this kind of — what the Institute does in general. What does my lab research? Well, we research a number of different things, but I’ll highlight a few here. One is this beautiful structure that are the highways of the brain. It’s really important for communication. But we found that actually these pathologies seem to be able to hijack this pathway to go to different regions of the brain. And we think that this is related to progression of disease. So regions that are interconnected have a lot of connections with each other, more likely to develop pathology than regions that are not. But importantly we also found that there are certain regions that are really highly interconnected, but they don’t develop pathology. And now we can understand what made that region resilient to developing pathology.
We also look at some of those genetic risk factors. So these are in your DNA. Two of the most common versions that lead to Parkinson’s are called L R R K 2, or “lark 2,” and GBA1. What we found by investigating them is that having one of these mutations seems to reduce the ability of cells to dispose of those pathological aggregates. We have also found by modeling through the whole brain that they can change the speed of progression of disease, change the speed of progression of those pathologic aggregates from one region to another. We also look into that trash bin. So that trash bin is full of those misfold proteins. But there’s also stuff, other stuff in there. We think that these are mistakenly discarded proteins that could have a functional role on disposing the aggregates and therefore could be potential therapeutic targets. We also recently looked into those neurons with Lewy bodies.
This is something that was not done before, what’s actually happening in neurons when they develop an aggregate. And we found that what happens is that those are not happy cells. I mentioned that earlier, but more specifically, there’s disruption of the cellular communication. Those neurons are no longer able to communicate with their partners efficiently, and there’s also deficiency in energy management. So they’re really having a lot of difficulty. Okay, so importantly, we do all this work because once we know what’s going wrong, we can develop targeted therapies to address those. We aim to reinforce cellular pathways, and we have ongoing work on this. We also have targeted some of those genetic risk factors to see if we can modify those and move them back towards a healthy state. We aim to slow or stop the progression of pathology throughout the brain.
So what else is going on here at VAI? Well, I wanted to highlight this. I think, if you came to one of the recent Public Lecture Series, you probably heard about this as well. We developed what we call the West Michigan Neurodegenerative Disease Program, or MiND Program. The mission is to provide critical resources to accelerate our research, to make sure we have all the potential resources we can have to really understand Parkinson’s disease. The main initiatives are a brain bank, a biofluid repository, and the patient cell platform where we can take those cells, put them in culture like I had mentioned. So you can put them in a dish and understand something fundamental about those cells.
And so, since you may have already heard about this recently, I’m just gonna highlight the brain bank because one of my roles here at the Institute is that I direct the brain bank. It’s a first of its kind neurodegenerative disease brain bank in West Michigan. And we help, it helps us really uncover what’s happening in human disease. I told you about we can put cells in culture, we can work on mouse models, but we really wanna understand human disease. We need to go to the human tissue. So what do we actually do with the human brain?
Well one of the interesting things we can do with recent technologies is that you have this brain that’s got gray matter and white matter, and you can look inside of it. But actually, it’s opaque. So what if we cleared the brain? So this is now the same slice and what’s behind it is just a grid of paper. So you can tell that you can see through the brain, but we’ve now cleared this brain so you can see everything in that whole slice of tissue without the interference of opacity. And what allows us to do is then label things like tau. So this is tau, it’s one of the misfolded proteins in disease. You can see that when this person died, they had really profound tau pathology. Not only in the temporal lobe, which is at the bottom, but also up in the frontal lobe. And this is some of the regions controlling that executive function. And so we think that’s why Alzheimer’s disease, for example, progresses. We have problems with executive function, we can now look at this at the whole brain level.
We can also capture those cellular fingerprints. I had mentioned that we understand now what’s happening in neuron with Lewy pathology, ’cause we used a new technology to capture those neurons. We’ve now done this in the substantia nigra. This is this black substance. Actually if you look at it under fluorescence, it’s no longer black anymore. But we label it, here in cyan for those dopaminergic neurons. This isn’t a healthy brain. But we also now look in the Parkinson’s disease brain, where there are very few of those neurons left. The other color magenta here, that’s the pathology. So the remaining neurons, the ones that are left, they mostly have this pathology. But what we had done is we then captured the cellular signature so we can try to understand what’s different in a dopaminergic neuron in a healthy brain, and now what’s happening in Parkinson’s, and can we figure out ways to reverse that.
So that’s where I’ll end about talking about the Institute. But I get a lot of questions about where are we currently in the broader context of Parkinson’s disease? How close are we to treatments that will slow or stop progression of disease? Well, this is all done at the clinical trial level. Once we get something that we really find from preclinical studies, like one I’ll mention, that’s really promising, we can then take it to clinical trials. This comes in three phases. The first phase is a safety phase. We are gonna put this in humans for the first time, and we better be sure that this is a safe thing to do. And so we test it at multiple doses and figure out if there’s any toxicity or any other side effects of these treatments. So it’s in very few people, ’cause if something went wrong, you wouldn’t want it in a large population.
Phase 2 is still further safety testing. But often, now we move to larger populations, ’cause phase one went well. And we also move, often, to the target population. So we’ll move to including some Parkinson’s disease patients, for example, to make sure that even if it was safe in, in young healthy people, perhaps maybe in an older population, we may need to make sure that’s safe as well. But it also gives us a first glance of efficacy. So you may hear some results from Phase 2 trial saying something looks really promising for Parkinson’s disease. That’s great. It’s a really great way to find that preliminary evidence that this could be useful for Parkinson’s disease.
But the one we really look to is the Phase 3. This is really large. Studies usually done across multiple countries, many different sites, hundreds of patients. And it is double-blinded, which means the person giving you does not know what they’re giving you and you don’t know what you’re getting, and you get evaluated, based typically right now on reported symptoms.
And this is compared to placebo, which means you got something that has no potential therapy. You get to see whether you can, in an unbiased way, see if that therapeutic has an effect. So where are we with Parkinson’s disease? This is a really complicated figure. It’s published every year about where we are with therapeutic trials. I’m just gonna walk you through. There’s three concentric circles. The outside one is Phase 1, inside middle one is Phase 2 and the inside is Phase 3. So things have to move in that sequence. They have to go phase 1, 2, 3. And this is the most that has ever been on this, this clinical trial database. But you can see there’s two sides. To the bottom side, “ST,” that’s symptomatic therapies. These are things we’re trying to figure out better ways, your neurologists are figuring out better ways to treat the symptoms that you have, better ways to make sure you have more on less off periods. “DMT” Is disease-modifying therapies. These are things that we actually think can modify disease, and by that we mean somehow slow or stop the progression of disease. You also see there are many different colors in the upper right. These relate to different categories of therapy. You’ll see up there for example what’s the color? Yellow? Yellow. You’ll see LRRK2. That was one of the genes I had mentioned. So, so one of the ways we are like pretty confident that we’re targeting right pathway for targeting the gene that is actually, has a variant that causes disease in human patients. So often we target things based on, first, on the genetic information.
So LRRK2 kinase inhibitors are some of the most advanced therapies right now. GBA is also up there. That’s another gene. But you’ll see there’s other things up there as well. Anti-Inflammatories. GLP-1 R agonists. This is a diabetic therapy and this is the one of the ones, actually some of these were funded through the International Linked Clinical Trials. You can see them highlighted in green here. So some of these, now you can see none in the Phase 1 because many of these get to skip that Phase 1, they’re already known to be safe in human population. And so we skip it. We go to Phase 2, Phase 3. That allows us an accelerated opportunity to see how these affect patients.
So some other news in Parkinson’s disease, maybe you heard about this. These are those misfolded proteins I talked about. They can go through this misfolding process into elongated proteins. This happens, we think, in the brain. We know what happens in the test tube, that you can take a bit of misfolded protein, you add some more a non-misfolded protein and we’ll misfold that. So what we did after we gained that biological insight — in this case I’m talking about the field as a whole, not my personal lab — is we took advantage of that. You can look at biofluids from Parkinson’s disease, from the cerebral spinal fluid, and you can barely see alpha-synuclein. It’s barely there. And so it’s not sufficient amount to see and differentiate Parkinson’s from non-Parkinson’s. But if you take a bit of that and then put it into this system where you can amplify it through recruitment of further synuclein, now you can detect it.
And for the first time, there was recent publication this year you can see this announcement from Michael J. Fox Foundation April last year, sorry. So one year ago that we can do this and we can pretty confidently say whether you have Parkinson’s disease alpha-synucleinopathy or not. So this is specific for this misfolded protein. There are forms of Parkinson’s disease, especially rare genetic forms, that do not develop this particular protein pathology. They have a little bit different disease course and usually those ones will not show up on this assay. But for the majority of patients, if you have Parkinson’s disease, this will tell you yes or no, but it may not help you much ’cause you already know you have Parkinson’s disease. But what this is useful for is for example designing those clinical trials. If we have an alpha-synuclein-based therapy, we don’t want to recruit patients that don’t have alpha-synucleinopathy.
And so clinicians are very excited about this. This has allowed also to move to a biological staging system for Parkinson’s disease. So what we mean by that is that up to this point, we define Parkinson’s disease clinically. You go to your neurologist, typically you go through a neurological exam, they send you home, you — if they think you might have Parkinson’s, they’ll test you on levodopa. If you’re responsive to that, likely you have Parkinson’s. But this allows us to move to biological definition to understand really what’s the underlying disease. It’s the same as if you went to the doctor and you got a cholesterol test. You understand not, you don’t have to say you just have heart disease or vascular disease. You can understand specifically what the biological component of that is that you need to treat. So there’s another exciting development you can see, announced first in January this year.
And then finally the last one I wanted to highlight is that we have other ways to look. We think that alpha-synuclein pathology may begin outside of the brain in the peripheral nervous system. And I showed that person, in their whole central and peripheral nervous system. You saw that even in your skin you have nerves and you think that those nerves may contain alpha-synuclein. Now the company has developed an assay to diagnose Parkinson’s from a skin punch. So another exciting development of the Parkinson’s field. I can tell you from my clinician friends, they’re very excited about this.
So takeaways from today’s talk. The brain, I hope you appreciate, is a wonderful network of billions of neurons. The brain’s also plastic. So I showed you that brain of the patient with Parkinson’s disease that really had the depleted substantia nigra. We think that about 50% of those neurons have already died by the time a person comes to clinic to get diagnosed with Parkinson’s disease. And that means that the brain has done a lot of work to make sure you don’t notice the fact that you have, that those neurons are already dying. So the brain, the brain has ways to figure things out and compensate. So if we can intervene, the brain, early on enough, the brain can figure the rest out.
But we have this problem, the proteins which are important for and critical for function, sometimes misfold. And the misfolding, especially as we age, can lead to accumulation of these and disruption of neuronal function. So I gave you some of the highlights of what’s going on at the Institute and also some of the main highlights for, big news stories around the world. We’re all working hard to try and fight this, and I highlighted some of the ways in which we think about disease as a biological process to try to counter. So that’s the end of my talk, but I wanted to also highlight, you’re all clearly involved in your community and interested in research being done. So I just wanted to highlight a couple other things the Institute does. In September together with Dr. Darren Moore and Laurent Roybon, we’re — I’m hosting this Grand Challenges in Parkinson’s Disease.
What we do is we know that we’re not doing all the research. We bring the best scientists from all around the world to come here and talk about their latest research, things that maybe haven’t published yet and give us new insights maybe for our own research. But in conjunction with that, what we do is we host something called Rallying to the Challenge. This is a meeting for people with Parkinson’s and their care partners, and it is a great way we bring the scientists, the same scientists that have come from around the world. Often they’ll give a more basic lecture like I have for people with Parkinson’s. But also you get to tell us what you think. Are we pursuing the correct areas of research? Is there something I left out that we should be putting more focus on? So it’s a great way for all the scientists here around the world to interact with people with Parkinson’s and their care partners. So with that I’ll finish up and happy to take questions and invite Maranda back on stage.
Maranda [34:03]:
Thank you again. We now have an opportunity for questions. We have folks with microphones available here in the auditorium. If you have a question, raise your hand, they’ll bring a microphone to you. We also have a large group joining us online, and if you are online and you have a question, please use that chat function and we will try to get to as many of those questions as we can as well. Anyone wanna start us off? Right there? Start in the back.
Audience member [34:36]:
You spoke a little bit about brain plasticity. Is that something that’s known, or is it positive, or how’s that, how do we know what that does?
Michael Henderson [34:45]:
Yes. So brain plasticity is this whole own field of research. There are a lot of people that are really interested in this. The brain is plastic. So most of your neurons, once they die, they’re gone. We have no way to recover those specific neurons. But all the remaining neurons that had similar function, they have the ability to compensate for that. So what, for example, we think happens with Parkinson’s, are those remaining dopaminergic neurons that are left. They can sprout more terminals, they can release more dopamine and that’s the way that they can compensate is plasticity, is the way the brain is trying to compensate for the deficit that is occurring — is gonna happen. Also in memory dysfunction, many other regions of the brain, the brain is well-known to have this ability. And also, unfortunately though, that plasticity, we lose it a bit with age. So the newborn brain is extremely plastic. We have many more neurons when we’re born than we will a few years later. And that’s because the ones that are not needed are pruned. And so as we age though, some of that plasticity goes down. We think that’s one of the reasons also that these are aging-related diseases, is that the brain can’t compensate as well as we age.
Maranda [36:00]:
Follow up.
Audience member [36:05]:
Uh, and are there known ways to assist the brain plasticity?
Michael Henderson [36:11]:
Yes. So people are working on that. One of the ways is through neurotrophic factors. So there are things that are, like GDNF which is a glial-derived neurotrophic factor. And basically glia, which are the non-neurons of the brain, these are astrocytes and other, cell types. They want those neurons to survive and they can secrete factors that make or are pro-survival. So they increase the survival of neurons. So some of the trials in Parkinson’s, I think they may have been up on there are for some of these neurotrophic factors. There have been study trials in the past that failed trying those, but I think people are figuring out new ways and things they may have not done correctly in those earlier trials to try and make those effective. So that is definitely an ongoing area of research.
Audience member [37:00]:
Thank you.
Maranda [37:02]:
Next question here in the front. Sorry, not sure where we’re going. Gotcha.
Audience member [37:16]:
Thank you for your talk. You talked about the brain bank and getting, doing some research with actual brains. Are people able to donate their brains to the Van Andel Institute for study? And how does that work?
Michael Henderson [37:29]:
Yeah, that’s a great question. I would urge you not to donate your brain now, wait ‘til, [audience laughter] ‘til later. But yes. So this is something, what we have done, is to set this up, and we’re aiming to set this up in a manner that we can collect from anyone who’s interested and willing to donate. So we’re doing this currently, we’re finalizing a contract with Gift of Life Michigan. So they’re the same group, if you pass away and you want to donate your organs, you can donate them. Can’t normally donate your brain because you can’t transplant those. But this is a way for, so we’re working with them to be able to develop that. So we are hoping to have like a final, a finalized process for that ready very soon.
Maranda [38:13]:
Good question. If we can bring a mic here to the front.
Audience member [38:25]:
Thank you. Ready? Thanks. Hi. So I know that this might be a little bit like not what was covered, but, I have a question about like protein formation. So you have like your alpha chains and your beta-pleated sheets, and we know that the alpha-synuclein is a soluble monomer. But when it becomes misfolded, those beta-pleated sheets are, it’s like a heavy crossover. So is that what stops it from being able to be broken down by, say, like an autophagosome?
Michael Henderson [38:55]:
Yes. So theoretically, even those more insoluble forms can still be degraded. What we think happens is in some cases, they get too long to be engulfed. So the very long fibrils, yes, those can no longer, you know, be engulfed ’cause the organelle that would engulf them is too small. But what we think actually more of the problem is the fact that they just accumulate to such a degree that they, I think, what we, what we’re seeing when we see a Lewy body is actually the cells trying to kind of put it to the side. So if we can’t take out the trash, nobody’s coming to pick up the trash, maybe we, like, shove it to one side of the kitchen, and, and we can mostly go about our business and that’s okay as long as it’s sitting over there. And so we think that’s probably what the cell is doing. It’s got too much of this trash tries to sequester into the Lewy body, and that allows it to retain function for longer, but eventually they’re too much. And so even at that point, though, even at the early step, it’s probably because of a failure of these normal degradation pathways that they have to go to that method of sequestering it.
Audience member [40:03]:
I had a question too. When it came to, the deep brain stimulation. How does that work with a Parkinson’s patient?
Michael Henderson [40:11]:
Yeah, so deep brain stimulation is very interesting because it doesn’t have anything to do with the substantia nigra. It’s basically compensating. And the way that it does that is, if you remember, I showed you the inside of the brain and the basal ganglia. So this is the regions inside of the brain that are really critical for all this initiation of movement and smoothness of movement. And the substantia nigra modulates this. Well, we think when we lose the substantia nigra, there’s, there’s dysfunction in that. So you have more certain excitatory pathways, less of an inhibitory pathway, and that leads to, it’s a complex circuit, but basically there’s an overall loss of excitation from that pathway to your cortex. So that motor neuron is telling you to give that thumbs up, which hope you’re all doing now is, is no longer getting the same signal from the basal ganglia to, to tell it to go.
And so what deep brain stimulation does is, basically we find a part in that pathway where you can stimulate it a bit and like get, and get, reset that pathway, get it to start having its normal function again. It’s not quite the same as what dopamine does. It’s, but it’s to kind of bypass the fact that you would need dopamine at all. And that’s usually why for example, take deep brain stimulation: not usually the first choice, right? So usually it’s a choice once levodopa, perhaps it’s not working as well anymore. And it works in that case because it bypasses the need for dopamine at all.
Audience member [41:38]:
So the, the deep brain stimulation only, it only will help with, like, the motor issues.
Michael Henderson [41:45]:
Yeah, so deep brain stimulation, we typically think would still only help with the motor symptom because it’s not, not hitting the same pathways that would lead to, for example, dementia or any of these gastrointestinal issues or other nausea.
Maranda [42:04]:
In the middle?
Audience member [42:10]:
I also thank you for that presentation. A two-part question. The navigation of neurons into various parts of the brain, does that explain why every Parkinson’s patient is different, that the symptoms are different? And then secondly, you talked about resistant areas of the brain and what are you learning about what makes those resistant?
Michael Henderson [42:33]:
Yep, two great questions. So we think that the pathology occurs in different regions of the brain and, for sure that is definitely why every person with Parkinson’s will have a different disease, a different disease course. The other parts of that, so, for example, different, there are different subsets of disease. Some of them progress more quickly, some progress more slowly. Oftentimes the genetic forms will start early, but then have a much slower disease course. And that’s partially due to the fact that many of those genetic forms don’t actually have alpha-synuclein misfolded. So they don’t have the protein pathology that will go through different parts of the brain. What those typically are, are just the dysfunction of those dopamine neurons only. So they only affect the substantia nigra, and then the fact that, so then that makes the rest of the brain can still function normally except for that particular motor circuit. So those are a couple different reasons. We think different people have different disease courses. And then the second question was about, remind me what that was?
Audience member [43:43]:
What, what are you learning about the resistant areas of the brain? And how does that help?
Michael Henderson [43:46]:
Sure. So one of the things that we’ve started to do, is we can basically model the progression of these pathologies through the brain and then that’s how we identify regions that certainly would think just by the fact that they’re highly connected should have pathology and they don’t. So we call them resilient regions. Those resilient regions now we’re probing in to see what’s different about them. And actually, this is the early days for us to uncover that. But we are uncovering a lot of potential cell signaling pathways. For example, those regions seem to have higher basal energy metabolism. So they may have be more efficient at energy metabolism. They may have other different cell-type markers, for example, one type of protein called kinase that’s important for signaling. These are actually really nice for therapeutic development because they’re basically kind of on-off-type proteins. You can turn ’em on, turn them off. And so what we’re doing is we’re narrowing down that list of proteins to ones that we think are really contributing to disease and then we can target them via molecules. So that’s kind of, that’s our strategy and understanding what made that region resilient, and then trying to hone in on what the potential therapeutic molecules could target that pathway.
Audience member [44:59]:
So we think of, we talk about Parkinson’s as a movement disorder and you’re connecting the protein pathology, these, these, misfolding A-synuclein proteins, I think you made a connection there with the, the movement. But you know, some of the most annoying symptoms, I can attest to [laugh] of Parkinson’s are non-motor, anxiety, OCD, this kind of thing. Is the, is the protein pathology connected to those symptoms as well, or only to motor symptoms? And does the, do these non-motor symptoms, are they a function of the degradation of the substantia nigra as well, or is this a whole different system that’s being affected? And is it being affected by the proteins or some other problem?
Michael Henderson [45:52]:
Yes, so that’s a great question and this is a big hypothesis in the field. I would say we’re still testing it, but what I can tell you is that we certainly can find that protein pathology in different brain regions and that’s associated with the different symptoms that are experienced. So one, the two examples I would give you, one is that gastrointestinal dysfunction, as I mentioned, is one potential area, the non-motor symptom. And so what scientists have done is then probed into the entire nervous system. So your, your brain controls your whole body, but your gut has its own nervous system that controls gut motility. And what turns out is that many of those neurons actually get alpha-synuclein pathology as well. So in that case we think that that may be one of the causes of gastrointestinal dysfunction. Another one is cognition. So cognition, as I mentioned, is more of a cortical. So it’s, it’s outside of the brain, or the front of the brain. And what we found is that at end of life, those people that had more cognitive symptoms, they also have more of this pathology in those cortical regions that control those higher-level thinking. So those are a couple examples. I would say that it’s not always a one-to-one. That’s difficult to say, you know, oh, this person had this particular symptom, we found the exact spot in the brain that was responsible and it had this pathology. But generally, we think that is true.
Audience member [47:18]:
So the, these misfolding proteins perhaps messing with serotonin and so forth? Is that, could that be a cause of the anxiety or, or or …
Michael Henderson [47:29]:
Yeah, that’s a good question and I don’t, as far as, as far as I know, I don’t know the full answer to that. One of the reasons that’s most impacted by many of these pathologies, including alpha-synuclein, is the amygdala. And this region controls a lot of our, kind of, fear response and also kind of other response, situational responses. And so like I said, it is not always a one-to-one. Like this is definitely like, even the brain, we’re still learning a lot about like, what’s actually controlling — for example, for depression we know SSRIs work, but actually we still don’t actually understand exactly how those work. And so, so generally we think that is true, but I, we can’t give a one-to-one for like this particularly, but that is definitely an ongoing area of research.
Audience member [48:20]:
Thank you. Great, great lecture. Thanks.
Maranda [48:23]:
Quick question. What role does exercise play in prevention and in slowing progress?
Michael Henderson [48:30]:
Great question. So exercise, I think, is generally important for us all. We should all exercise. Cardiovascular disease, Alzheimer’s disease, Parkinson’s disease has certainly been shown that if you maintain part of that healthy lifestyle, eat healthy, exercise, this is, leads to better outcomes. But within Parkinson’s disease in particular, exercise is thought to be very important. And it goes a little bit back to the plasticity question. We think that what you’re doing by moving constantly is, you’re keeping those circuits active, you’re figuring out ways your brain, if it’s active in those circuits, it figure out, figures out ways to retain that. So, uh I think especially for people with Parkinson’s, usually neurologists will recommend that you exercise as much as you’re physically able to. Things like dancing classes, dancing with Parkinson’s is definitely big. I think it’s really important to find ways to keep moving.
Maranda [49:33]:
Good. Let’s take one from our online friends.
Moderator [49:36]:
We have a virtual attendee who asks, “What specific epigenetic marks are playing a role in making certain neuronal populations more vulnerable to PD?”
Michael Henderson [49:50]:
I don’t know [audience laughter].
Maranda [49:53]:
You stumped him.
Michael Henderson [49:54]:
So epigenetics is not my main field, but it’s something we investigate. And actually, epigenetics is really interesting because we think about it a lot in the context of diseases like cancer. Because what happens in cancer, those cells are constantly dividing and then something goes wrong. The cells are supposed to die and, and then they’re not; they’re proliferating much more than they should be. Neurons don’t proliferate. And so the role that epigenetics has is still a little bit unclear, it’s a little bit early days for Parkinson’s disease. So we know that it must play some role, certainly which genes are expressed are changed in neurons. That’s one thing I told you we’re investigating, but we don’t know if there’s a specific underlying epigenetic cause of that, or if this is all part of a coordinated system for gene expression. So great question. I don’t personally know the answer to that but, uh but certainly an active and very new area of investigation for neurodegeneration generally.
Maranda [50:56]:
And the final question.
Audience member [50:58]:
Hi, thank you for this today. I’m here for my brother. He has Parkinson’s, but he started with ulcerative colitis and you mentioned a GI connection. I happen to have Crohn’s, so I’m very involved in the, the Crohn’s Foundation. So you just mentioned the gut has its own nervous system, and earlier on a slide, and I’ll tell you this is way over my head so it’s, I’m just gonna be basic, but, I noticed something about anti-inflammatory, antioxidants, microbiome, things like that. Have you noticed and found any diet connections? Now I know diet doesn’t fix Crohn’s either, but is there anything, that we can do? Obviously eat healthier, but have you found anything specific that we can do for Parkinson’s to help keep us going and lessen the severity of things?
Michael Henderson [51:53]:
Yes, I think this is another important question. So one of the nice things but difficult things about some of the Parkinson’s research is we, like in labs like mine, we investigate specific mechanisms, try to understand the specific cellular signaling pathways. But that’s not something you can immediately act on. You can immediately act on things like exercise and diet. And I think you can ask your brother about it. I think a lot of people with Parkinson’s disease do do this. They understand that each person with Parkinson’s disease has a different disease course, they may have different things. So this is actually what makes that, it’s really important for patients, it just makes the research more difficult, because controlling diet is extremely hard. I don’t know if you’ve ever — I’ve tried to go on like specific things to try and see how it made me feel. It’s very difficult to kind of control very specifically what you eat. We’re not, kind of, in a space age where we take a pill that has very specific contents. But I would tell you, from the Parkinson’s disease literature, people are investigating this. There are certainly kind of, stories of people that have changed their diet and it’s made a huge difference for their Parkinson’s. One of the ways in which it can do that is that we, if patients are already taking levodopa, for example, it can change the metabolism of that within the gastrointestinal system. So that’s one way that it can just improve, kind of, maybe they have to take a lower dose of levodopa now, ’cause they’ve improved that. Another area of research that’s also very complex, but up and coming, is the microbiome. So microbiome is a huge number of molecules that just live in our bodies. Clearly Parkinson’s disease microbiome appears different than healthy microbiome, but it’s not always clear in which way that it is.
And that’s because there’s thousands and thousands of those species that may have slightly different, kind of, versions of ’em in different people. I’ve tried to read that literature and it’s complex, but people have started bypassing that altogether. And the way that they do that is they’re saying, this is a healthy microbiome, this is Parkinson’s. What if we just took that healthy microbiome and put it in a person with Parkinson’s? I don’t know if that was up there, but this is one of the type of clinical trials that’s ongoing is basically fecal transplant. If you take a healthy person’s fecal matter, put it in a Parkinson’s patient and now — they do non-blind it, I’m not sure exactly how to double blind that, but [audience laughter] that is done, and, and there’s colloquial evidence that some people do much better, when that’s done. And we have to wait on the clinical trial to find the, kind of, find the final result. But that’s the other side of, kind of, diet. So certainly diet is important, but it may need to be very individualized in terms of what works well for each individual person. But this fecal transplant is gaining traction, and that may be another way to kind of replace your microbiome with a healthy microbiome and maybe help sustain, at least, symptom management.
Maranda [55:05]:
Interesting. All right, so Van Andel Institute, known for 100% hope. Every dollar raised goes directly to the research. I wanna talk about hope from the work you’re doing. What gives you the most hope on the topic of Parkinson’s and the day-to-day for you and your associates?
Michael Henderson [55:23]:
Well, I think one of the things actually I’m most excited about is how much interest there is. So both from the community, the Parkinson’s community is very involved, but also from scientists. So there’s been a lot of focus from scientists, there’s been private foundations that have put a lot of money into this and this has really helped because, you know, if you get more people interested, you’ll get more answers. I, my lab is not gonna find all the answers, and so if there are more labs researching this, then I can chat with them. They develop some new technique that I can use, then that’s really what’s helped us progress. Things like the Linked Clinical Trials that then bring those kind of sites, insights from the lab and now try to bring them to the bedside. That’s really helped make a lot of progress. When I started Parkinson’s disease research, there was not much on that very complicated figure I showed at the end. And the fact that now there is, makes me hope that some of those will then provide promise for patients and then we can, like what has happened in Alzheimer’s disease field, Parkinson’s is a little bit emulating and learning from what has happened in that field. And so what we now hope is that we can make good progress. And what we understand from Alzheimer’s is that even when you find something that may be disease-modifying, it may not be the only thing that’s needed. And so, so it’s not gonna put me out of a job anytime soon. I’m sure we have plenty to learn about Parkinson’s, but I’m also very hopeful for that day when I can change that slide from “no disease-modifying therapies” and, and tell you about the ones that are disease-modifying.
Maranda [56:58]
Thank you for your work. We so appreciate it. Thank you.
You can find out more about his work on the vai.org website, check it out. You can also find out about upcoming events. We have two more informational discussions like this. They will be in September and in December, take a look at those topics. Very interesting. And the Institute just does such a great job with keeping us informed about the work they’re doing. Also, for those of you that are joining us in-person, we have a special invitation for you to actually tour the Van Andel Institute and see some of the labs and the things that we’re doing. So if you’d like to do that, you’re welcome to stay for that as well. Again, thank you so much for sharing your expertise and for the good work you’re doing. Thank you for joining us today and I hope you have a great afternoon — I gotta say it — where you live. Thank you.