Penn Medicine researchers will advance their understanding of the underlying causes of cognitive decline in individuals with Lewy body diseases, such as Parkinson’s disease, and identify biomarkers that predict which individuals are more likely to develop dementia with a grant from $18 million from the National Institutes of Health/National Institute on Aging. The goal of this comprehensive program is to understand the factors that determine who develops dementia, and how quickly, in order to develop therapies that can slow the progression of the disease.
Nearly one million Americans currently suffer from Parkinson’s disease (PD), and an estimated 1.4 million people have Parkinson’s disease or dementia with Lewy bodies. Both are caused by the buildup of an abnormal protein in the brain called α-synuclein (αSyn). The buildup of αSyn forms clumps called Lewy bodies, leading to problems with movement and cognition. Although these diseases have a common underlying cause, individuals express symptoms in different ways. Some people experience cognitive decline, such as impaired memory and judgment, early in their diagnosis, others develop it a few years later, and some never do. Similarly, some people struggle early on with motor functions, such as walking or swallowing, while others develop these symptoms years after diagnosis. There are currently no FDA-approved treatments available that slow the progression of these diseases.
“Regardless of timing, these symptoms appear to share some underlying processes. We hope that the differences in individuals’ diseases can elucidate the cause of neurodegeneration and help us develop therapies that delay the onset of cognitive decline,” says Alice Chen- Plotkin, MD, Parker Family Professor of Neurology, director of the Molecular Integration in Neurological Diagnosis (MIND) Initiative, and executive director of this newly funded program. “Ideally, instead of Parkinson’s being a disease that can ultimately disrupt all aspects of an individual’s life, we could slow its progression so much that it would only be a minor inconvenience.”
Viewing Lewy body diseases through four different lenses
The grant supports four different projects within the Perelman School of Medicine and emphasizes collaboration across disciplines. Edward Lee, MD, PhD, co-director of Penn’s Institute on Aging and leader of the Penn Medicine Brain Bank, and Sharon staff.
David Irwin, MD, associate professor of Neurology, will lead a project examining how αSyn buildup interacts with b-amyloid plaques (amyloid) and tau neurofibrillary tangles (tau), which cause other neurodegenerative diseases, most notably Alzheimer’s. His goal is to understand how the interplay between these elements affects the loss of cognition.
Virginia M.-Y. Lee, PhD, MBA, John H. Ware, Third Endowed Professor in Alzheimer’s Research in the Department of Pathology and Laboratory Medicine, will investigate how the misfolding and clumping of αSyn affects the way it spreads through the brain. She hypothesizes that the way the αSyn folds and clumps affects the speed at which it spreads in an individual’s brain.
Lee first discovered the role of αSyn, as well as amyloid and tau in neurodegenerative diseases, along with her late partner, John Q. Trojanowski, a professor of Geriatric Medicine and Gerontology in Pathology and Laboratory Medicine.
Chen-Plotkin will oversee one of two projects examining how different genetic factors in individuals influence the distribution of αSyn. Chen-Plotkin’s project is based on previous research that identified a genetic marker for Parkinson’s. She will use Brain Bank tissue collected from thousands of individuals with neurodegenerative diseases to search for additional genetic markers that correlate with the development of various Lewy body diseases and then model these genetic changes in neurons.
For the second project, Kelvin C. Luk, PhD, associate professor of Pathology and Laboratory Medicine, will model these genetic variations in mice and determine whether gene editing techniques can regulate the spread of αSyn and potentially slow its progression. neurodegenerative diseases.
The team will validate their findings by identifying patients in the clinic who have a specific biomarker and monitoring their progress over time in a clinical cohort led by Daniel Weintraub, MD, professor of psychiatry. That is, if the researchers believe that a genetic marker is associated with early loss of motor function but with late cognitive decline, they would identify patients with that marker through genetic testing, and track their disease over time follow to see if this is indeed the case. experience the symptoms they hypothesized.
While these projects have a specific focus, the multi-project nature of the program allows us to work together to learn how these different systems work together to cause individual manifestations of disease. We hope that the constant feedback from employees will accelerate our research and help us translate our findings into real therapies that improve the lives of individuals and their families.”
Alice Chen-Plotkin, MD, Parker Family Professor of Neurology, Director of the Molecular Integration in Neurological Diagnosis (MIND) Initiative
This project is supported by a grant from the NIH/NIA (P01 AG084497).
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