Structural Determinants of Tau Aggregation in Disease

Project Summary

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.