Newswise – LA JOLLA, CA. – September 6, 2022 Research led by Francesca Marassi, Ph.D., professor at Sanford Burnham Prebys, helps reveal the molecular secrets of macular degeneration, which causes nearly 90% of all age-related vision loss . The study, recently published in the Biophysical Journaldescribes the flexible structure of a key blood protein implicated in macular degeneration and other age-related diseases, such as Alzheimer’s disease and atherosclerosis.
“Proteins in the blood are under constant and changing pressure due to the different ways blood flows through the body,” says Marassi. “For example, blood flows more slowly through the small blood vessels in the eyes than through the larger arteries around the heart. Blood proteins must be able to respond to these changes, and this study gives us fundamental truths about how they adapt to their environment, which is essential for targeting these proteins for future treatments.
There are hundreds of proteins in our blood, but the researchers focused on vitronectin, one of the most abundant. In addition to circulating in high concentrations in the blood, vitronectin is found in the scaffolding between cells and is also an important component of cholesterol.
Vitronectin is a key player in many age-related diseases, but for Marassi’s team, the most promising target is macular degeneration, which affects up to 11 million people in the United States. This number is expected to double by 2050.
“This protein is an important target for macular degeneration because it accumulates in the back of the eye, causing vision loss. Similar deposits appear in the brain in Alzheimer’s disease and in the arteries in atherosclerosis,” says Marassi. “We want to understand why this happens and use this knowledge to develop new treatments.”
To address this question, the researchers were interested in how the protein changes its structure at different temperatures and under different levels of pressure, approximating what happens in the human body.
“Determining the structure of a protein is the most important part of determining its function,” adds Marassi. Through detailed biochemical analysis, the researchers discovered that the protein can subtly change shape under pressure. These changes cause it to bind more readily to calcium ions in the blood, which researchers say leads to the buildup of calcified plaque deposits characteristic of macular degeneration and other age-related diseases.
“It’s a very subtle rearrangement of the molecular structure, but it has a big impact on how the protein works,” says Marassi. “The more we learn about the protein at the structural and mechanistic level, the more likely we are to successfully target it with treatments.”
This structural knowledge will streamline the development of treatments for macular degeneration, as it will allow researchers and their partners in the biotech industry to design custom antibodies that selectively block the protein’s calcium binding without disrupting its other important functions in the brain. ‘organization.
“It will take some time to convert it into a clinical treatment, but we hope to have a working antibody as a potential treatment in a few years,” says Marassi. “And since this protein is so abundant in the blood, there may be other exciting applications for this new knowledge that we don’t even know about yet.”
Other study authors include Ye Tian, Ph.D., Kyungsoo Shin, Ph.D., Alexander E. Aleshin, Ph.D., Sanford Burnham Prebys Medical Discovery Institute, and Wonpil Im, Lehigh University.
This study was supported by grants from the National Institutes of Health (GM 118186, CA030199), the National Science Foundation (MCB1810695), and the Canadian Institutes of Health Research (201711MFE-395794-210656), and a postdoctoral fellowship from the Sanford Burnham Prebys Fishman Fund.
The DOI for the study is 10.1016/j.bpj.2022.08.044
About Sanford Burnham Prebys
Sanford Burnham Prebys is a leading independent biomedical research institute dedicated to understanding human biology and disease and advancing scientific discovery to have a profound impact on human health. For more than 45 years, our research has produced breakthroughs in cancer, neuroscience, immunology, and childhood disease, and is rooted in our NCI-designated Cancer Center and our advanced drug discovery. For more information, visit us at SBPdiscovery.org or on Facebook facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.