What can protein shape tell us about Alzheimer’s disease?

John Yates, John Lytton Young Professor in the Department of Integrative Structural and Computational Biology at The Scripps Research Institute, discusses this question.

Faculty Bio:

John R. Yates III is the John Lytton Young Professor in the Department of Integrative Structural and Computational Biology at The Scripps Research Institute. He received a B.A in Zoology and an M.S. in Chemistry from the University of Maine at Orono. He obtained his Ph.D. in Chemistry at the University of Virginia in the laboratory of Donald F. Hunt with a dissertation entitled Protein Sequencing by Tandem Mass Spectrometry. He performed postdoctoral research in the laboratory of Leroy E. Hood at California Institute of Technology. At the University of Washington, he obtained the rank of Associate Professor with tenure before moving to The Scripps Research Institute in LaJolla, CA. His research interests include development of integrated methods for tandem mass spectrometry analysis of protein mixtures, bioinformatics using mass spectrometry data, and biological studies involving proteomics. He is the lead inventor of the SEQUEST software for correlating tandem mass spectrometry data to sequences in the database and developer of the shotgun proteomics technique for the analysis of protein mixtures. His laboratory has developed the use of proteomic techniques to analyze protein complexes, posttranslational modifications, organelles and quantitative analysis of protein expression for the discovery of new biology. He has received numerous awards such as the American Society for Mass Spectrometry (ASMS) research award, the Pehr Edman Award in Protein Chemistry, the ASMS Biemann Medal, the HUPO Distinguished Achievement Award in Proteomics, Herbert Sober Award from the ASBMB, and the Christian Anfinsen Award from The Protein Society, the 2015 ACS’s Analytical Chemistry award, 2015 The Ralph N. Adams Award in Bioanalytical Chemistry, the 2018 Thomson Medal from the International Mass Spectrometry Society, the 2019 John B. Fenn Distinguished Contribution to Mass Spectrometry award from the ASMS, the 2019 HUPO Award in Discovery, and the 2024 Pittsburgh Society Award in Analytical Chemistry. Dr. Yates served as an Associate Editor at Analytical Chemistry for 15 years and is currently the Editor in Chief at the Journal of Proteome Research.

Transcript:

Alzheimer’s disease is one of the most challenging medical problems today. By the time symptoms such as memory loss appear, damage in the brain has often been developing for years. That makes early detection one of the most important goals in Alzheimer’s research.A key feature of the disease is protein misfolding. Proteins are the molecular machines that carry out most of the work in our cells. For them to function properly, they must fold into precise three-dimensional shapes. In Alzheimer’s disease, some proteins lose their correct shape—a problem called proteostasis dysregulation.Our research asked a simple question: Could these structural changes in proteins be detected in the blood? If so, might they serve as early warning signs of Alzheimer’s disease?To investigate this, we analyzed blood plasma samples from more than 500 individuals, including healthy volunteers, people with mild cognitive impairment, and patients diagnosed with Alzheimer’s disease. Using mass spectrometry, we measured thousands of proteins at once and examined subtle structural changes in proteins circulating in the bloodstream.We then applied machine learning to identify patterns in these protein structures associated with Alzheimer’s disease. From this analysis, we discovered a small group of proteins whose structural changes appear to signal disease progression.In particular, peptides derived from three proteins—C1QA, clusterin, and apolipoprotein B—formed a diagnostic panel capable of distinguishing healthy individuals, people with early cognitive impairment, and those with Alzheimer’s disease with more than 80% accuracy.This work suggests that structural changes in proteins circulating in the blood may serve as conformational biomarkers for Alzheimer’s disease. Such tests could eventually help doctors detect the disease earlier, monitor its progression, and identify patients who may benefit most from emerging therapies.Detecting Alzheimer’s earlier could mean treating it earlier—and improving outcomes for millions of people worldwide.

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John Yates, Scripps Research Institute - Detecting Alzheimer’s Disease Through Changes in Protein Shape

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John Yates, Scripps Research Institute - Detecting Alzheimer’s Disease Through Changes in Protein Shape