The global prevalence of Parkinson's disease has doubled in the past 25 years. While research into this extremely diverse neurodegenerative disorder is very active, there is much left to be uncovered about the underlying cause of the disease. Recently, Northwestern Medicine investigators have discovered novel genetic factors contributing to the risk of Parkinson's disease, which may lead to potential therapeutic targets. Steven Lubbe, PhD, assistant professor of Neurology at Feinberg, discusses these findings recently published in the journal Brain.
“I hope over the next 10 to 20 years we're able to make larger inroads in identifying and understanding the causes of movement disorders across the world in all individuals.” — Steven Lubbe, PhD
Lubbe discusses his work investigating the underlying cause of Parkinson's disease and other neurodegenerative disorders using large-scale genomics.
Additional Reading
Target Audience
Academic/Research, Multiple specialties
Learning Objectives
At the conclusion of this activity, participants will be able to:
Accreditation Statement
The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Credit Designation Statement
The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Disclosure Statement
Steven Lubbe, PhD, has nothing to disclose. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. Feinberg School of Medicine's CME Leadership and Staff have nothing to disclose: Clara J. Schroedl, MD, Medical Director of CME, Sheryl Corey, Manager of CME, Allison McCollum, Senior Program Coordinator, Katie Daley, Senior Program Coordinator, Michael John Rooney, Senior RSS Coordinator, and Rhea Alexis Banks, Administrative Assistant 2.
Erin Spain, MS [00:00:10] This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. The skin is the largest organ of the body. And skin diseases from psoriasis to melanoma affect as many as one in three Americans at any given time. Today's guest, Dr. Kathleen Green, has greatly advanced basic molecular research related to skin diseases. She joins us today to talk about some recent discoveries in her lab that could lead to future therapeutic targets for skin diseases. Dr. Green as the Joseph L. Mayberry Senior Professor of Pathology and Toxicology at Feinberg and the Associate Director of Basic Sciences Research at the Lurie Cancer Center. Welcome, Dr. Green.
Kathleen Green, PhD [00:01:00] Hi, Erin. It's wonderful to be here with you today to talk to you about skin.
Erin Spain, MS [00:01:04] Yes, let's talk about skin. That beautiful organ I just mentioned. Tell me about skin, how important and complex this organ is.
Kathleen Green, PhD [00:01:13] Well, skin is absolutely essential for us to live life on land as terrestrial organisms. And it actually is quite complex. It performs a number of functions called the barrier. So the skin is a barrier against mechanical stress, against microbes like viruses and bacteria. It also helps us keep water in, so it prevents water loss. So it performs a number of functions that allow us to live life on land. And how does it do this? Well, it's a complex organ. The outer surface is a tissue called the epidermis. The epidermis is a multilayered tissue that turns over about every 28 days. I think we're all familiar with the fact that our skin turns over, it desquamates, and this is a very important functional aspect of the tissue. So how does it do this? So there are proliferating cells deep in the epidermis, and those proliferating cells give off daughter cells that ultimately decide to stop dividing. Then they move from that basal proliferating layer superficially to the outer surface of the epidermis. So this is the process of turnover and it's a very dynamic process. And during this process, the skin is producing lipids, proteins, and other things that are essential to form that barrier. Now, during that process, all those cells have to stick together. So this gets to some of the work that we do in our laboratory. They have to stick together through molecules called cadherins, and if they don't stick together, then the barrier falls apart. And obviously this is not good for us. So the skin performs this essential function through a dynamic process of regeneration.
Erin Spain, MS [00:02:51] So your lab focuses on cell adhesion, as you were saying, and the role that it plays in human skin, especially in pathological processes such as cancer, autoimmune disorders and inherited diseases. Tell me more about this work that's being done in your lab here at Feinberg.
Kathleen Green, PhD [00:03:06] Absolutely happy to. So as I mentioned, those cells, the regenerating cells in the epidermis have to be held together or the whole tissue falls apart. So these adhesion molecules are essential for the integrity of the epidermis. They're also a target for a number of different kinds of disorders. So autoimmune antibodies that are generated against our own proteins, and we all are familiar with there are many kinds of autoimmune diseases, but some of those actually target these adhesion molecules, cause them to go away from the surface of the skin cells, and this causes blistering. It's a disorder called pemphigus, but there are also mutations that give rise to similar kinds of blistering disorders or other kinds of rashes and disorders that cause skin disease and inflammation. And there are even bacterial toxins that actually cleave off the extracellular adhesive domains of these adhesion molecules and again, cause blistering. So obviously, these adhesion molecules are essential for the integrity of the tissue. But one of the things we're interested in, in our lab, is that they play other functions, too. They control the immune system. So the skin is an important immune barrier as well. They actually control the multilayering and the development of that tissue in the first place. So they do many, many things and we're trying to understand how these adhesion molecules do those things.
Erin Spain, MS [00:04:29] You're a cell biologist. Your work specifically focuses on a group of proteins called cadherins, as well as intercellular junctions called desmosomes. So just explain those to me at the very basics and the crucial role that they play.
Kathleen Green, PhD [00:04:43] So happy to tell you about these molecules which are called cadherins. Now the cadherins are proteins that span the plasma membrane. Now what's the plasma membrane? It is the outer lipid membrane that surrounds every cell. And the cadherins pass that membrane once, and so they have a domain outside the cell, that's the adhesive domain. And it meets up with another domain on an adjacent cell to form that adhesive interface. So the cadherin also has a domain inside the cell that interacts with cytoskeleton filaments that contribute to strong adhesion. It also interacts with signaling molecules that signal to the nucleus, environmental signals that are important for the cell to understand what's going on in its environment. So these modules developed during evolution from primitive cadherins that were actually first found in single celled organisms. And I think this is so cool. These primitive cadherins, what were they doing in single celled organisms? Well, it turns out people think they were involved in capturing prey, and then they were later used by other organisms like sponges, to bring cells together into multicellular sheets called epithelia. And we're very interested in how these cadherins helped us form these multicellular epithelial sheets.
Now, you asked me about desmosomes, which is an area we are very interested in. Well, those desmosomes also contain cadherins, but they appeared later in evolution in vertebrates. And in vertebrates, of course, we're getting bigger, our tissues are more complex. A lot of them experience mechanical stress and these desmosomes, it was thought, were important in these tissues that experienced mechanical stress, like the skin and the heart, in integrity, tissue integrity. But they also developed other functions that I think we'll get into talking a little bit more about. And the skin and heart, actually, there are a number of disorders that are caused by interfering with these important molecules in those mechanically stressed tissues.
Erin Spain, MS [00:06:45] Thank you for that background. And it's fascinating. And really, you've done pioneering work in desmosomes. I want you to tell me a little more about that and some of the projects that you've done in the past and that you're currently doing in your lab.
Kathleen Green, PhD [00:06:58] We were beginning at the very beginning of desmosome biology and the old days when people were actually identifying clones that encode the different desmosome molecules. So there are a number of these different components that we are studying and we are still studying today to understand their respective functions in desmosomes. Some of these molecules are involved in anchoring the intermediate filament cytoskeleton to the cell membrane, and this anchorage is absolutely essential for strong adhesion. So mutations in these molecules, either these anchoring molecules or the adhesion molecules themselves, can give rise to these cardio cutaneous disorders. And you might be interested in hearing a little bit more about these disorders because we're trying to understand how desmosomes, when you interfere with them, how that leads to these disorders. So the cardiac disorders arise through mutations in multiple desmosome molecules and can give rise to something called arrhythmogenic cardiomyopathy. Now these cardiomyopathies can lead to sudden death, particularly in well-exercised individuals. So sudden cardiac arrest. Now, this is something that's in the news a lot because there are basketball players, soccer players, for instance. Occasionally they just sort of without any notice whatsoever can, you know, fall down and have these incidents of sudden cardiac arrest. And it turns out that a number of these, a proportion are due to mutations in desmosome molecules. So in some countries, like Italy, athletes are screened for mutations in desmosome molecules because they want to know whether they're at risk for sudden cardiac death. So we're very interested in how these mutations can give rise to this heart disorder, but also mutations can give rise to the skin disorders. And so we're trying to understand the extent to which the mechanical properties of desmosomes or their signaling properties, like their relationship with the immune system, might be leading to some of these diseases.
Erin Spain, MS [00:09:01] And also desmosomes are in cancer as well. And this has to do with some of the work that you do in the Lurie Cancer Center here at Northwestern. Tell me about that relationship.
Kathleen Green, PhD [00:09:12] Yeah, we're very interested in communication between cells that don't only communicate through desmosomes, but how desmosomes change communication with other cells through things like secreted factors that go from one cell to another. And the reason we got interested in melanoma is it turns out that one of these cadherins that we are particularly interested in, and I'll introduce this term desmogleins. So desmogleins are the star of the show of the paper that we're going to be talking about a little bit. And desmogleins are one of the more evolutionarily advanced cadherins. Desmoglein 1, one of the desmogleins, is only found in terrestrial vertebrates and it's only found in complex tissues, and in stratified, multilayered tissues like the epidermis that we talked about already. And we found that desmoglein 1 can actually cause cells that don't express it to stratify. So it's important for the multilayering, it's important for holding cells together. But a recent function that we found for it is that it acts as an environmental stress sensor. So this is a little bit of background to get into melanoma. I promise we're getting there. But what we found is that sunlight, which is very important for the tanning response, so sunlight signals to our epidermis to produce pigment in cells called melanocytes. And those cells that produce the pigment deliver that pigment to their surrounding keratinocytes neighbors, and keratinocytes are the most abundant skin cells. If you just look at your skin, most of that skin, the color of your skin and everything is due to the pigment in those keratinocytes that was delivered by the melanocytes, the pigment producing cells. Now those pigment producing cells are subject to mutation by ultraviolet radiation from the sun. And so what we found, and the reason we got interested in melanoma and how those mutant cells give rise to this really serious tumor, is we found that the sunlight causes desmoglein 1 to go away normally temporarily in the keratinocytes, and that changes the factors that they're secreting, factors that the melanocytes take up and use to produce pigment. So desmoglein 1 we think is involved in this normal tanning response that communicates to melanocytes to produce pigment. But if it's not tanned normally that's temporary. So desmoglein 1 comes back. If it's not, if it's chronic, if that loss is chronic, then what happens is you get a sustained inflammatory response. Now, in terms of in the context of disease, human disease, where desmoglein mutations give rise to chronic loss, you get inflammatory skin disorders like one we'll talk about in a little bit more. But it turns out that melanoma cells can make it go away chronically. Melanoma cells can communicate to the adjacent keratinocytes to tell desmoglein 1 to go away, and that is hijacking this normal tanning response for their own benefit. So they surround themselves with an inflammatory cocoon that leads to a pro-tumorigenic environment, that creates an environment that causes them to proliferate and move more to invade. So we're really interested in how keratinocytes and their adjacent melanocytes are communicating and how that communication is good normally, but how it goes wrong in melanoma to promote melanoma progression. So I'm not sure if that explanation makes sense, but that's how we got interested in melanoma.
Erin Spain, MS [00:12:49] This is really fascinating stuff and I'm interested to hear a little bit about one of your latest breakthroughs that was published in Developmental Cell. And this focuses on a potential future therapeutic target for inflammatory skin diseases. Please dive into this discovery and what you found.
Kathleen Green, PhD [00:13:04] Yes, absolutely. So I think a segway into this is getting back to this cadherin, which is found recently in evolution, the one that's called Desmoglein 1. So this is a project that was the thesis project of Marihan Hegazy, who was a Driscoll graduate program student, and she just recently defended and it was, you know, went out with a big bang with this Developmental Cell paper. So we're really excited for her. She really drove this paper. And also she was co-mentored by Lisa Godsel, who is actually a former DGP student as well, and now she's a research associate professor in my group. And so this was really a team effort and I'm speaking on their behalf. So what Marihan was really interested in, given the importance of this desmoglein molecule. So we know it's important in holding cells together. We had evidence that it was acting as an environmental sensor, and we have evidence that it's important in human inflammatory disorders because it's missing in patients that have something called SAM syndrome. So this is a syndrome where you have skin inflammation, but you also have allergies. So it's a systemic disease and it's caused by biallelic mutations in desmoglein 1. So both alleles, both chromosomes are affected. Desmoglein 1 isn't completely gone. But either there are truncated versions that are rapidly degraded, or in one case that was the highlight of this paper, there is a mutation that leads to trafficking defects. Now what do I mean by trafficking defects? So intracellular trafficking is sort of like you can imagine your car out on the highway and there are many different decisions that car has to make about where to go to end up in the right place at the right time. So there are intersections, there are decisions, you know, what highway to get on, what road to get off on. Well, trafficking of protein in cells is very similar. Those cargos or the car has to decide where to go and there's machinery that gets it to the right place. And it helps make the decision to get out to where it's going, and in this case, to the plasma membrane. So the outer surface of the cell. So Marihan knew how important it was, especially because there was a disease where trafficking was impaired. So what is the machinery that gets desmoglein to the right place? And so she went through a protein-protein interaction screen. So this is a way of looking for all the new binding partners that might be involved in this trafficking machinery and found something called VPS35. Now what's that? So VPS35 is part of a bigger machine, a bigger protein machine called the retromer. And the retromer is something that is also ancient, so it's found in yeast originally. And we know now that in mammals it's important to get things either to intracellular compartments like the golgi. That's one of the intracellular compartments important for protein synthesis. Or to get it out to the plasma membrane through a process of recycling. So she hypothesized that this VPS would be important for getting desmoglein to the surface and through the process of experiments in this paper, she proved that basically. She showed that this machinery was important for desmoglein 1. Now, getting to your question about, okay, how does this relate to disease? Is this retromer a potential therapeutic target? Well, it turns out that there is a small molecule chaperon called R55, and this small molecule chaperon, and there are other ones that are actually now being made by some of our collaborators that may be less toxic and may be even better drugs. But she used R55 because it was commercially available and she was able to demonstrate that the disease mutant desmoglein could get to the cell surface better if you improved the retromer functions, stabilize the retromer through this R55. So this really is at the heart of identifying this potential therapeutic to improve desmoglein function by getting it to where it's supposed to go.
Erin Spain, MS [00:17:06] And there could be implications with these findings for other skin diseases as well.
Kathleen Green, PhD [00:17:11] Yeah, absolutely. And, and I didn't mention it, but it's important to note, I think, that the retromer has not really been on the radar screen of skin biologists so much. It has been on the radar screen of neurobiologists. And in fact, R55 and similar compounds have been used in preclinical studies for Alzheimer's and Parkinson's disease. So we reached out to some of those investigators to help provide guidance because no one's ever used it before in skin. And we were actually able to paint R55 on the surface of the dorsal surface of mouse skin and show that desmoglein got to the membrane better. So that opens the possibility that it could actually be used in vivo to improve desmoglein localization. So yeah, getting back to your question about disorders, psoriasis, for instance, is a more common disorder. Everyone knows someone with psoriasis, right? And it turns out that desmoglein 1 expression is decreased in psoriasis. So we think that in these more common disorders, its loss could also be contributing to some of the inflammation that we see in these common disorders. So it opens up the possibility of the retromer as a potential target in other skin diseases.
Erin Spain, MS [00:18:24] With all these new possibilities out there, tell me what is next on the horizon? What can we expect from your lab in the coming months and years?
Kathleen Green, PhD [00:18:33] So we're very excited about the potential translational impact of some of these basic science discoveries. But we still have so much to learn. Desmoglein 1 is just one new cargo, one thing that we found binds to this retromer component VPS35. But in the skin, like I said, it's not been on people's radar screens. What are the other cargos that retromers might be involved in trafficking in skin? We need to understand that before we can really translate this discovery to other disorders, because we don't want to mess up other trafficking components as well. So we do know actually that there's another cargo called GLUT1, which is a glucose transporter. Now, glucose metabolism is also extremely important in skin, and we know that, right? And in psoriasis, glucose metabolism has shown to be extremely important, and an increase in glucose metabolism can contribute to some of the phenotypes in psoriasis, some of that disorder. So we need to really understand the balance of the retromer, and the extent to which it's important for desmoglein 1 and GLUT1 trafficking, for instance. And we know that balance is important because we actually were able to look in a desmoglein knockout animal where desmoglein 1 is not there for the retromer to bind to. And it turns out that the retromer is now more binding to GLUT1. And so that's increasing GLUT1 expression and possibly glucose metabolism in these animals. So it's really important for us to understand the whole landscape of retromer function in the skin before we can translate it effectively. One thing I didn't mention that I would like to mention is that we're not only translating and communicating to people how understanding adhesion is going to be important for human health and inflammatory skin disorders. But we actually are also working with patients and patient's families. So one of the disorders we're studying is something called Darier disease. And this disorder is not caused by mutations in desmosome molecules, but it's caused by mutations in something that affects intracellular calcium regulation. And calcium is important for desmosomes. So these mutations in these patients lead to defects in desmosome assembly. And we're so fortunate because there's a family whose daughter has this disorder who is supporting us to do work to help cure her, essentially. So we're screening drugs that will help ameliorate these calcium deficiencies and help make desmosomes better. And so that's another thing that I've been able to do as a fundamental cell biologist, work with families who have these disorders and really have direct contact with them and see how we're making their lives better.
Erin Spain, MS [00:21:14] Well, Dr. Kathleen Green, thank you for sharing that. It's fascinating to know that you are working one-on-one with patients and their families as well. We're very excited to hear about these new findings in your lab. And we look forward to this whole new world that you've opened up here for your lab to study.
Kathleen Green, PhD [00:21:29] This has been really fantastic and I really appreciate the opportunity to talk about the work in our lab. And again, I would just like to make a shout out to people in the lab because it's through their hard work and creativity and teamwork that gets this all done. So I thank them and all the people who previously worked in my lab as well.
Erin Spain, MS [00:21:49] Well, thank you so much for coming on the show today.
Kathleen Green, PhD [00:21:52] Thank you, Erin.
Erin Spain, MS [00:22:00] And thanks for listening. And be sure to subscribe to this show on Apple Podcasts or wherever you listen to podcasts and rate and review us. Also, for medical professionals, this episode of Breakthroughs is available for CME Credit. Go to our website: Feinberg.Northwestern.edu and search CME.