Blocking Assembly of Tau Protein into Toxic Structures Associated with Alzheimer's Disease

Paul Seidler, PhD
University of California, Los Angeles (Los Angeles, CA)

Mentors

David Eisenberg, PhD
University of California, Los Angeles
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2019
Disease:
Alzheimer's Disease
Award Amount:
$94,536
Grant Reference ID:
A2016588F
Award Type:
Postdoctoral Fellowship
Award Region:
US Southwestern

This grant is made possible in part by support from Alzheimer’s Los Angeles.

Paul Seidler, PhD

Tau Structures: From Proteopathic to Protective

Summary

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.

Details

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 postdoctoral research fellow at UCLA in the Molecular Biology Institute, working 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, studying chemistry and biology, and working as a teaching assistant in the Chemistry Department. There, he had several terrific mentors and teachers who were instrumental in helping him to discover his passion for basic research, and his appreciation for the structure-based understanding of human biology. Motivated by these passions, he pursued a PhD in structural biology from the University at Buffalo under the supervision of Dr. Daniel Gewirth at the Hauptman-Woodward Institute. For his dissertation research, Paul studied a special type of protein called a chaperone, which helps other proteins in the cell "fold" into specific structural assemblies, ie, a requirement for proper biological function. Paul carried out research to further understand the detailed biochemical and atomic-level mechanisms by which chaperones act, and learned about structure-based drug discovery. After graduate school, Paul continued this fundamental research trajectory, seeking to understand how protein misfolding leads to the formation of toxic structural assemblies that are found in Alzheimer's disease (AD). Paul now works with other pioneering researchers in Dr. David Eisenberg's lab to investigate atomic resolution structures of these toxic assemblies, and is using these structures to design and discover therapeutic molecules that will target and neutralize toxic assemblies that are characteristically found in AD.

Personal Story

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.

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