Tau Structures: From Proteopathic to Protective
This project will expand our understanding of Alzheimer’s disease by delineating the structural assemblies that are available to tau, another amyloid protein that, along with amyloid beta, is associated with AD. Toxic forms of the protein will be identified and used as a template enabling the design of peptide agents that block the assembly of these structures. Natural variations in tau that protect against the formation of toxic assemblies will be studied to uncover new possibilities for therapeutic intervention, and to gain insights into the mechanisms by which amyloid fibers form, propagate, and exert toxicity.
Tau protein helps to stabilize the internal structure of neurons in ways that are important for neuronal function. However, the conversion of tau from a normal structural state into pathological assemblies is associated with Alzheimer’s disease (AD). Pathological tau structures include amyloid fibers, and a smaller species of tau, called an oligomer, which is thought to promote the spread of pathological tau assemblies throughout the brain. The overarching aim of my research is to develop methods and agents that block the formation and spread of toxic tau conformations. Using the atomic structures of the tau amyloid fiber core determined by myself and members of our lab using a new technique called micro-electron diffraction I am designing inhibitors to target the tau amyloid structure. Furthermore I am working to use an analogous approach to solve the structure of the tau oligomer. I am also pursuing an orthogonal inhibitor design strategy, which consists of studying protective mutations I've identified that are capable of suppressing tau assembly into toxic conformations. Using this approach, I hope to discover additional classes of evolutionarily-inspired tau inhibitors that will complement my structure-based design efforts.
About the Researcher
Paul Seidler, PhD, is a research scientist at UCLA in the Molecular Biology Institute, working as a senior-level postdoctoral fellow in the laboratory of Dr. David Eisenberg, a leader in structural biology of amyloid-related diseases. Paul earned his bachelor's and master's degrees from Buffalo State College where he studied chemistry and biology and worked as a teaching assistant in the Chemistry Department. There, he discovered a passion for basic research, and an appreciation for mechanistic and structural biology. Paul earned a PhD in structural biology from the University at Buffalo at the Hauptman-Woodward Institute. There he studied molecular chaperones, a special type of protein that helps other proteins in the cell "fold" into active shapes. At UCLA Paul continues research in this realm, seeking to correct protein misfolding that leads to toxic effects in Alzheimer's disease (AD). Paul determined several atomic resolution structures of a protein called tau, whose misfolding is thought to contribute to progressive neurodegeneration in AD. Guided by these structures, Paul has designed therapeutic molecules that will target and neutralize misfolded tau assemblies. Much of Paul’s current focus is on developing the candidate drug molecules he designed for therapeutic use in humans.
As an individual whose family, like many others, has seen the effects of Alzheimer's, I desperately hope for viable treatments options. As a research scientist, I am fascinated by the biological circumstances that lead to Alzheimer's disease (AD); in fact many of the areas of science that continue to drive me culminate in the molecular events that lead to this disease. Thanks to dedicated scientists who have worked for over a decade to understand the molecular basis of AD, I am fortunate to be nearing the cusp of what I believe will be a medical revolution, one in which an arsenal of therapeutic agents will soon emerge. BrightFocus Foundation has funded, and continues to fund, many of these scientists who were key in making these discoveries. With its support, I am excited to be in a position where I can now design and test strategies and agents to combat this disease.
First published on: August 1, 2016
Last modified on: June 30, 2019