The future of Parkinson’s disease

0:00Suzanne Pfeffer:This is Stanford Engineering's The Future of Everything, and I'm your host, Russ Altman. Since we started this show eight years ago, it's become an archive of amazing and impactful work by my Stanford colleagues. Research is not something that just happens in the lab, and as you'll hear on this show, the research at Stanford can impact areas like health, technology, law, and business, and many other topics that can affect everyday life. We hope you'll tune in to learn more about how research has the potential to help your life and to help the lives of people you care about in your family and your community.

0:32And what we found was the antennas grew back. The cells began again to make those neuroprotective factors. And this cell, which was retracting its axon on its pathway to death, actually came back. And we actually saw restoration of talking between these two neurons, restoration back to normal. So it wasn't just stopping disease, it was reversing the process.

1:05Suzanne Pfeffer:This is Stanford Engineering's The Future of Everything, and I'm Russ Altman. Today, Suzanne Pfeffer from Stanford University will tell us that our understanding of Parkinson's disease at the molecular level is increasing, and we have a better understanding of what's going on in the brain. so much so that we can now detect early signs of Parkinson's 20 years before the big bad symptoms really occur. This is leading to new opportunities for treatments that are quite exciting. It's the future of Parkinson's disease. You want to help shape future episodes of the podcast? Leave a review and tell us what you would like to hear next.

1:39Suzanne Pfeffer:We'll see what we can do. In fact, today's episode with Suzanne Pfeffer was suggested by a reviewer who said, how about a little bit more on Parkinson's disease. It affects millions of people. Many of us know someone, a loved one or a friend who suffers from the disease. So we found a local expert, Dr. Suzanne Pfeffer, and we're going to be talking about Parkinson's disease today. In addition, today we're continuing our feature, The Future in a Minute. At the end of my conversation with Suzanne, I'll ask her some rapid fire questions and she'll give us some rapid fire answers. And again, before we get started, remember to rate and review the show.

2:12Suzanne Pfeffer:It helps us and it helps others learn about the show.

2:22Suzanne Pfeffer:Parkinson's disease is a terrible disease that affects millions of Americans. It's thought of as a motor disease, a motion disease. People get problems with walking smoothly. They get a tremor. They get a lot of motor disturbances. And it can progress over the years to become worse and worse. The treatments are not very good. There's deep brain stimulation, which can last for about seven years. And there's medications which last for about five years, but then the side effects of those medications outweighs their benefit, and we often have to stop them. Well, Suzanne Pfeffer is a biochemist and a professor of biochemistry at Stanford University, and she's an expert at the molecules that go wrong in Parkinson's disease.

3:04Suzanne Pfeffer:She's studying them, and she's learning more about what goes wrong in the disease. And importantly, she's generating hypotheses about new ways to treat the disease, not just when the symptoms come on in your older age, but very early when you're first showing signs that you might have a risk for the disease. It's very exciting, and she'll be telling us about it. Suzanne, you're a biochemist. What led you to make the decision to do deep dive in a disease like Parkinson's disease? I was actually really lucky. So we were studying a small set of family of proteins called Rab proteins, and they control how proteins are put in the right place in cells.

3:44And our collaborator, Dario Alessi at the University of Dundee, made a discovery that an enzyme that's really important in Parkinson's makes a change to my favorite protein. And he didn't know about my favorite protein. And out of the blue, I got a phone call, Suzanne, we need your help. We want to understand how your proteins are part of Parkinson's. And that was a totally life-changing experience. And he's the most wonderful collaborator. So now we're celebrating our 10th year of direct collaboration. And I have learned so much and the work is really so meaningful. So it was serendipity that his discovery led to my set of proteins.

4:22And here we are.

4:24Suzanne Pfeffer:So biochemists, just to stick on this topic for a couple of minutes, biochemists are known for their kind of commitment to basic science. You know, in fact, you were probably studying these proteins and they were probably interesting to you biochemically and they did interesting things. Is it a big, hard decision to say, I'm now going to think about this as the understanding a disease and maybe even getting involved in the development of treatments, where before it was just the pure kind of curiosity-driven research? I'm just very interested in your decision about how to balance those two. I'm sure they're both passions for you.

4:57So the reason I'm a biochemist is I want to understand how proteins, these tiny little molecules, make us able to do all the things that humans can do. So fundamentally, that's the reason I'm interested in these molecules. So any connection to disease makes the work all the more meaningful, because it's not just working out just the picture of a cell and what it is, it has real consequences for people. And that has been one of the most wonderful parts of the last 10 years. The work is super meaningful.

5:28Suzanne Pfeffer:Great. Okay. So I think it would be good for us to have a little tutorial on like what we need to know about Parkinson's disease to appreciate the current frontier challenges and the work that you're doing. So maybe tell me a little bit about the disease. How should we think of it? What do we know about the causes of just for starters? Okay. So let's start with the causes. So most of the causes are probably environmental. We absolutely know that pesticide exposure can greatly increase your risk of Parkinson's, even trigger it directly. And so that's bad news for farmers and people that live in regions, even living near golf courses may be dangerous, right?

6:08We never think of that. You think of getting a retirement home, a condo facing the golf course. Well, that may not be the best plan.

6:14Suzanne Pfeffer:So these are actively used pesticides, not just historical ones. In the U.S., they have still not been outlawed. The Europeans are ahead of us, but it's very, our environment is for sure linked to Parkinson's disease. Now, for scientists, that makes it difficult because a person comes at age 65 with disease, we don't know where they've lived and what they might have been exposed to. So when there are genetic causes of disease, it gives us an inroads to study the process. And especially if those genetic forms, the kind that are inherited in your family from your parents, your grandparents, when those forms come on in a way that doctors identify very similar to the ones caused by pesticides, it gives scientists a really important clue that we can zoom in exactly on that specific form of disease, understand what's gone wrong with that particular gene change to cause the disease, and then see how does that link to the other forms of disease.

7:16Suzanne Pfeffer:So is it the case that some people have the genetic predisposition to Parkinson's, but that other people just have the environmental exposures and perhaps don't have the genetics and still get the disease? Absolutely. But what's important is, even if you have a genetic predisposition, it's not a guarantee that you'll get disease. So we call this penetrance. And so in some populations, in some mutations, it may be you have a 50-50 chance of getting Parkinson's. So then if you have that 50-50 chance plus exposure to pesticides or smog or other unknown environmental factors, also the chemicals used for dry cleaning, those can be problematic.

7:59attic for, so workers who've worked in a dry cleaning store, for example, may be of increased risk. Also, if you're a boxer, you got hit in the head or too many football concussions, that can also increase your risk. So it's going to be a combination. Okay.

8:15Suzanne Pfeffer:And so tell me a little bit about what actually goes wrong. We know it's a brain disease. What happens in the brain? So, and this is really important and it actually guides our work. So the two most common forms of neurodegeneration in people are number one, of course, Alzheimer's disease is the most prevalent, but the second most common one is Parkinson's. And we always try to say what's the difference between them. So Parkinson's is classified as a movement disorder. So you may know someone who has what we call a resting tremor. That's what people usually think of, where a hand at rest is showing a tremor only at rest, or it may be the head has a shake or the foot has a shake or the tongue.

9:00So people think of Parkinson's as being a tremor disease, but it's actually a movement disorder. And what it is, it's related to how smoothly you're able to initiate movement, stop, keep your balance, and not walk rigidly. So walking slow and highly rigid is a very predominant sign of actual Parkinson's disease beyond the resting tremor.

9:24Suzanne Pfeffer:And have we isolated the areas of the brain that are preferentially damaged? Yes. So again, this is what we're trying to understand. There's a specific circuit in the brain that controls movement, this starting and stopping of movement and the rigidity. And this is called the nigrostriatal circuit. And in Parkinson's, it's the nigrostriatal circuit that is vulnerable, that is the cells die and are unable to do this process of controlling movement. And that's different than Alzheimer's. Alzheimer's can be different regions of the brain. And people with Alzheimer's present in very different ways.

10:06So some people make it very angry, very hostile. Some people just lose their memory. Some people have trouble swallowing. So again, in Alzheimer's, it could be different regions of the brain. And we're trying to understand in Parkinson's, why is it specifically this circuit that's especially vulnerable? And that's the focus of our work. Great.

10:26Suzanne Pfeffer:And one more question, and this comes from my personal, you mentioned that many people have family and friends, and in fact, I did, my uncle. And two of the words that, two of the diseases that were bandied about when they were making a diagnosis on my uncle was both Parkinson's disease and Lewy body dementia. So can you just tell us a little bit about like, what are the differences and similarities? Are these the same disease or are they different diseases? It was very confusing to the family since both of them were bandied about. So Lewy bodies are these accumulations of a protein called synuclein that are seen and typically found in Parkinson's disease.

11:05Now, late stage Parkinson's often will develop into Lewy body dementia. And often there's a crossover in symptoms where you can have Parkinsonian symptoms in outright Alzheimer's. But let's just focus to keep it simple. in Parkinson's, the brains you see have Lewy bodies that are full of synuclein. And it's not at all for sure if they're the cause or the consequence, but they are characteristic of most, but not all forms of Parkinson's. And people would like to call it a Lewy body disease, but Lewy body dementia is where you have Lewy bodies in other regions of the brain that are consistent with the dementia, the inability to remember things and to have that kind of brain function.

11:56Great.

11:56Suzanne Pfeffer:Well, thank you very much for this tutorial. So now we all have a kind of a shared understanding of these circuits, but you made some intriguing comments about some molecules, and I think we should try to understand where you are in your research and what we've learned. So tell me a little bit more. You said there were some molecules that are involved in, I think, well, I reviewed your papers, what they call the trafficking of proteins, where it tells the proteins in the cell where they need to be to do their job. So tell me about how those things are involved with the disease and then some of the other molecules that are important.

12:30So we were talking before about how scientists use genetic forms of disease to really understand what's going on. So we studied two proteins that are, when mutated, the most common risk factors for Parkinson's. And that's an enzyme called leucine-rich repeat kinase 2, or LRRK2. We call it LARC2.

12:52Suzanne Pfeffer:LARC2, nice and easy to say. Yeah. And the other is a lysosomal enzyme. I'll say what that is. It's a protein called GBA, glucocerebrosidase. And if you have... So the problem with the LARC2 is you have a mutation. LARC2 becomes what we call hyperactive. So LARC2 makes a change on a protein. It puts a little charge piece, a little modification, changes the structure of a protein. And if the mutation does this too often, okay, too much of it. And so when it happens too much, what happens is it blocks a process in the brain that we discovered, which is generating a little antenna on the surface of the cell.

13:38And that antenna is called a primary cilium. It's involved in signaling. So it's listening for signals, chemical signals that require the antenna that make this cell change.

13:49Suzanne Pfeffer:It's a very fun idea that cells would have antennas in it. It's very attractive because of course they need to communicate. So it's fun that there's actually kind of like an antenna. It's a physical antenna. It's pretty, and they're beautiful little structures. Anyway, they're on nerve cells and they're on the supporting cells around the neurons. And what we discovered specifically in the nigrostriatal circuit, the part that's important in Parkinson's, the cells talk to each other. So here, this is a cell that secretes dopamine. These are the ones that die in Parkinson's. What they do is they send out a long process, a little extension, we call it an axon, to another region of the brain.

14:29And they secrete a signal when they are stressed. and the antenna has to receive that signal. And that makes this cell produce protective factors that make this cell happy. So normally if this guy's stressed, the job of this one is to send happiness factors so these cells are happier. They're better able to deal with stress. And what we discovered is if you have the hyperactive form, the two active form of that LARC2, these cells lose their antennas. So this guy's stressed. He's sending a signal. This guy doesn't know it's happening. It doesn't have an antenna, so it can't send back those protective factors.

15:09And so then this cell starts to retract its axon as part of its process to die. And that's something we want to stop in Parkinson's disease. So we're trying to understand how we can rescue that antenna so it can get the signal to send back the neuroprotective factors.

15:26Suzanne Pfeffer:Now, you mentioned these two proteins, the LARC2 and and the one that begins with a G. GBA. GBA, thank you. Are they part of the antenna, or are they part of the distress signal, or both? Good question. So what we know is that LARC2 blocks the process of the antenna being there. So in LARC2 mutation, half of the cells lose their antennas. In the GBA, the cells keep their antennas, but they're not functional. The antenna's broken. It can't sense the signal. And we showed that the GBA mutation changes the structure, so it can't signal anymore. So it's there, but it can't do its job. So, you know, one of the things that you said, you gave a scenario of a 65-year-old, but I know that there's a question about when these pathological changes in the brain start.

16:22Suzanne Pfeffer:And what do we know about this? And are we seeing these malfunctioning cilia, if you will, primary cilia? Are we seeing them very early? Or do we understand how quickly that happens in the disease process? We don't know that yet in humans. So, so far, we've only looked at brains from people who passed away at the age of 85. And we clearly see in all forms of Parkinson's, not just the genetic forms, but the kind that we don't know the cause of that are likely due to environment plus some genetic factors, we see the antenna go away. They go away more in Parkinson's than in control brains from people of the same age.

17:03And so we don't know how early in humans. In mice, it's pretty early. In mice, it's at eight weeks, we can see the problem. But remember, only half of the cells lose their antenna. So the other half are still there. And what we think is happening, it's, this is kind of like a, it's a slow process. So, so you have half the cells, maybe you're making half as much neuroprotective factors, but at, by the time you're 65, it's, it isn't enough because it's been all those years, a slow process. And this comes back to, to earlier symptoms of Parkinson's disease. So we know in Parkinson's, 20 years before you have a resting tremor or rigidity of walking, 20 years earlier, you have a couple of symptoms.

17:53One is constipation. Now, anybody can have constipation. That's not proof you're going to get Parkinson's. But you may have something which is called REM sleep behavior disorder. This is where when you're sleeping, you're acting out your dreams. And these are often sometimes violent dreams. So you're, you will be kicking and punching and your partner will say, Hey, you're waking me up. You're kind of dangerous over there. What's going on? If you have REM sleep behavior disorder, there's a very high probability. And this is 20 years before anything else. There's a very high probability that you will get Parkinson's.

18:31It's not a, it's something I wouldn't want to be diagnosed with.

18:34Suzanne Pfeffer:Yes. So the constipation is not very specific, but the REM disorder is. And also loss of smell. So just like in COVID, where many people lost their sense of smell, an early symptom of Parkinson's, 15 years before you have any of the movement symptoms, will be a loss of sense of smell. And most people don't really notice when they're losing their sense of smell. They may start wearing stronger perfume because they don't realize it, but it's something, it's very subtle and yes, it's really tested. And something for the future, I hope, is that everyone, when they go for their annual physical exam, will take a scratch and sniff test, which costs a dollar or something to offer people.

19:21It's very inexpensive, but it's something we should be monitoring, whether people are, how sensitive and able they are to sense.

19:29Suzanne Pfeffer:Yeah, the last few minutes of your comments, and I know you've written about this, make me understand why we shouldn't think of Parkinson's as something that just hits us when we're old, but there actually probably should be, as part of your primary care, a certain amount of surveillance for these different symptoms that you've just described. Absolutely, absolutely. This is Russ Altman, your host of The Future of Everything, and I'm speaking with Suzanne Pfeffer. We're going to move on to treatment as something I wanted to ask Suzanne about, because we now have a pretty good understanding of Parkinson's disease, some of the molecular problems in the brain.

20:04Suzanne Pfeffer:So Suzanne, what is the current state of treatment for Parkinson's disease and what's good and what's bad about the current treatments? So one of the challenges and limitations, the treatments right now are just treating symptoms. so basically you would be given something that will help the resting tremor or help you be able to coordinate movement a little better but the problem is is that after about five years those you with time you need to increase your dose and increase your dose and increase your dose and then at some point it has a bad consequence which is it caused something called dyskinesia which are these movements which you can't control, and it's very embarrassing and very uncomfortable for people to have those.

20:50There's also great success with something called deep brain stimulation, where they actually place an electrode into the brain to try to counteract some of the signals. And that works very, very well for about seven years. But then at some point, that also stops. So we need something that's not temporary for these people because you can live a long time with Parkinson's and the symptoms, you know, you really would like to be able to button your shirt when you get up in the morning or be mobile and independent and not worry about a freezing of gait where you basically cannot move forward. I mean, that would be terrible if you're trying to go about your daily life.