Unfolding the Mystery of Misfolded Proteins: Dr. Kathy Maguire-Zeiss’s Research on Neurodegeneration
- Naama Ben-Dor
- 1 day ago
- 7 min read
From her unexpected start in biochemistry to leading Georgetown’s Department of Neuroscience, Dr. Kathy Maguire-Zeiss discusses her research on misfolded proteins, neurodegenerative diseases, and the future of the field.
A Journey of Scientific Discovery
Dr. Kathy Maguire-Zeiss is a professor and Chair of the Department of Neuroscience at the Georgetown University School of Medicine. Her laboratory, which focuses on the molecular mechanisms underlying neurodegeneration, has investigated a range of questions important for better understanding conditions like Parkinson’s Disease. Beyond her notable research discoveries, Dr. Maguire-Zeiss has been recognized for her exceptional leadership as a mentor and educator, which has earned her Georgetown University’s “President's Distinguished Scholar-Teacher Award” in 2024, as well as Georgetown Women in Medicine’s “Karen Gale Outstanding Achievement Award” in 2023.
Dr. Maguire-Zeiss exemplifies a scientific career built on curiosity, collaboration, and value-based leadership. In this interview, she shares the journey leading her to the brain and discusses research, as well as her outlook on the future of science research.
Neurodegeneration
With the rapid technological advances that have shaped recent decades, the medical field has achieved immense progress. Thanks to improved public health measures and breakthrough treatment innovations, mortality rates for many leading causes of death have been in steady decline. The American Heart Association reported that between 1970 and 2022, heart disease mortality rates dropped 66%. Cancer mortality rates have similarly shown a dramatic 34% decrease, according to the American Cancer Society. These worldwide trends are enabling humans to achieve longer lifespans—an undeniably exciting triumph. As the global population ages, however, a new culprit is emerging: neurodegenerative diseases. Unlike the majority of the body’s cells, neurons are generally unable to divide and regenerate, and are thus vulnerable to various conditions that result from the accumulated wear-and-tear of daily life. Alzheimer’s disease, reported as the sixth leading cause of death worldwide in 2021, has increased in prevalence by approximately 168.7% since 1990. Parkinson’s disease, the second most common neurodegenerative disorder, has increased by 220.07% over that same timeframe. As conditions like these afflict higher percentages of the population, the need to research them is becoming increasingly pressing.
Although the causes for most neurodegenerative diseases are not entirely understood, many of them share common features. One notably distinctive feature, observed in several disorders such Alzheimer’s disease, Parkinson’s disease, Lewy Body Dementia, and Huntington’s disease—to name a few—is the presence of pathological misfolded proteins. While the underlying causes of these disorders differ among them, along with the major protein involved with each, it is widely accepted that misfolded molecules play an important role in their pathology. What that role is, however, is not as clear. As neurodegenerative diseases approach the forefront of concerns for our aging society, it is becoming increasingly crucial to identify, characterize, and study the effects of misfolded proteins in such conditions. Researchers like Dr. Kathy Maguire-Zeiss are leading such efforts and paving the way for important progress in the field of neurodegeneration.
Her Unconventional Journey to the Brain
To understand how researchers are combating these rising numbers, we look to the work of Dr. Kathy Maguire-Zeiss, whose own path to the brain was anything but traditional. Although she now chairs Georgetown’s Department of Neuroscience, Dr. Maguire-Zeiss has never formally studied neurobiology. In fact, the road leading her to scientific research was, in many ways, serendipitous. After receiving an acceptance from Albright College— the only school she applied to— Dr. Maguire-Zeiss discussed her options for areas of study with the faculty.
“My dad and I had done science fairs in grade school, and it seemed like science was kind of cool… So when they asked me ‘Do you like biology and chemistry?’ and I was like ‘Yeah,’ [they] said, ‘Well, biochemistry seems right for you.’ ‘So that’s how I ended up in biochem.’”
Through her summer job as a pharmacy technician, she became interested in human disease, prompting her friend— and future husband— to advise her to pursue a related subject. Heeding his suggestion, she completed a Ph.D. in Pharmacology, researching RNA stability in a cancer lab at the Pennsylvania State University College of Medicine. During her subsequent position as a postdoctoral fellow at the University of Pennsylvania— a leader in Alzheimer’s research at the time— she discovered a deep interest in neuroscience.
“I'm a biochemist, so I was always interested in misfolded proteins—and they kept appearing in these neurodegenerative disorders… And it was just a fascinating thing to try to understand what was going on in the brain.“
After completing her postdoctoral training, Dr. Maguire-Zeiss began a research-track position at the University of Rochester, working for Dr. Bob Hamill, who she described as her “greatest mentor.” While she helped to run Dr. Hamill’s lab, which was treating Parkinson’s and Alzheimer’s patients at the time, he gave her “free rein” to study anything else that interested her.
Pivot to Neurodegeneration
At the University of Rochester, where she worked for over a decade, Dr. Maguire-Zeiss began studying various aspects of neurodegeneration. In some of her early work, for example, she applied her postdoc experiences utilizing an adenovirus model—in which harmless viruses are used to deliver new genes to cells—to explore potential new gene therapy mechanisms for neurological conditions. Concurrently, she began studying the role of various proteins in neurodegenerative disorders— a focus that has characterized her research ever since, and which she continues to explore in her current work at Georgetown University.
Parkinson’s & α-synuclein
One of the proteins that has been especially central to her work, α-synuclein, is known to form misfolded aggregates in the brain called “Lewy Bodies.” These structures have been closely associated with various neurodegenerative disorders, such as Parkinson’s Disease. As Dr. Maguire-Zeiss began exploring the role of misfolded proteins in neurodegenerative disorders, she became interested in the molecular effects of misfolded α-synuclein. Together with her colleagues, she demonstrated that these aggregates are not merely an inert feature of the disease, but that they increase oxidative stress in neurons and influence their membrane conductance. Going further to explore the role of α-synuclein in promoting neuroinflammation, her lab showed that α-synuclein can directly interact with microglia, the main immune cell of the brain, causing them to adopt a pro-inflammatory phenotype that may exacerbate disease pathology.
Asked which of her discoveries was most significant to her, Dr. Maguire-Zeiss highlighted a research project spearheaded by an undergraduate student in her lab that investigated the molecular mechanism by which α-synuclein activates microglia. In their experiments, they demonstrated that misfolded α-synuclein binds to two specific receptors (TLR1 and TLR2) on the surface of microglia, the brain’s primary immune cell, and causes them to pair up, or ‘dimerize.’ This binding triggers a pro-inflammatory cascade that prompts the microglia to release neurotoxic molecules.
This finding not only elucidated an important molecular pathway through which α-synuclein exerts pathological effects, but also highlights a potential therapeutic target for Parkinson’s Disease. Beyond the exciting applications that these findings could inspire, Dr. Maguire-Zeiss was especially fulfilled by the opportunity it gave her student to launch his research career.
“It wasn’t because of me, but this helped him along the way… So for me, it feels like a significant paper in that way. And he went on to be a Forbes ‘30 Under 30’ guy—like an amazing, amazing person. So, I think that paper’s really important.”
HAND & Tat
In parallel to their work on Parkinson's disease, the Maguire-Zeiss lab has also made important contributions to understanding the mechanisms of HIV-Associated Neurocognitive Disorders (HAND), through a partnership with Dr. Katherine E. Conant at Georgetown. Despite modern advancements in HIV treatment, which have significantly improved long-term health outcomes in recent decades, almost half of all individuals with HIV experience a range of cognitive impairments known as HAND. These symptoms, ranging from memory and attention deficits, to learning and executive function difficulties, resemble features of conditions like Alzheimer’s and Parkinson’s Disease— which are similarly associated with neuroinflammation, . Due to findings demonstrating the neuroinflammatory properties of Tat, a toxic protein released by HIV-infected cells, Dr. Conant and Dr. Maguire-Zeiss sought to explore its effects on the brain.
In a paper published in 2016, they shared new insights on Tat, revealing a mechanism by which it may promote neuroinflammation in patients with HIV. By stimulating a population of brain cells called astrocytes to increase expression of matrix metalloproteinases (MMPs), a group of enzymes that may activate inflammation pathways, their experiments uncover a signaling cascade triggered by Tat, with potentially impactful therapeutic application. In a later study that further examined the effects of Tat-stimulated increases in MMP expression, they showed that these enzymes can disrupt neuronal signaling in the hippocampus by breaking down 'perineuronal nets'—scaffolding structures critical for maintaining healthy brain circuitry. Similar to the research philosophy characterizing much of her other research, Dr. Maguire-Zeiss noted that this work, too, was strongly propelled by a student in her laboratory.
“Mostly it drives from students’ interests. Students come and they're interested in something, and, at this point in my career it's really great because I can say, 'okay, let's give that a try.'”
Leadership & The Future of Scientific Collaboration
Dr. Maguire-Zeiss’s genuine care for the success and wellbeing of her students has had a significant and perceptible impact beyond the lab, as well. In 2024, she was chosen to receive the “President’s Award for Distinguished Scholar-Teachers” at Georgetown University— an honor awarded to only a few faculty members each year, who demonstrate exceptional commitment to both scholarly research and excellent teaching. Beyond teaching both undergraduates and medical students in neurobiology-related subjects, and chairing the Department of Neuroscience at the Georgetown University School of Medicine, she has also served as a resident minister on campus in undergraduate housing. Her commitment to embodying Georgetown’s Jesuit values, such as collaboration and “People for Others,” has shaped her holistic attitude both to teaching and to research.
“We are a research-intensive, student-oriented university. That's our mission. So we need to work in a way that promotes that mission, right?... All of that is considered when you're deciding where you’re going to go with your research. You need to ask ‘Who am I? Who can I include in my research to make it better? Will it help the patient?’”
The Next Frontier
Looking towards the future of neurodegeneration research, Dr. Maguire-Zeiss notes that the origin of sporadic disorders remains to be better elucidated and understood. When asked about her own future research directions, however, she hopes to prioritize her students’ interests and support their initiatives.
For readers of The Catalyst considering a future in research, Dr. Maguire-Zeiss stresses the importance of passion-driven work:
“We need people who really are interested in discovering new things in the area they're in… Because you have to get up every day, and go in and do your experiments, even when they don't work— which happens more times than when they do. If you don't really love what you're doing, it's hard to get in there and do the work.”
Ultimately, Dr. Maguire-Zeiss’s career is a testament to that very mindset. From her early beginnings in biochemistry to her transition into neuroscience and leadership positions as an educator and mentor, her journey demonstrates that genuine curiosity, coupled with a value-based approach, is fundamental to building a meaningful and fulfilling career.
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