Kathleen Maguire-Zeiss: Discovering Shared Insights into Common Brain Disorders
Quick quiz: Which neurodegenerative brain disease has, as its hallmarks, inflammation, oxidative stress, and abnormal clumps of misfolded protein: (a) Alzheimer’s disease (b) Parkinson’s disease (c) traumatic brain injury?
Answer: a, b, and c.
Which is why Kathleen Maguire-Zeiss, PhD, was delighted to come to Georgetown University Medical Center in 2007. “I feel at home here,” she says. “I work with a community of scientists in the Department of Neuroscience who are all doing research on brain disorders that have a lot in common.”
Maguire-Zeiss and her fellow neuroscientists share insights and collaborate in research together and with graduate students. “There is a real sense of energy here, a vital and infectious hub of activity designed to understand these disorders,” she says. “We believe that what we discover in one of them will have relevance to the others.”
Maguire-Zeiss’s slice of the research pie is her work on the misfolded proteins that clog certain parts of the brain in people with Parkinson’s disease, an expertise she brought with her from the University of Rochester. The protein, known as alpha (α)-synuclein, is the main ingredient in the so-called Lewy bodies found in sporadic, or common, Parkinson’s disease patients, as well as in the rarer inherited forms of the disease. By the time a patient is diagnosed, between 50-70 percent of dopamine neurons have died in a part of the brain known as the substantia nigra, and the Lewy bodies are found in the few remaining neurons there. They are the hallmark pathological feature of the disease.
Still, α-synuclein is deeply mysterious to all who study it because its “normal” function in the brain and elsewhere in the central nervous system is unclear. That is also the case for amyloid, the primary protein ingredient in the plaque found in brains of Alzheimer’s disease patients. Interestingly enough, Maguire-Zeiss says, some α-synuclein is also found in amyloid plaques. Together, these two diseases affect up to 6 million Americans, and more diagnoses are expected due to the aging population of Baby Boomers. To date, no curative treatments exist.
But even though the “healthy” role of α-synuclein remains unknown, Maguire-Zeiss is making inroads into what happens when α-synuclein goes awry. It is now known that the protein has the ability to rapidly change its chemical shape (misfold), producing toxic effects, and it is believed that some environmental agents, such as pesticides, herbicides, and industrial chemicals, can push the protein to morph its conformation. Maguire-Zeiss’ is beginning to solve the next piece of the puzzle – what those misfolded proteins do to a nerve cell, like in the substantia nigra of Parkinson’s disease patients. It is there that dopamine neurons are concentrated, and where they are rapidly and repeatedly activated, compared to other neurons around the body, so they are the most affected, Maguire-Zeiss says.
She, and her laboratory, found that overexpression of misfolded α-synuclein produces oxidative stress on neurons and forces pores to form on the cell membrane that are not supposed to be there, which causes the cells to become leaky. “We think that these pores allow ions to come in and that is why the cells die,” Maguire-Zeiss says. She and her research team then used a commercially available antibody to block this effect. “You can watch the leakiness stop when you puff the antibody on top of a damaged cell,” she says. “It seems as though the antibody blocks the pore.” Her laboratory has been working with Howard Federoff, MD, PhD, Executive Vice President for Health Sciences, and colleagues at the University of Rochester on a method to stop pore formation. They identified antibodies that recognize specific forms of misfolded α-synuclein.
Maguire-Zeiss is now testing the antibodies as therapy in animal models of Parkinson’s disease. She has also shown that inflammation is involved early in the disease process, suggesting that anti-inflammatory agents could represent another important therapeutic avenue.
“We think a cycle of inflammation, oxidative stress, and α-synuclein misfolding feeds on each other to create Parkinson’s disease, given genetic and/or environmental triggers,” Maguire-Zeiss says. “When we figure these things out, the biggest hurdle to treatment will be early diagnosis – preventing the disease before it begins in individuals at risk.”
“And – that is where collaboration with my fellow neuroscientists comes in,” Maguire-Zeiss says with a smile.
By Renee Twombly, GUMC Communications
