Detecting the Shape Changing Protein Tau in Alzheimer’s Disease

Lukasz Joachimiak, PhD
The University of Texas Southwestern Medical Center (Dallas, TX)
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2022
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2019060S
Award Type:
Standard
Award Region:
US Southern
Lukasz Joachimiak, PhD

Structural Determinants of Tau Aggregation in Disease

Summary

The tau protein deposits in the brain of Alzheimer’s patients. The tau protein normally adopts a “good” shape and with age converts into a “bad” shape. We aim to understand how tau changes into the “bad” shape to help understand how to detect this in patients and develop therapies to prevent it.

Details

We aim to understand how tau changes into the pathogenic conformation to help detect these aberrant conformations in patients and develop therapies to prevent their accumulation.

We propose to study the fundamental events that drive changes in tau conformation to form an aggregation-prone conformation of tau monomer, as an understanding of this process could have profound implications to detect and modify disease.  To understand the structure and origins of aggregation-prone tau monomer we propose to determine what pattern of post-translational modifications, including phosphorylation, convert tau into this pathogenic conformation and use hybrid structural biology approaches to understand how these modifications in tau alter the structure to promote the formation of pathogenic conformations.

Our recent work indicates that tau monomer exists in two stable and separable conformational ensembles we have termed “inert” and “aggregation-prone” -- this concept is highly novel and provocative. The aggregation-prone form is uniquely capable of self-assembly and can act as a seed for larger assemblies in cells and in vitro. We can also create this species in vitro, or isolated from human or mouse brain. More recent work indicates that the aggregation-prone form occurs very early in disease in a mouse model, long before the fibrils associated with pathogenic form. These conclusions about tau conformational rearrangements coincident with initial pathogenesis of tauopathy have potentially profound implications.

A structural understanding of tau conformational ensembles will permit the discrimination between normal and pathogenic states. These insights will define the exposure of specific epitopes yielding clues for disease-specific biomarkers and greatly facilitate targeting pathogenic conformations of tau for clearance before larger aggregates can form.

About the Researcher

Dr. Joachimiak is an Assistant Professor in the Center for Alzheimer’s and Neurodegenerative Diseases at UT Southwestern Medical Center where he is a Marie Effie Cain Endowed Scholar in Medical Research. He received his undergraduate degree in biochemistry from the University of Wisconsin-Madison where he was a Hilldale Fellow working in the lab of Dr. Elizabeth Craig studying yeast molecular chaperones. He received his PhD from the University of Washington where he worked with Dr. David Baker to develop computational methods to design protein-protein interactions. These efforts yielded the first experimentally validated examples of computationally engineered highly selective protein complexes, designed protein interface hydrogen bonding networks and de novo designed protein complexes. He did his postdoctoral work at Stanford University with Dr. Judith Frydman, there he implemented computational and structural approaches to define architectures and mechanics of large and dynamic complexes. He identified an evolutionarily conserved topological arrangement for the hetero-oligomeric essential protein folding machine and explained how this macromolecular chaperone limits aggregation of many proteins including the amyloidogenic huntingtin and alpha-synuclein proteins. His work at Stanford was supported by a Ruth Kirschstein postdoctoral award. He joined the faculty at UT Southwestern in 2016 as an Effie Marie Cain Endowed Scholar in Medical Research. His lab develops computational and structural approaches to probe the conformations of proteins and complexes. His current interests are focused on understanding the evolutionary principles that modulate local protein conformations that mitigate protein aggregation. In particular, he is interested in incipient changes in the tau protein conformation that drive pathogenicity and how cellular factors including molecular chaperones or post-translational modifications mediate this process. In collaboration with Dr. Diamond at UT Southwestern he is using knowledge of tau conformations to design antibodies against pathogenic conformations of tau. Dr. Joachimiak has a secondary appointment in the Department of Biochemistry and is affiliated with the Molecular Biophysics Graduate Program at UT Southwestern.

Personal Story

I am honored to have been selected to receive a BrightFocus Alzheimer’s Disease Research grant, and I would like to personally thank all the BrightFocus donors for their support and generosity. This financial support enables my lab to carry out research that is too risky to be funded by conventional funding agencies and allows us to pursue cutting edge and novel research with the ultimate goal of identifying new treatments for Alzheimer’s Disease.

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