How Cell Function Can Shed Light on Neurodegeneration with Vladimir Gelfand, PhD

Erin Spain, MS: ALS is a devastating disease that currently has no cure, but new research from Northwestern Medicine has revealed a key mechanism underlying the development of motor neuron diseases such as ALS, offering new insights into potential treatment options. This new finding, published in the Journal of Neuroscience, comes from the lab of Vladimir Gelfand, the Leslie B. Arey Professor of Cell, Molecular, and Anatomical Sciences and of Cell and Developmental Biology here at Feinberg. He was the senior author of this study. We welcome him to the show today to talk about this research and other recent high impact research from his lab, which has a focus on the role of the cytoskeleton, the complex framework that gives cells their shape, movement, and internal order in diverse biological functions. Thanks for being here, Dr. Gelfand. 

Vladimir Gelfand, PhD: Thank you.   

Erin Spain, MS: Your lab focuses on the cytoskeleton. Can you give us an overview of your lab's research and how understanding this system helps explain both how healthy cells function and what goes wrong in cases like neurodegenerative diseases like ALS? 

Vladimir Gelfand, PhD: So essentially, we're working on the cytoskeleton and mostly on one component of the cytoskeleton that's called microtubules. And microtubules are a very important part of the cytoskeleton because they have multiple functions. They're important for cell division and also between cell divisions, they support trafficking of all intracellular organelles to all the parts of the cell. And obviously, it's the most important in neuronal cells because neuronal cells form very long processes. So you need to have roads that support that communication. Microtubules are exactly those roads. And there are special proteins that are called motor proteins that move along those roads, carrying a lot of components that are required for neurons to properly function. And that's why a lot of neurodegenerative diseases are caused by mutations either in cytoskeletal components or in motor proteins or something that regulates motor proteins. And that's our link to neurodegeneration. Most of our research, not all, but most of our research is done in fruit flies and drosophila. And you might ask why we need drosophila if we're interested in human disease. But the answer is very simple. A lot of components of the cytoskeleton are conserved between flies and humans. And research in flies is much faster than research in mammals, because to create a mutant mouse, you need a year. And then you study it, and it's very expensive. Doing the same kind of genetics in flies is much faster and much cheaper. And once we get something in flies, the next step would be, of course, to transfer that to the mammalian system. And we have plenty of colleagues here at Northwestern who can do it much better than they can. That's why we are mostly, not exclusively, but mostly focused on drosophila genetics. 

Erin Spain, MS: I will say, I have seen some stunning images out of your lab of the fruit flies. Tell me about the role that imaging plays in your research and how Northwestern is able to support this really advanced imaging to help you do this work. 

Vladimir Gelfand, PhD: That's really a great question, because imaging is a big part of what we do. We look at different cargos and look at components of the cytoskeleton. And we look at not only in fixed and stained cells, but we do live cell microscopy. It's pretty tricky, because when you do your fluorescent imaging, you can damage cells very easily by light that you use to image. So you need to have very sensitive equipment to do so. And we're very lucky to have a lot of advanced microscopy tools, both in our own lab and in the Northwestern imaging facility. And I am, in addition to running my own lab, I am the chair of the advisory committee for the imaging facility. So I help the director of the imaging, Gina, to work on getting the latest techniques. So in terms of imaging, I think our facility is one of the best in the country, and that contributes to our research and as well to the research of other people at Northwestern. 

Erin Spain, MS: This is basic science research leading to some really important discoveries, including this latest paper in the Journal of Neuroscience, which uncovers a key mechanism in neurodegenerative diseases such as ALS. So your team focused on a gene called Ataxin-2. And what does this gene normally do in healthy motor neurons? And tell me a little bit about what you discovered and what happens when it mutates. 

Vladimir Gelfand, PhD: Ataxin-2 is a very important regulator of transcription, of making RNA and making different proteins. The most common mutation of Ataxin-2 is addition of polyglutamate sequences at the end of the protein. And when there are too many polyglutamates, the protein started to aggregate and stop functioning normally. And what we discovered that those changes affect dynamics of microtubules very dramatically. So essentially, changes in Ataxin-2 affect the cytoskeleton. And that is what the last paper in Journal of Neuroscience is about. And we're now continuing this work trying to understand how the proteins affected by Ataxin affect microtubule dynamics and what's the mechanism for that. So we're continuing work not on Ataxin-2 directly, but on all the downstream proteins that are affected by Ataxin-2. One thing that I want to mention is that in addition to normal function of microtubules that work as tracks, we discovered in our own lab that microtubules themselves can move in the cell and movement of microtubules in the cell can lead to dramatic changes of cell shape. For example, initial stages of neuronal outgrowth are driven by microtubules pushing against the tip of the process. And that was discovered in our research in our work a few years ago. And that's a process that Ataxin-2 might change. So in addition to being simple passive tracks, microtubules themselves pretty actively affect cell shape.  

Erin Spain, MS: You showed in this nature physics study, cytoplasm, the fluid inside cells, isn't still but full of this sort of swirling vortex-like motion. Tell us about that and what does that mean now for how we think about how cells organize and move materials? 

Vladimir Gelfand, PhD: We have a whole series of papers, even early papers, that show for the first time that bulk movement of the cytoplasm is very often powered by movement of microtubules themselves. And it's especially well seen in big cells, because in big cells, a lot of movements are done by bulk movement of the cytoplasm. And we're studying, in addition to neurons, we're studying ovaries. And in Drosophila ovaries, it's a very interesting system. It's a cluster of 16 cells connected by bridges. One of those cells becomes an oocyte and the other 15 cells are feeding the oocyte with all the components.And bulk flow of the cytoplasm drives movement from nurse cells to the oocyte. And then inside the oocyte, it's like a washing machine. It drives the movement of the cytoplasm. So everything that enters the oocyte gets rotated in that washing machine. So we have a whole bunch of experimental papers showing that. And fairly recently, we started to collaborate with our colleagues at Flatiron Institute in New York City, who are physicists and who modeled what we observe in the microscope, doing theoretical papers. And nature physics paper is a part of that study. And we're continuing our collaboration. We have funding from Flatiron Institute to do that kind of research. 

Erin Spain, MS: Tell me about the importance of these types of collaborations across institutions to really bring the best minds together to look at this research from different angles. 

Vladimir Gelfand, PhD: That's a very important part of research. And what I love about academic research, we cannot have all the expertise and all the technology and everything we need in one lab. It's just not feasible. And our lab is actually pretty small. And I like it this way because I know who is doing what and then how. But that means that if we need something that we don't have currently in the lab, very often it's much easier to find a colleague who knows the technique and collaborate. And we have a whole bunch of collaborations in the Northwestern and outside the Northwestern. For example, we're not doing mouse work, but what attacks into mutations are doing in the fly. So the next obvious step would be to see if we have the same thing in the mammalian system. And we are collaborating with people at Northwestern who are studying Ataxin into here in the mouse system. And we probably are going to really move that from the fly work up the evolutionally changed to mammalian work. 

Erin Spain, MS: In another one of your recent studies published in the Journal of Cell Biology, your team discovered that vimentin filaments, once thought to be rigid and static, actually move along microtubules inside living cells. Why was this such a surprising discovery, and how does it change the way scientists think about the cytoskeleton? 

Vladimir Gelfand, PhD: So essentially what we discovered, and that was quite an unexpected discovery. For years and years, intermediate filaments have been considered by other people to be a stable cytoskeleton that is not dynamic at all. And in some cases, probably it is. But what we discovered is that in addition to being a stable component of the cell, vimentin filaments themselves are the cargo that moves along the microtubules. And we have some hints of that, because at the very beginning of my scientific career, when I still was in Russia, we injected the inhibitory antibody against one of the motor proteins into a cell. And we showed that the distribution of intermediate filaments changes dramatically. But now, with the addition of new imaging technologies, we can observe behavior of individual intermediate filaments in vivo. And I have to say, it's a very difficult task, simply because the diameter of intermediate filaments is less than what you can see in a microscope. So we have to attach some tags on intermediate filaments to observe it. And when we did that, in collaboration with Jennifer Lipitskov-Schwarz's lab at the Janeli Institute, we see that they move all the time, and it's quite unexpected. And we're now studying very extensively what's the mechanism of that movement. And it looks like there's some very interesting things coming here, which are probably very early to talk about, but my gut feeling is going to be something pretty major.   

Erin Spain, MS: What was the reaction from the community, the scientific community? This is the kind of thing that would rewrite a textbook, I would think.   

Vladimir Gelfand, PhD: Initially, nobody believes it, because scientific community is pretty conservative. Then there's a stage when people believe it, and then when it becomes a textbook thing. And I strongly suspect that a lot of research is going to be like that. 

Erin Spain, MS: How might all this new understanding influence the way that we approach diseases like ALS that affects the nervous system? 

Vladimir Gelfand, PhD: A lot of diseases affect intracellular transport, and especially a lot of neurodegenerative diseases, simply because neurons have very long processes, and they're more sensitive to those changes than any other cells. So in a normal cell, things can get where they need to get by diffusion. It takes more time, but they're not going to suffer too much. If you take a neuron, a human neuron can have a process that's more than one meter in length. And doing stuff by diffusion is totally impossible. So a lot of neurodegenerative diseases are diseases of cytoskeleton and motor proteins.And that's why I really think what we're doing is important for neurodegeneration.   

Erin Spain, MS: There are so many exciting things happening in your lab. Can you talk about what's next?   

Vladimir Gelfand, PhD: We have two main directions. One, we're trying to figure out how microtubule dynamics is regulated, and that was directly prompted by the research on Ataxin-2 that we're talking about, because we can see that microtubule dynamics is very strongly affected there, and we're trying to figure out what's a molecular mechanism. And second, about vimentin and intermediate filaments, we're trying to see how the dynamics of intermediate filaments that we discovered affects cell migration and cell shape changes. And that's pretty important because cell migration is important for embryonic development, and also cell migration is changed when the normal cells become cancerous cells, because cancerous cells can invade and can move abnormally, and it could be related to abnormal dynamics of intermediate filaments. So it's potentially disease-related, but when we do basic science, we are asking basic science questions. When it's done, then we start looking if it can be used for medical applications. 

Erin Spain, MS: What message would you like to leave about the research coming out of your lab and your hope for the future? 

Vladimir Gelfand, PhD: I don't know for how long I will be able to maintain my lab because I'm not really very young already, but I hope to be useful advising people, and I hope to be useful continuing doing research, maybe not as a PI, but as a member of somebody's lab. When I talk to students, I tell them that doing science is like an addiction. If you're addicted to it and you cannot live without it, then you should do it. If you're not, you shouldn't go there because you're going to incur so much pain for papers rejected, grants triaged, and all of that. And I know why we're doing it because we simply cannot stop. And if you have that kind of passion, you should go to science. If not, you shouldn't. 

Erin Spain, MS: Well, thank you so much for coming on the show and just explaining some of these recent publications that really show all these new discoveries coming out of your lab and underscores the importance of basic science research. So again, thank you for your time today. 

Vladimir Gelfand, PhD: Thank you so much. 

Erin Spain, MS: Thanks for listening. Please click the bell to receive notifications about our latest episodes and follow us on social media @NUFeinbergMed to stay up to date with our latest research findings. 

Physicians who listen to this podcast may claim continuing medical education credit after listening to an episode of this program.

Target Audience

Academic/Research, Multiple specialties

Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

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.

American Board of Surgery Continuous Certification Program

Successful completion of this CME activity enables the learner to earn credit toward the CME requirement(s) of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Disclosure Statement

Vladimir Gelfand, PhD, has nothing to disclose. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. FSM’s CME Leadership, Review Committee, and Staff have no relevant financial relationships with ineligible companies to disclose.

All the relevant financial relationships for these individuals have been mitigated.