A new center established at Washington University School of Medicine in St. Louis aims to accelerate research into biomarkers of neurodegenerative conditions such as Huntington’s and Parkinson’s diseases, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and the so-called tauopathies, a group that includes Alzheimer’s disease along with rarer diseases such as frontotemporal dementia, corticobasal syndrome and progressive supranuclear palsy. The Tracy Family Stable Isotope Labeling Quantitation Center for Neurodegenerative Biology (Tracy Family SILQ Center) helps researchers discover, study and validate biomarkers of such diseases, with a goal of identifying new drug targets and creating better diagnostic and prognostic tests.
Many neurodegenerative diseases are characterized by the gradual accumulation of toxic clumps of certain proteins in the brain. The specific protein involved varies by disease — for example, amyloid beta is integral to Alzheimer’s disease, alpha-synuclein to Parkinson’s — but what stays the same is an unhealthy tendency of the protein to aggregate, often due to faulty regulation or a malformed shape. By attaching a label to key proteins in the brain, researchers can track their production and clearance, and identify the factors that influence turnover. Further, by using labeled proteins in samples from other parts of the body such as cerebrospinal fluid or blood, researchers can also make highly precise measurements of proteins associated with disease and track how they change over time and under specific conditions. Such data can lead to crucial insights into how each disease develops and open up new avenues to diagnosing, preventing or treating it.
“Neurodegenerative diseases are terrible diseases that currently have limited treatment options,” said Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology and the center’s director. “Using labeled proteins is a powerful way of accelerating discovery for such diseases. Many different investigators are interested in using a labeled-protein approach to studying Parkinson’s, ALS, MS, frontotemporal dementia and more. But using this approach is not trivial as it requires considerable resources in terms of specialized equipment and expertise. Based on our success in Alzheimer’s disease, we established this center to help develop this approach across different disease areas and accelerate progress toward better diagnostics and therapeutics.”
The Tracy Family SILQ Center contains seven cutting-edge mass spectrometers and several robotics units. The center’s faculty includes Nicolas Barthélemy, PhD, an assistant professor of neurology, and Kanta Horie, PhD, a voluntary research associate professor of neurology. Barthélemy and Horie have extensive experience developing biomarkers for Alzheimer’s disease. Barthélemy is developing a blood-based diagnostic test for Alzheimer’s disease based on a form of the protein tau, while Horie has shown that a different form of tau in the spinal fluid can indicate the stage of disease. Recruitment for additional faculty and staff members is underway.
The center builds on a technique known as SILK (for stable isotope labeling kinetics) developed in 2006 by Bateman in the lab of David Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology. Using the technique, Bateman showed that production and clearance of amyloid beta is altered in the brains of people with Alzheimer’s disease decades before their memory and thinking begins to change. This finding became one of the key pieces of evidence that Alzheimer’s dementia occurs at the tail end of a largely invisible disease process in which years of unbalanced protein kinetics gradually add up to neurological damage and cognitive decline.
SILK has since been extended to other proteins and other diseases. Bateman and other School of Medicine researchers are taking part in two SILK research collaborations, one aimed at tau protein, which has been linked to cognitive decline in Alzheimer’s and other tauopathies; and the other focused on neurofilament light protein, which increases in diseases such as Alzheimer’s, Parkinson’s, Huntington’s and ALS.
The original SILK technique also has been expanded to measure other aspects of protein behavior beyond kinetics, which is why the word “quantitation” is used in the center’s name instead of “kinetics.” For example, SILQ has enabled the first, and currently best, way to estimate plaques of the Alzheimer’s associated protein amyloid in the brain by measuring the ratio of two forms of amyloid in the blood. This technique forms the basis of a blood test that is now offered in the clinic to doctors and patients.
School of Medicine researchers who join the center gain access to its resources and funding, and the option to propose research projects and collaborate with center faculty. The center currently is on the ninth floor of the Steven & Susan Lipstein BJC Institute of Health building, but it will move to a larger space in the Neuroscience Research Building when it opens in 2023. The center is supported by $10 million in gifts and grants from the Tracy Family, Richard Frimel and Gary Werths, GHR Foundation, David Payne, the Willman Family and other generous donors brought together by The Foundation for Barnes-Jewish Hospital.